The molecular composition of the excitatory synapse is incompletely defined due to its dynamic nature across developmental stages and neuronal populations. To address this gap, we apply proteomic mass spectrometry to characterize the synapse in multiple biological models, including the fetal human brain and human induced pluripotent stem cell (hiPSC)-derived neurons. To prioritize the identified proteins, we develop an orthogonal multi-omic screen of genomic, transcriptomic, interactomic, and structural data. This data-driven framework identifies proteins with key molecular features intrinsic to the synapse, including characteristic patterns of biophysical interactions and cross-tissue expression. The multi-omic analysis captures synaptic proteins across developmental stages and experimental systems, including 493 synaptic candidates supported by proteomics. We further investigate three such proteins that are associated with neurodevelopmental disorders-Cullin 3 (CUL3), DEAD-box helicase 3 X-linked (DDX3X), and Y-box binding protein-1 (YBX1)-by mapping their networks of physically interacting synapse proteins or transcripts. Our study demonstrates the potential of an integrated multi-omic approach to more comprehensively resolve the synaptic architecture.

Optimisation of transcranial magnetic stimulation protocol parameters can potentially improve their efficacy through theoretical mathematical models. This study aims to develop an elaborate but still parsimonious quantitative model for understanding the dosage-dependency of Theta-Burst Stimulation (TBS).

We propose a calcium-dependent nonlinear model that uses Michaelis-Menten kinetics to represent competing molecular pathways in postsynaptic neurons during TBS intervention. The model integrates four subsystems: calcium dynamics, modulation substances, MEP learning, and metaplasticity, with a particular focus on the interaction between facilitatory and inhibitory signalling cascades.

Our model successfully reproduces experimental findings from various TBS protocols, including the reversal of after-effects observed in prolonged stimulation. The simulation results suggest that the competing molecular pathways with distinct calcium sensitivities and temporal dynamics determine the direction of after-effects.

This proposed model represents a substantial advancement in understanding TBS-induced neuromodulation by providing testable predictions for untested TBS protocols and offers complementary insights into the underlying neural mechanisms.

This model offers a basic framework for potentially incorporating complex, nonlinear relationships between TBS parameters and after-effects under various neurological and psychiatric conditions. It also provides a valuable tool for later protocol optimisation and guiding future experimental designs.

Early episodic memory impairment in Alzheimer's disease (AD) is linked to synaptic dysfunction from amyloid β-protein oligomers (oAβ), particularly affecting the dentate gyrus mossy fiber-CA3 pathway. The APPNL-G-F mouse model exhibits early deficits in mossy fiber long-term potentiation (mf-LTP).

We administered the β-adrenergic receptor agonist isoproterenol (ISO) in vivo and phosphodiesterase type 4 inhibitor GSK356278 in vitro to assess their impact on mf-LTP and contextual fear memory. Fluorescence lifetime imaging (FLIM)-Förster resonance energy transfer (FRET) microscopy was used to visualize impaired and rescued cyclic adenosine monophosphate (cAMP) signaling in dentate gyrus neurons.

ISO prevented mf-LTP impairment at 3-4 mo and improved memory by 7 mo. GSK356278 inhibited mf-LTP deficits in a dose-dependent manner. ISO also reduced hyperphosphorylation of synapsin I and microgliosis.

These findings suggest that β-AR activation and phosphodiesterase 4 (PDE4) inhibition mitigate oAβ-induced memory deficits, supporting enhanced cAMP signaling as a therapeutic target for early AD.

Early episodic memory deficits in AD linked to oAβ-induced synaptic dysfunction. Isoproterenol and GSK356278 improve mossy fiber-LTP and fear memory deficits. FLIM-FRET shows treatments restore cAMP signaling in dentate gyrus neurons. Isoproterenol reduces synapsin I hyperphosphorylation and microgliosis. Enhancing cAMP signaling may help mitigate early memory deficits in AD.

N-methyl-D-aspartate (NMDA)-induced spine shrinkage proceeds independently of ion flux and requires the initiation of de novo protein synthesis. Using subtype-selective pharmacological and genetic tools, we find that structural plasticity is dependent on ligand binding to GluN2B-containing NMDA receptors (NMDARs) and signaling via the GluN2B carboxy-terminal domain (CTD). Disruption of non-ionotropic signaling by replacing the GluN2B CTD with the GluN2A CTD leads to an increase in spine density, dysregulated basal protein synthesis, exaggerated long-term depression mediated by G-protein-coupled metabotropic glutamate receptors (mGluR-LTD), and epileptiform activity reminiscent of phenotypes observed in the Fmr1 knockout (KO) model of fragile X syndrome. By crossing the Fmr1 KO mice with animals in which the GluN2A CTD has been replaced with the GluN2B CTD, we observe a correction of these core fragile X phenotypes. These findings suggest that non-ionotropic NMDAR signaling through GluN2B may represent a novel therapeutic target for the treatment of fragile X and related causes of intellectual disability and autism.

A-kinase anchoring protein 79/150 (AKAP79/150) is a crucial scaffolding protein that positions various proteins at specific synaptic sites to modulate excitatory synaptic intensity. As our understanding of AKAP79/150's biology deepens, along with its significant role in the pathophysiology of various human disorders, there is growing evidence that reveals new opportunities for therapeutic interventions. In this review, we examine the fundamental structure and primary functions of AKAP79/150, emphasizing its pathophysiological mechanisms in different nervous system disorders, particularly inflammatory pain, epilepsy, depression, and Alzheimer's disease. We also discuss its potential therapeutic implications for patients suffering from these conditions.

Persistent and maladaptive drug-related memories represent a key component in drug addiction. Converging evidence from both preclinical and clinical studies has demonstrated the potential efficacy of the memory reconsolidation updating procedure (MRUP), a non-pharmacological strategy intertwining two distinct memory processes: reconsolidation and extinction-alternatively termed "the memory retrieval-extinction procedure". This procedure presents a promising approach to attenuate, if not erase, entrenched drug memories and prevent relapse. The present review delineates the applications, molecular underpinnings, and operational boundaries of MRUP in the context of various forms of substance dependence. Furthermore, we critically examine the methodological limitations of MRUP, postulating potential refinement to optimize its therapeutic efficacy. In addition, we also look at the potential integration of MRUP and neurostimulation treatments in the domain of substance addiction. Overall, existing studies underscore the significant potential of MRUP, suggesting that interventions predicated on it could herald a promising avenue to enhance clinical outcomes in substance addiction therapy.

