Adult neural stem cells and schizophrenia

Table 1 Studies of schizophrenia risk genes and related signaling pathways in adult neurogenesis

Genes or signaling pathways	Effects on adult neurogenesis	Behavior deviations	Ref.	Post-mortem or genetic studies
DISC1	Suppression of Disc1 expression results in accelerated neuronal integration, mispositioning of new DG granule cells, accelerated dendritic development, premature cell cycle exit and differentiation	Hyper-locomotion, depressive-like behavior, cognitive deficits (object place recognition test, Morris water maze test)	[16,18,20,23]	[130-132]
NRG1	NRG1 treatment induces increased ventral DG cell proliferation and neurogenesis.NRG1 regulates both excitatory and inhibitory synaptic transmission in the adult brain and abnormal neurotransmission and/or synaptic plasticity have been observed in the schizophrenic brain	Nrg1 hypomorphs showed hyperactivity in a number of tests, including the novel open-field test and the alternating-Y maze, impaired social behavior and increased aggression	[36,37,133]	[30-32]
SNAP-25	Snap-25 mutant mice display histologically and electrophysiologically immature DG neurons. Inactivation of Snap-25 in adult neural stem cells results in enhancement of proximal dendritic branching of new-born neurons in the DG and robust efferent mossy fiber output to the CA3 region	Working memory deficits, impaired contextual fear-discrimination learning	[47,48]	[43,44]
CACNA1C	Cacna1c deletion results in decreased progenitor proliferation and reduced survival of new-born neurons	Cacna1c heterozygous mice display reduced locomotion, fear learning, and impaired spatial memory	[57-61]	[53-56]
Reelin	Adult Reeler mutants show decreased proliferation, aberrant migration and dendritic development of new-born neurons	Heterozygous Reeler mice show a significant reduction in contextual fear conditioned learning and an age-dependent decrease in prepulse inhibition of startle	[82-84,86]	[69-71,74-77]
Wnt signaling	Overexpression of stabilized β-catenin leads to enlarged brain and expanded neural precursor population. Wnt7a knockout mice show fewer neural stem cells. Wnt5a knockdown decreases the number of immature neurons. Tcf4 heterozygotes show reduced size of neural stem cell pool and impaired maturation and survival of adult-born neurons	Dvl knockout mice display reduced social interaction and deficits in prepulse inhibition of acoustic and tactile startle. Forebrain-specific β-catenin knockout mice show a depression-like phenotype. Apc heterozygote shows hypoactivity and a severe performance deficit in working memory	[90,96,106,107,134,135]	[98-100,112]
Notch signaling	Inactivation of Notch1 blocks self-renewal of neural stem cells, reduces mitotic progenitors and neurogenesis. Adult deletion of RBPj leads to depletion and exhaustion of neural stem cells	Notch1 heterozygote displays deficits in spatial learning and memory	[100,121,122,128,129]	[116-118]

APC: Adenomatous polyposis coli; CA3: Cornu ammonis 3; CACNA1C: Calcium voltage-gated channel subunit alpha1 c; DG: Dentate gyrus; DISC1: Disrupted in schizophrenia 1; Dvl: Dishevelled; NRG1: Neuregulin-1; SNAP-25: Synaptosomal-associated protein, 25kDa; Tcf4: T-cell factor 4.