Repeated administration of ketamine (KET) has been used to model schizophrenia-like symptomatology in rodents, but the psychotomimetic neurobiological and neuroanatomical underpinnings remain elusive. In parallel, the unmet need for a better treatment of schizophrenia requires the development of novel therapeutic strategies. Cannabidiol (CBD), a major non-addictive phytocannabinoid has been linked to antipsychotic effects with unclear mechanistic basis. Therefore, this study aims to clarify the neurobiological substrate of repeated KET administration model and to evaluate CBD's antipsychotic potential and neurobiological basis. CBD-treated male rats with and without prior repeated KET administration underwent behavioral analyses, followed by multilevel analysis of different brain areas including dopaminergic and glutamatergic activity, synaptic signaling, as well as electrophysiological recordings for the assessment of corticohippocampal and corticostriatal network activity. Repeated KET model is characterized by schizophrenia-like symptomatology and alterations in glutamatergic and dopaminergic activity mainly in the PFC and the dorsomedial striatum (DMS), through a bi-directional pattern. These observations are accompanied by glutamatergic/GABAergic deviations paralleled to impaired function of parvalbumin- and cholecystokinin-positive interneurons, indicative of excitation/inhibition (E/I) imbalance. Moreover, CBD counteracted the schizophrenia-like behavioral phenotype as well as reverted prefrontal abnormalities and ventral hippocampal E/I deficits, while partially modulated dorsostriatal dysregulations. This study adds novel insights to our understanding of the KET-induced schizophrenia-related brain pathology, as well as the CBD antipsychotic action through a region-specific set of modulations in the corticohippocampal and costicostrtiatal circuitry of KET-induced profile contributing to the development of novel therapeutic strategies focused on the ECS and E/I imbalance restoration.

Neurostimulation protocols are increasingly used as therapeutic interventions, including for brain injury. In addition to the direct activation of neurons, these stimulation protocols are also likely to have downstream effects on those neurons' synaptic outputs. It is well known that alterations in the strength of synaptic connections (long-term potentiation, LTP; long-term depression, LTD) are sensitive to the frequency of stimulation used for induction; however, little is known about the contribution of the temporal pattern of stimulation to the downstream synaptic plasticity that may be induced by neurostimulation in the injured brain. We explored interactions of the temporal pattern and frequency of neurostimulation in the normal cerebral cortex and after mild traumatic brain injury (mTBI), to inform therapies to strengthen or weaken neural circuits in injured brains, as well as to better understand the role of these factors in normal brain plasticity. Whole-cell (WC) patch-clamp recordings of evoked postsynaptic potentials in individual neurons, as well as field potential (FP) recordings, were made from layer 2/3 of visual cortex in response to stimulation of layer 4, in acute slices from control (naive), sham operated, and mTBI rats. We compared synaptic plasticity induced by different stimulation protocols, each consisting of a specific frequency (1 Hz, 10 Hz, or 100 Hz), continuity (continuous or discontinuous), and temporal pattern (perfectly regular, slightly irregular, or highly irregular). At the individual neuron level, dramatic differences in plasticity outcome occurred when the highly irregular stimulation protocol was used at 1 Hz or 10 Hz, producing an overall LTD in controls and shams, but a robust overall LTP after mTBI. Consistent with the individual neuron results, the plasticity outcomes for simultaneous FP recordings were similar, indicative of our results generalizing to a larger scale synaptic network than can be sampled by individual WC recordings alone. In addition to the differences in plasticity outcome between control (naive or sham) and injured brains, the dynamics of the changes in synaptic responses that developed during stimulation were predictive of the final plasticity outcome. Our results demonstrate that the temporal pattern of stimulation plays a role in the polarity and magnitude of synaptic plasticity induced in the cerebral cortex while highlighting differences between normal and injured brain responses. Moreover, these results may be useful for optimization of neurostimulation therapies to treat mTBI and other brain disorders, in addition to providing new insights into downstream plasticity signaling mechanisms in the normal brain.

Alzheimer disease (AD) is a prevalent neurodegenerative disorder that affects synapses and leads to progressive cognitive decline. The role of N-methyl-D-aspartic acid (NMDA) receptors in the pathogenesis of AD is well-established as they contribute to excitotoxicity and neurodegeneration in the pathological process of extrasynaptic glutamate concentration. However, the therapeutic potential of the NMDA receptor antagonist memantine in rescuing synaptic damage is limited. Research indicates that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors also play a significant role in AD. Abnormal transcription, expression, and localization of AMPA receptors lead to synaptic dysfunction and damage, contributing to early cognitive impairment in AD patients. Understanding the impact of AMPA receptors on AD pathogenesis and exploring the potential for the development of AMPA receptor-targeting drugs are crucial. This review aims to consolidate recent research findings on AMPA receptors in AD, elucidate the current state of AMPA receptor research and lay the foundation for future basic research and drug development.

The CC chemokine ligand 2 (CCL2, also known as MCP-1) and its cognate receptor CCR2 have well-characterized roles in chemotaxis. CCL2 has been previously shown to promote excitatory synaptic transmission and neuronal excitability. However, the detailed molecular mechanism underlying this process remains largely unclear. In cultured hippocampal neurons, CCL2 application rapidly upregulated surface expression of GluA1, in a CCR2-dependent manner, assayed using SEP-GluA1 live imaging, surface GluA1 antibody staining, and electrophysiology. Using pharmacology and reporter assays, we further showed that CCL2 upregulated surface GluA1 expression primarily via Gαq- and CaMKII-dependent signaling. Consistently, using i.p. injection of lipopolysaccharide to induce neuroinflammation, we found upregulated phosphorylation of S831 and S845 sites on AMPA receptor subunit GluA1 in the hippocampus, an effect blocked in Ccr2-/- mice. Together, these results provide a mechanism through which CCL2, and other secreted molecules that signal through G-protein coupled receptors, can directly regulate synaptic transmission.

Synaptic plasticity constitutes a fundamental process in the reorganization of neural networks that underlie memory, cognition, emotional responses, and behavioral planning. At the core of this phenomenon lie Hebbian mechanisms, wherein frequent synaptic stimulation induces long-term potentiation (LTP), while less activation leads to long-term depression (LTD). The synaptic reorganization of neuronal networks is regulated by serotonin (5-HT), a neuromodulator capable of modify synaptic plasticity to appropriately respond to mental and behavioral states, such as alertness, attention, concentration, motivation, and mood. Lately, understanding the serotonergic Neuromodulation of synaptic plasticity has become imperative for unraveling its impact on cognitive, emotional, and behavioral functions. Through a comparative analysis across three main forebrain structures-the hippocampus, amygdala, and prefrontal cortex, this review discusses the actions of 5-HT on synaptic plasticity, offering insights into its role as a neuromodulator involved in emotional and cognitive functions. By distinguishing between plastic and metaplastic effects, we provide a comprehensive overview about the mechanisms of 5-HT neuromodulation of synaptic plasticity and associated functions across different brain regions.

Neuronal excitatory synapses are primarily located on small dendritic protrusions called spines. During synaptic plasticity underlying learning and memory, Ca2+ influx through postsynaptic NMDA-type glutamate receptors (NMDARs) initiates signaling pathways that coordinate changes in dendritic spine structure and synaptic function. During long-term potentiation (LTP), high levels of NMDAR Ca2+ influx promote increases in both synaptic strength and dendritic spine size through activation of Ca2+-dependent protein kinases. In contrast, during long-term depression (LTD), low levels of NMDAR Ca2+ influx promote decreased synaptic strength and spine shrinkage and elimination through activation of the Ca2+-dependent protein phosphatase calcineurin (CaN), which is anchored at synapses via the scaffold protein A-kinase anchoring protein (AKAP)150. In Alzheimer's disease (AD), the pathological agent amyloid-β (Aβ) may impair learning and memory through biasing NMDAR Ca2+ signaling pathways toward LTD and spine elimination. By employing AKAP150 knock-in mice of both sexes with a mutation that disrupts CaN anchoring to AKAP150, we revealed that local, postsynaptic AKAP-CaN-LTD signaling was required for Aβ-mediated impairment of NMDAR synaptic Ca2+ influx, inhibition of LTP, and dendritic spine loss. Additionally, we found that Aβ acutely engages AKAP-CaN signaling through activation of G-protein-coupled metabotropic glutamate receptor 1 (mGluR1) leading to dephosphorylation of NMDAR GluN2B subunits, which decreases Ca2+ influx to favor LTD over LTP, and cofilin, which promotes F-actin severing to destabilize dendritic spines. These findings reveal a novel interplay between NMDAR and mGluR1 signaling that converges on AKAP-anchored CaN to coordinate dephosphorylation of postsynaptic substrates linked to multiple aspects of Aβ-mediated synaptic dysfunction.

Our group previously showed that genetic or pharmacological inhibition of the cystine/glutamate antiporter, system xc -, mitigates excitotoxicity after anoxia by increasing latency to anoxic depolarization, thus attenuating the ischaemic core. Hypoxia, however, which prevails in the ischaemic penumbra, is a condition where neurotransmission is altered, but excitotoxicity is not triggered. The present study employed mild hypoxia to further probe ischaemia-induced changes in neuronal responsiveness from wild-type and xCT KO (xCT-/-) mice. Synaptic transmission was monitored in hippocampal slices from both genotypes before, during and after a hypoxic episode. Although wild-type and xCT-/- slices showed equal suppression of synaptic transmission during hypoxia, mutant slices exhibited a persistent potentiation upon re-oxygenation, an effect we termed 'post-hypoxic long-term potentiation (LTP)'. Blocking synaptic suppression during hypoxia by antagonizing adenosine A1 receptors did not preclude post-hypoxic LTP. Further examination of the induction and expression mechanisms of this plasticity revealed that post-hypoxic LTP was driven by NMDA receptor activation, as well as increased calcium influx, with no change in paired-pulse facilitation. Hence, the observed phenomenon engaged similar mechanisms as classical LTP. This was a remarkable finding as theta-burst stimulation-induced LTP was equivalent between genotypes. Importantly, post-hypoxic LTP was generated in wild-type slices pretreated with system xc - inhibitor, S-4-carboxyphenylglycine, thereby confirming the antiporter's role in this phenomenon. Collectively, these data indicate that system xc - interference enables neuroplasticity in response to mild hypoxia, and, together with its regulation of cellular damage in the ischaemic core, suggest a role for the antiporter in post-ischaemic recovery of the penumbra.

Alteration of synaptic function in the dorsal horn (DH) has been implicated as a cellular substrate for the development of neuropathic pain, but certain details remain unclear. In particular, the lack of information on the types of synapses that undergo functional changes hinders the understanding of disease pathogenesis from a synaptic plasticity perspective. Here, we addressed this issue by using optogenetic and retrograde tracing ex vivo to selectively stimulate first-order nociceptors expressing Nav1.8 (NRsNav1.8) and record the responses of spinothalamic tract neurons in spinal lamina I (L1-STTNs). We found that spared nerve injury (SNI) increased excitatory postsynaptic currents (EPSCs) in L1-STTNs evoked by photostimulation of NRsNav1.8 (referred to as Nav1.8-STTN EPSCs). This effect was accompanied by a significant change in the failure rate and paired-pulse ratio of synaptic transmission from NRsNav1.8 to L1-STTN and in the frequency (not amplitude) of spontaneous EPSCs recorded in L1-STTNs. However, no change was observed in the ratio of AMPA to NMDA receptor-mediated components of Nav1.8-STTN EPSCs or in the amplitude of unitary EPSCs constituting Nav1.8-STTN EPSCs recorded with extracellular Ca2+ replaced by Sr2+ In addition, there was a small increase (approximately 10%) in the number of L1-STTNs showing immunoreactivity for phosphorylated extracellular signal-regulated kinases in mice after SNI compared with sham. Similarly, only a small percentage of L1-STTNs showed a lower action potential threshold after SNI. In conclusion, our results show that SNI induces presynaptic modulation at NRNav1.8 (consisting of both peptidergic and nonpeptidergic nociceptors) synapses on L1-STTNs forming the lateral spinothalamic tract.

Alzheimer's disease (AD) is a serious neurodegenerative disease and brings a serious burden to society and families. Due to lack of effective drugs for the treatment of AD, it's urgent to develop new and effective drug for the treatment of AD.

The study aimed to investigate the potential of Zexieyin formula (ZXYF), a Chinese medicine formula, for the treatment of AD and its potential mechanism of action.

We used chronic scopolamine (SCOP) induction mice model and APP/PS1 mice to reveal and confirm ZXYF for the treatment of AD with donepezil (DON) as a positive reference. The learning and memory function were detected by morris water maze test (MWM) and y-maze test. Moreover, western blot and immunofluorescence were used to detect the molecular mechanism of ZXYF for the alleviation of AD in hippocampus. Lastly, pharmacological technology was applied to evaluate AMPA receptor involved in the role of ZXYF in the treatment of AD.

The results showed that ZXYF could improve memory and learning deficits both in two AD models including scopolamine (SCOP)-induced mice model and APP/PS1mice. Moreover, ZXYF or not DON increased expressions of BrdU/DCX and Ki67 positive cells in dentate gyrus (DG), up-regulated the levels of AMPA subunit type (GluA1) and PKA in hippocampus in SCOP-induced mice model, although ZXYF and DON activated CaMKII, CaMKII-phosphorylation, CREB, CREB-phosphorylation and PSD95 in hippocampus in SCOP-induced mice model. ZXYF also activated CaMKII, CaMKII-phosphorylation and GluA1 in HT22 cells. Furthermore, transient inhibiting AMPA receptor was capable of blocking the effects of ZXYF to treat AD in MWM and suppressing the number of BrdU/DCX positive cells increased by ZXYF in DG in SCOP-induced mice model, but had no effect on the alteration of Ki67 positive cells.

ZXYF had the therapeutic effects on AD-treatment, which activated CaMKII to promote AMPA receptor (GluA1) and subsequently up-regulated PKA/CREB signaling to facilitate neurogenesis to achieve enhanced postsynaptic protein.

Trisomy of human chromosome 21 (Hsa21) results in a constellation of features known as Down syndrome (DS), the most common genetic form of intellectual disability. Hsa21 is orthologous to three regions in the mouse genome on mouse chromosome 16 (Mmu16), Mmu17 and Mmu10. We investigated genotype-phenotype relationships by assessing the contribution of these three regions to memory function and age-dependent cognitive decline, using three mouse models of DS, Dp1Tyb, Dp(17)3Yey, Dp(10)2Yey, that carry an extra copy of the Hsa21-orthologues on Mmu16, Mmu17 and Mmu10, respectively.

Prior research on cognitive function in DS mouse models has largely focused on models with an extra copy of the Mmu16 region and relatively little is known about the effects of increased copy number on Mmu17 and Mmu10 on cognition and how this interacts with the effects of aging. As aging is is a critical contributor to cognitive and psychiatric changes in DS, we hypothesised that ageing would differentially impact memory function in Dp1Tyb, Dp(17)3Yey, and Dp(10)2Yey, models of DS.

Young (12-13 months and old (18-20 months mice Dp1Tyb, Dp(17)3Yey and Dp(10)2Yey mice were tested on a battery of object recognition memory test that assessed object novelty detection, novel location detection and associative object-in place memory. Following behavioral testing, hippocampal and frontal cortical tissue was analysed for expression of glutamatergic receptor proteins using standard immunoblot techniques.

Young (12-13 months and old (18-20 months mice Dp1Tyb, Dp(17)3Yey and Dp(10)2Yey mice were tested on a battery of object recognition memory test that assessed object novelty detection, novel location detection and associative object-in place memory. Following behavioral testing, hippocampal and frontal cortical tissue was analysed for expression of glutamatergic receptor proteins using standard immunoblot techniques.

Our results show that distinct Hsa21-orthologous regions contribute differentially to cognitive dysfunction in DS mouse models and that aging interacts with triplication of Hsa21-orthologous genes on Mmu10.

In 1973, two papers from Bliss and Lømo and from Bliss and Gardner-Medwin reported that high-frequency synaptic stimulation in the dentate gyrus of rabbits resulted in a long-lasting increase in synaptic strength. This form of synaptic plasticity, commonly referred to as long-term potentiation (LTP), was immediately considered as an attractive mechanism accounting for the ability of the brain to store information. In this historical piece looking back over the past 50 years, we discuss how these two landmark contributions directly motivated a colossal research effort and detail some of the resulting milestones that have shaped our evolving understanding of the molecular and cellular underpinnings of LTP. We highlight the main features of LTP, cover key experiments that defined its induction and expression mechanisms, and outline the evidence supporting a potential role of LTP in learning and memory. We also briefly explore some ramifications of LTP on network stability, consider current limitations of LTP as a model of associative memory, and entertain future research orientations.

Protein phosphatase 1 (PP1) regulates synaptic plasticity and has been described as a molecular constraint on learning and memory. There are three neuronal isoforms, PP1α, PP1β, and PP1γ, but little is known about their individual functions. PP1α and PP1γ are assumed to mediate the effects of PP1 on learning and memory based on their enrichment at dendritic spines and their preferential binding to neurabin and spinophilin, major PP1 synaptic scaffolding proteins. However, it was recently discovered that human de novo PP1β mutations cause intellectual disability, suggesting an important but ill-defined role for PP1β. In this study, we investigated the functions of each PP1 isoform in hippocampal synaptic physiology using conditional CA1-specific knockout mice. In stark contrast to classic PP1 function, we found that PP1β promotes synaptic plasticity as well as spatial memory. These changes in synaptic plasticity and memory are accompanied by changes in GluA1 phosphorylation, GluN2A levels, and dendritic spine density and morphology, including silent synapse number. These functions of PP1β reveal a previously unidentified signaling pathway regulating spine maturation and plasticity, broadening our understanding of the complex role of PP1 in synaptic physiology.

The relative amount of AMPA receptors expressed at the surface of neurons can be measured using superecliptic pHluorin (SEP) labeling at their N-terminus. However, the high signal variability resulting from protein overexpression in neurons and the low signal observed in intracellular vesicles make quantitative characterization of receptor trafficking difficult. Here, we establish a real-time live-cell assay of AMPAR trafficking based on fluorescence lifetime imaging (FLIM), which allows for simultaneous visualization of both surface and intracellular receptors. Using this assay, we found that elevating amyloid-beta (Aβ) levels leads to a strong increase in intracellular GluA1 and GluA2-containing receptors, indicating that Aβ triggers the endocytosis of these AMPARs. In APP/PS1 Alzheimer's disease model mouse neurons, FLIM revealed strikingly different AMPAR trafficking properties for GluA1- and GluA3-containing receptors, suggesting that chronic Aβ exposure triggered the loss of both surface and intracellular GluA3-containing receptors. Interestingly, overexpression of protein phosphatase 1 (PP1) also resulted in GluA1 endocytosis as well as depressed synaptic transmission, confirming the important role of phosphorylation in regulating AMPAR trafficking. This new approach allows for the quantitative measurement of extracellular pH, small changes in receptor trafficking, as well as simultaneous measurement of surface and internalized AMPARs in living neurons, and could therefore be applied to several different studies in the future.

The brain responds to experience through modulation of synaptic transmission, that is synaptic plasticity. An increase in the strength of synaptic transmission is manifested as long-term potentiation (LTP), while a decrease in the strength of synaptic transmission is expressed as long-term depression (LTD). Most of the studies of synaptic plasticity have been carried out by induction via electrophysiological stimulation. It is largely unknown in which behavioural tasks such synaptic plasticity occurs. Moreover, some stimuli can induce both LTP and LTD, thus making it difficult to separately study the different forms of synaptic plasticity. Two studies have shown that an aversive memory task - inhibitory avoidance learning and contextual fear conditioning - physiologically and selectively induce LTP and an LTP-like molecular change, respectively, in the hippocampus in vivo. Here, we show that a non-aversive behavioural task - exploration of new space - physiologically and selectively elicits a biochemical change in the hippocampus that is a hallmark of LTP. Specifically, we found that exploration of new space induces an increase in the phosphorylation of GluA1(Ser831), without affecting the phosphorylation of GluA1(Ser845), which are biomarkers of early-LTP and not NMDAR-mediated LTD. We also show that exploration of new space engenders the phosphorylation of the translational regulator S6K and the expression of Arc, which are features of electrophysiologically-induced late-LTP in the hippocampus. Therefore, our results show that exploration of new space is a novel non-aversive behavioural paradigm that elicits molecular changes in vivo that are analogous to those occurring during early- and late-LTP, but not during NMDAR-mediated LTD.

Ischemic strokes originate whenever the circulation to the brain is interrupted, either temporarily or permanently, resulting in a lack of oxygen and other nutrients. This deprivation primarily impacts the cerebral cortex and striatum, resulting in neurodegeneration. Several experimental stroke models have demonstrated that the potent antioxidant quercetin offers protection against stroke-related damage. Multiple pathways have been associated with quercetin's ability to safeguard the brain from ischemic injury. This study examines whether the administration of quercetin alters glutamate NMDA and GluR1 receptor signaling in the cortex and striatum 72 h after transient middle cerebral artery occlusion. The administration of 10 mg/kg of quercetin shielded cortical and striatal neurons from cell death induced by ischemia in adult SD rats. Quercetin reversed the ischemia-induced reduction of NR2a/PSD95, consequently promoting the pro-survival AKT pathway and reducing CRMP2 phosphorylation. Additionally, quercetin decreased the levels of reactive oxygen species and inflammatory pathways while increasing the expression of the postsynaptic protein PSD95. Our results suggest that quercetin may be a promising neuroprotective drug for ischemic stroke therapy as it recovers neuronal damage via multiple pathways.

Alzheimer's Disease (AD) is associated with brain accumulation of synaptotoxic amyloid-β (Aβ) peptides produced by the proteolytic processing of amyloid precursor protein (APP). Cognitive impairments associated with AD correlate with dendritic spine and excitatory synapse loss, particularly within the hippocampus. In rodents, soluble Aβ oligomers impair hippocampus-dependent learning and memory, promote dendritic spine loss, inhibit NMDA-type glutamate receptor (NMDAR)-dependent long-term potentiation (LTP), and promote synaptic depression (LTD), at least in part through activation of the Ca2+-CaM-dependent phosphatase calcineurin (CaN). Yet, questions remain regarding Aβ-dependent postsynaptic CaN signaling specifically at the synapse to mediate its synaptotoxicity. Here, we use pharmacologic and genetic approaches to demonstrate a role for postsynaptic signaling via A kinase-anchoring protein 150 (AKAP150)-scaffolded CaN in mediating Aβ-induced dendritic spine loss in hippocampal neurons from rats and mice of both sexes. In particular, we found that Ca2+-permeable AMPA-type glutamate receptors (CP-AMPARs), which were previously shown to signal through AKAP-anchored CaN to promote both LTD and Aβ-dependent inhibition of LTP, are also required upstream of AKAP-CaN signaling to mediate spine loss via overexpression of APP containing multiple mutations linked to familial, early-onset AD and increased Aβ production. In addition, we found that the CaN-dependent nuclear factor of activated T-cells (NFAT) transcription factors are required downstream to promote Aβ-mediated dendritic spine loss. Finally, we identified the E3-ubiquitin ligase Mdm2, which was previously linked to LTD and developmental synapse elimination, as a downstream NFAT target gene upregulated by Aβ whose enzymatic activity is required for Aβ-mediated spine loss.Significance Statement Impaired hippocampal function and synapse loss are hallmarks of AD linked to Aβ oligomers. Aβ exposure acutely blocks hippocampal LTP and enhances LTD and chronically leads to dendritic spine synapse loss. In particular, Aβ hijacks normal plasticity mechanisms, biasing them toward synapse weakening/elimination, with previous studies broadly linking CaN phosphatase signaling to this synaptic dysfunction. However, we do not understand how Aβ engages signaling specifically at synapses. Here we elucidate a synapse-to-nucleus signaling pathway coordinated by the postsynaptic scaffold protein AKAP150 that is activated by Ca2+ influx through CP-AMPARs and transduced to nucleus by CaN-NFAT signaling to transcriptionally upregulate the E3-ubiquitin ligase Mdm2 that is required for Aβ-mediated spine loss. These findings identify Mdm2 as potential therapeutic target for AD.

Alzheimer's disease (AD) is a leading cause of dementia in the elderly. Mitogen-activated protein kinase phosphatase 1 (MKP-1) plays a neuroprotective role in AD. However, the molecular mechanisms underlying the effects of MKP-1 on AD have not been extensively studied. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level, thereby repressing mRNA translation. Here, we reported that the microRNA-429-3p (miR-429-3p) was significantly increased in the brain of APP23/PS45 AD model mice and N2AAPP AD model cells. We further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 3'-untranslated region (3' UTR). Inhibition of miR-429-3p by its antagomir (A-miR-429) restored the expression of MKP-1 to a control level and consequently reduced the amyloidogenic processing of APP and Aβ accumulation. More importantly, intranasal administration of A-miR-429 successfully ameliorated the deficits of hippocampal CA1 long-term potentiation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated kinase (ERK1/2)-mediated GluA1 hyperphosphorylation at Ser831 site, thereby increasing the surface expression of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Together, these results demonstrate that inhibiting miR-429-3p to upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice, suggesting that miR-429/MKP-1 pathway may be a novel therapeutic target for AD treatment.

The rostromedial tegmental nucleus (RMTg) plays a crucial role in regulating reward-related behavior by exerting inhibitory control over the ventral tegmental area (VTA). This modulation of dopamine neuron activity within the VTA is essential for maintaining homeostasis in the reward system. Recently we have shown that activation of RMTg projections to the VTA during the acquisition of cocaine-conditioned place preference (CPP) reduces the rewarding properties of cocaine and decreases VTA dopamine neuron activity. By inhibiting dopamine neurons in the VTA, we hypothesized that RMTg projections hold the potential to restore reward system homeostasis disrupted by repeated cocaine use, and attenuate molecular adaptations in the reward system, including alterations in signaling pathways. Our study demonstrates that enhancing the GABAergic inputs from the RMTg to the VTA can mitigate cocaine-induced molecular changes in key regions, namely the VTA, nucleus accumbens (NAc), and prefrontal cortex (PFC). Specifically, we found that cocaine-induced alteration in the phosphorylation state of ERK (pERK) and GluA1 on serine 845 (S845) and serine 831 (S831), that play a major role in plasticity by controlling the activity and trafficking of AMPA receptors, were significantly reversed following optic stimulation of RMTg afferents to the VTA. These findings highlight the therapeutic potential of targeting the RMTg-VTA circuitry for mitigating cocaine reward. Ultimately, this research may pave the way for novel therapeutic interventions that restore balance in the reward system and alleviate the detrimental effects of cocaine.

Traumatic brain injury (TBI), Alzheimer's disease (AD), and epilepsy share proposed mechanisms of injury, including neuronal excitotoxicity, cascade signaling, and activation of protein biomarkers such as tau. Although tau is typically present intracellularly, in tauopathies, phosphorylated (p-) and hyper-phosphorylated (hp-) tau are released extracellularly, the latter leading to decreased neuronal stability and neurofibrillary tangles (NFTs). Tau cleavage at particular sites increases susceptibility to hyper-phosphorylation, NFT formation, and eventual cell death. The relationship between tau and inflammation, however, is unknown. In this review, we present evidence for an imbalanced endoplasmic reticulum (ER) stress response and inflammatory signaling pathways resulting in atypical p-tau, hp-tau and NFT formation. Further, we propose tau as a biomarker for neuronal injury severity in TBI, AD, and epilepsy. We present a hypothesis of tau phosphorylation as an initial acute neuroprotective response to seizures/TBI. However, if the underlying seizure pathology or TBI recurrence is not effectively treated, and the pathway becomes chronically activated, we propose a "tipping point" hypothesis that identifies a transition of tau phosphorylation from neuroprotective to injurious. We outline the role of amyloid beta (Aβ) as a "last ditch effort" to revert the cell to programmed death signaling, that, when fails, transitions the mechanism from injurious to neurodegenerative. Lastly, we discuss targets along these pathways for therapeutic intervention in AD, TBI, and epilepsy.

Following a spinal cord injury (SCI), secondary damage mechanisms are triggered that cause inflammation and cell death. A key component of this secondary damage is a reduction in local blood flow that initiates a well-characterised ischemic cascade. Downstream hypoxia and acidosis activate acid sensing ion channel 1a (ASIC1a) to trigger cell death. We recently showed that administration of a potent venom-derived inhibitor of ASIC1a, Hi1a, leads to tissue sparing and improved functional recovery when delivered up to 8 h after ischemic stroke. Here, we use whole-cell patch-clamp electrophysiology in a spinal cord slice preparation to assess the effect of acute ASIC1a inhibition, via a single dose of Hi1a, on intrinsic membrane properties and excitatory synaptic transmission long-term after a spinal cord hemisection injury. We focus on a population of interneurons (INs) in the deep dorsal horn (DDH) that play a key role in relaying sensory information to downstream motoneurons. DDH INs in mice treated with Hi1a 1 h after a spinal cord hemisection showed no change in active or passive intrinsic membrane properties measured 4 weeks after SCI. DDH INs, however, exhibit significant changes in the kinetics of spontaneous excitatory postsynaptic currents after a single dose of Hi1a, when compared to naive animals (unlike SCI mice). Our data suggest that acute ASIC1a inhibition exerts selective effects on excitatory synaptic transmission in DDH INs after SCI via specific ligand-gated receptor channels, and has no effect on other voltage-activated channels long-term after SCI.

The postsynaptic density (PSD) of excitatory synapses contains a highly organized protein network with thousands of proteins and is a key node in the regulation of synaptic plasticity. To gain new mechanistic insight into experience-induced changes in the PSD, we examined the global dynamics of the hippocampal PSD proteome and phosphoproteome in mice following four different types of experience. Mice were trained using an inhibitory avoidance (IA) task and hippocampal PSD fractions were isolated from individual mice to investigate molecular mechanisms underlying experience-dependent remodeling of synapses. We developed a new strategy to identify and quantify the relatively low level of site-specific phosphorylation of PSD proteome from the hippocampus, by using a modified iTRAQ-based TiSH protocol. In the PSD, we identified 3938 proteins and 2761 phosphoproteins in the sequential strategy covering a total of 4968 unique protein groups (at least two peptides including a unique peptide). On the phosphoproteins, we identified a total of 6188 unambiguous phosphosites (75% Collapse

The transient receptor potential cation channel, subfamily C, member 6 (TRPC6), has been believed to adjust the formation of an excitatory synapse. The positive regulation of TRPC6 engenders synapse enlargement and improved learning and memory in animal models. TRPC6 is involved in different synaptoprotective signaling pathways, including antagonism of N-methyl-D-aspartate receptor (NMDAR), activation of brain-derived neurotrophic factor (BDNF) and postsynaptic store-operated calcium entry. Positive regulation of TRPC6 channels has been repeatedly shown to be good for memory formation and storage. TRPC6 is mainly expressed in the hippocampus, particularly in the dentate granule cells, cornu Ammonis 3 (CA3) pyramidal cells and gamma-aminobutyric acid (GABA)ergic interneurons. It has been observed that TRPC6 agonists have a great influence on animal behavior including memory formation and storage The purpose of this review is to collect the available information on the role of TRPC6 in memory formation in various parts of the brain to understand how TRPC6-specific pharmaceutical agents will affect memory in distinct parts of the central nervous system (CNS).

Parkinson's disease (PD) is a common neurodegenerative disorder of middle-aged and elderly people, clinically characterized by resting tremor, myotonia, reduced movement, and impaired postural balance. Clinically, patients with PD are often administered levodopa (L-DOPA) to improve their symptoms. However, after years of L-DOPA treatment, most patients experience complications of varying severity, including the "on-off phenomenon", decreased efficacy, and levodopa-induced dyskinesia (LID). The development of LID can seriously affect the quality of life of patients, but its pathogenesis is unclear and effective treatments are lacking. Glutamic acid (Glu)-mediated changes in synaptic plasticity play a major role in LID. The N-methyl-D-aspartic acid receptor (NMDAR), an ionotropic glutamate receptor, is closely associated with synaptic plasticity, and neuroinflammation can modulate NMDAR activation or expression; in addition, neuroinflammation may be involved in the development of LID. However, it is not clear whether NMDA receptors are co-regulated with neuroinflammation during LID formation. Here we review how neuroinflammation mediates the development of LID through the regulation of NMDA receptors, and assess whether common anti-inflammatory drugs and NMDA receptor antagonists may be able to mitigate the development of LID through the regulation of central neuroinflammation, thereby providing a new theoretical basis for finding new therapeutic targets for LID.

Ninjinyoeito (NYT), a traditional Japanese medicine, is effective for improving physical strength and treating fatigue and anorexia. Recently, a clinical report revealed that NYT ameliorates cognitive dysfunction in Alzheimer's disease (AD) patients, although the mechanisms remain unclear. AD is a neurodegenerative disorder accompanied by a progressive deficit in memory. Current therapeutic agents are largely ineffective in treating cognitive dysfunction in AD patients. In this study, we investigated the effects of NYT on spatial memory impairment in a rat model of dementia. Rats were prepared with transient cerebral ischemia and intraventricular injection of β-amyloid1-42 for 7 days (CI + Aβ). NYT was orally administered for 7 days after cerebral ischemia. We evaluated spatial memory using the Morris water maze and investigated the expression of α-amino-3-hydroxy-5-4-isoxazole propionic acid receptor subunits, the phosphorylation level of glutamate receptor A (GluA)1 at serine sites S831 and S845, and the Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the hippocampus and prefrontal cortex of CI + Aβ rats. In the CI + Aβ rats, NYT treatment shortened the extended time to reach the platform. However, NYT did not restore the decrease in the hippocampal GluA1, GluA2, or CaMKII expression but increased prefrontal cortical phosphorylation levels of S845-GluA1 and CaMKII. Therefore, NYT may alleviate spatial memory impairment by promoting glutamatergic transmission involved in the phosphorylation of S845-GluA1 and CaMKII in the prefrontal cortex of CI + Aβ rats. Our results suggest that NYT is a valuable treatment for AD patients.

Palmitoyl acyltransferases (PATs) have been suggested to be involved in learning and memory. However, the underlying mechanisms have not yet been fully elucidated. Here, we found that the activity of DHHC2 was upregulated in the hippocampus after fear conditioning, and DHHC2 knockdown impaired fear induced memory and long-term potentiation (LTP). Additionally, the activity of DHHC2 and its synaptic expression were increased after high frequency stimulation (HFS) or glycine treatment. Importantly, fear learning selectively augmented the palmitoylation level of AKAP150, not PSD-95, and this effect was abolished by DHHC2 knockdown. Furthermore, 2-bromopalmitic acid (2-BP), a palmitoylation inhibitor, attenuated the increased palmitoylation level of AKAP150 and the interaction between AKAP150 and PSD-95 induced by HFS. Lastly, DHHC2 knockdown reduced the phosphorylation level of GluA1 at Ser845, and also induced an impairment of LTP in the hippocampus. Our results suggest that DHHC2 plays a critical role in regulating fear memory via AKAP150 signaling.

The formation of customized neural networks as the basis of brain functions such as receptive field selectivity, learning or memory depends heavily on the long-term plasticity of synaptic connections. However, the current mean-field population models commonly used to simulate large-scale neural network dynamics lack explicit links to the underlying cellular mechanisms of long-term plasticity. In this study, we developed a new mean-field population model, the plastic density-based neural mass model (pdNMM), by incorporating a newly developed rate-based plasticity model based on the calcium control hypothesis into an existing density-based neural mass model. Derivation of the plasticity model was carried out using population density methods. Our results showed that the synaptic plasticity represented by the resulting rate-based plasticity model exhibited Bienenstock-Cooper-Munro-like learning rules. Furthermore, we demonstrated that the pdNMM accurately reproduced previous experimental observations of long-term plasticity, including characteristics of Hebbian plasticity such as longevity, associativity and input specificity, on hippocampal slices, and the formation of receptive field selectivity in the visual cortex. In conclusion, the pdNMM is a novel approach that can confer long-term plasticity to conventional mean-field neuronal population models.

A multifactorial syndrome, Alzheimer's disease is the main cause of dementia, but there is no existing therapy to prevent it or stop its progression. One of the earliest events of Alzheimer's disease is the disruption of calcium homeostasis but that is just a prelude to the disease's devastating impact. Calcium does not work alone but must interact with downstream cellular components of which the small regulatory protein calmodulin is central, if not primary. This review supports the idea that, due to calcium dyshomeostasis, calmodulin is a dominant regulatory protein that functions in all stages of Alzheimer's disease, and these regulatory events are impacted by amyloid beta. Amyloid beta not only binds to and regulates calmodulin but also multiple calmodulin-binding proteins involved in Alzheimer's. Together, they act on the regulation of calcium dyshomeostasis, neuroinflammation, amyloidogenesis, memory formation, neuronal plasticity and more. The complex interactions between calmodulin, its binding proteins and amyloid beta may explain why many therapies have failed or are doomed to failure unless they are considered.

Activity-dependent changes in the number of AMPA-type glutamate receptors (AMPARs) at the synapse underpin the expression of LTP and LTD, cellular correlates of learning and memory. Post-translational ubiquitination has emerged as a key regulator of the trafficking and surface expression of AMPARs, with ubiquitination of the GluA1 subunit at Lys-868 controlling the post-endocytic sorting of the receptors into the late endosome for degradation, thereby regulating their stability at synapses. However, the physiological significance of GluA1 ubiquitination remains unknown. In this study, we generated mice with a knock-in mutation in the major GluA1 ubiquitination site (K868R) to investigate the role of GluA1 ubiquitination in synaptic plasticity, learning, and memory. Our results reveal that these male mice have normal basal synaptic transmission but exhibit enhanced LTP and deficits in LTD. They also display deficits in short-term spatial memory and cognitive flexibility. These findings underscore the critical roles of GluA1 ubiquitination in bidirectional synaptic plasticity and cognition in male mice.SIGNIFICANCE STATEMENT Subcellular targeting and membrane trafficking determine the precise number of AMPA-type glutamate receptors at synapses, processes that are essential for synaptic plasticity, learning, and memory. Post-translational ubiquitination of the GluA1 subunit marks AMPARs for degradation, but its functional role in vivo remains unknown. Here we demonstrate that the GluA1 ubiquitin-deficient mice exhibit an altered threshold for synaptic plasticity accompanied by deficits in short-term memory and cognitive flexibility. Our findings suggest that activity-dependent ubiquitination of GluA1 fine-tunes the optimal number of synaptic AMPARs required for bidirectional synaptic plasticity and cognition in male mice. Given that increases in amyloid-β cause excessive ubiquitination of GluA1, inhibiting that GluA1 ubiquitination may have the potential to ameliorate amyloid-β-induced synaptic depression in Alzheimer's disease.

Ketamine is shown to enhance excitatory synaptic drive in multiple brain areas, which is presumed to underlie its rapid antidepressant effects. Moreover, ketamine's therapeutic actions are likely mediated by enhancing neuronal Ca2+ signaling. However, ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist that reduces excitatory synaptic transmission and postsynaptic Ca2+ signaling. Thus, it is a puzzling question how ketamine enhances glutamatergic and Ca2+ activity in neurons to induce rapid antidepressant effects while blocking NMDARs in the hippocampus. Here, we find that ketamine treatment in cultured mouse hippocampal neurons significantly reduces Ca2+ and calcineurin activity to elevate AMPA receptor (AMPAR) subunit GluA1 phosphorylation. This phosphorylation ultimately leads to the expression of Ca2+-Permeable, GluA2-lacking, and GluA1-containing AMPARs (CP-AMPARs). The ketamine-induced expression of CP-AMPARs enhances glutamatergic activity and glutamate receptor plasticity in cultured hippocampal neurons. Moreover, when a sub-anesthetic dose of ketamine is given to mice, it increases synaptic GluA1 levels, but not GluA2, and GluA1 phosphorylation in the hippocampus within 1 hr after treatment. These changes are likely mediated by ketamine-induced reduction of calcineurin activity in the hippocampus. Using the open field and tail suspension tests, we demonstrate that a low dose of ketamine rapidly reduces anxiety-like and depression-like behaviors in both male and female mice. However, when in vivo treatment of a CP-AMPAR antagonist abolishes the ketamine's effects on animals' behaviors. We thus discover that ketamine at the low dose promotes the expression of CP-AMPARs via reduction of calcineurin activity, which in turn enhances synaptic strength to induce rapid antidepressant actions.

We propose and present converging evidence for the Cytoelectric Coupling Hypothesis: Electric fields generated by neurons are causal down to the level of the cytoskeleton. This could be achieved via electrodiffusion and mechanotransduction and exchanges between electrical, potential and chemical energy. Ephaptic coupling organizes neural activity, forming neural ensembles at the macroscale level. This information propagates to the neuron level, affecting spiking, and down to molecular level to stabilize the cytoskeleton, "tuning" it to process information more efficiently.

Transcription factors have a pivotal role in synaptic plasticity and the associated modification of neuronal networks required for memory formation and consolidation. The nuclear receptors subfamily 4 group A (Nr4a) have emerged as possible modulators of hippocampal synaptic plasticity and cognitive functions. However, the molecular and cellular mechanisms underlying Nr4a2-mediated hippocampal synaptic plasticity are not completely known. Here, we report that neuronal activity enhances Nr4a2 expression and function in cultured mouse hippocampal neurons (both sexes) by an ionotropic glutamate receptor/Ca2+/cAMP response element-binding protein/CREB-regulated transcription factor 1 (iGluR/Ca2+/CREB/CRTC1) pathway. Nr4a2 activation mediates BDNF production and increases expression of iGluRs, thereby affecting LTD at CA3-CA1 synapses in acute mouse hippocampal slices (both sexes). Together, our results indicate that the iGluR/Ca2+/CREB/CRTC1 pathway mediates activity-dependent expression of Nr4a2, which is involved in glutamatergic synaptic plasticity by increasing BDNF and synaptic GluA1-AMPARs. Therefore, Nr4a2 activation could be a therapeutic approach for brain disorders associated with dysregulated synaptic plasticity.SIGNIFICANCE STATEMENT A major factor that regulates fast excitatory synaptic transmission and plasticity is the modulation of synaptic AMPARs. However, despite decades of research, the underlying mechanisms of this modulation remain poorly understood. Our study identified a molecular pathway that links neuronal activity with AMPAR modulation and hippocampal synaptic plasticity through the activation of Nr4a2, a member of the nuclear receptor subfamily 4. Since several compounds have been described to activate Nr4a2, our study not only provides mechanistic insights into the molecular pathways related to hippocampal synaptic plasticity and learning, but also identifies Nr4a2 as a potential therapeutic target for pathologic conditions associated with dysregulation of glutamatergic synaptic function.

The regulation of neurons by circadian clock genes is thought to contribute to the maintenance of neuronal functions that ultimately underlie animal behavior. However, the impact of specific circadian genes on cellular and molecular mechanisms controlling synaptic plasticity and cognitive function remains elusive. Here, we show that the expression of the circadian protein TIMELESS displays circadian rhythmicity in the mammalian hippocampus. We identify TIMELESS as a chromatin-bound protein that targets synaptic-plasticity-related genes such as phosphodiesterase 4B (Pde4b). By promoting Pde4b transcription, TIMELESS negatively regulates cAMP signaling to modulate AMPA receptor GluA1 function and influence synaptic plasticity. Conditional deletion of Timeless in the adult forebrain impairs working and contextual fear memory in mice. These cognitive phenotypes were accompanied by attenuation of hippocampal Schaffer-collateral synapse long-term potentiation. Together, these data establish a neuron-specific function of mammalian TIMELESS by defining a mechanism that regulates synaptic plasticity and cognitive function.