Neuroplasticity signaling pathways linked to the pathophysiology of schizophrenia

Abstract

Schizophrenia is a severe mental illness that afflicts nearly 1% of the world's population. One of the cardinal pathological features of schizophrenia is perturbation in synaptic connectivity. Although the etiology of schizophrenia is unknown, it appears to be a developmental disorder involving the interaction of a potentially large number of risk genes, with no one gene producing a strong effect except rare, highly penetrant copy number variants. The purpose of this review is to detail how putative schizophrenia risk genes (DISC-1, neuregulin/ErbB4, dysbindin, Akt1, BDNF, and NMDA receptor) are involved in regulating neuroplasticity and how alterations in their expression may contribute to the disconnectivity observed in schizophrenia. Moreover, this review highlights how many of these risk genes converge to regulate common neurotransmitter systems and signaling pathways. Future studies aimed at elucidating the functions of these risk genes will provide new insights into the pathophysiology of schizophrenia and will likely lead to the nomination of novel therapeutic targets for restoring proper synaptic connectivity in the brain in schizophrenia and related disorders.

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

“…Similar to the DISC1 and neuregulin1 knockout mice, PSD95 homozygous KO's are not lethal, and the heterozygous animals share prepulse inhibition, hyperactivity, and enhanced LTP phenotypes (Desbonnet et al, 2009;Dyck et al, 2009;Kato et al, 2010;Le Greves et al, 2006;Yao et al, 2004). Interestingly, alterations in the localization and function of DISC1 and neuregulin1 are linked to abnormalities of the NMDA receptor signaling complex that includes PSD95 (Balu and Coyle, 2011;Geddes et al, 2011;Ma et al, 2013;Schmitt et al, 2011). The wellcharacterized effects of pharmacologic blockade of NMDA receptors, which yield a schizophreniform phenotype, support the hypothesis that disruption of synaptic plasticity, regardless of the mechanism, contributes to the signs and symptoms of schizophrenia.…”

Dysbindin-1C Is Required for the Survival of Hilar Mossy Cells and the Maturation of Adult Newborn Neurons in Dentate Gyrus

“…Intriguingly, if the development of schizophrenic symptoms is attributable to dysbindin-1 in the BLOC-1 complex, one would expect similar effects of other BLOC-1 subunits (44). Linkage and association studies have shown strong evidence for the involvement of the DTNBP1 gene in schizophrenia (45). However, except for BLOC1S3, genes encoding other BLOC-1 subunits have no significant association with schizophrenia risk although an epistatic interaction between DTNBP1 and MUTED may exist (46).…”

“…During early postnatal hippocampal neurogenesis, DISC1 restricts GABA-mediated Akt-mTOR signaling and exerts an inhibitory role on the maturation of adult-born neurons (50). Importantly, several schizophrenia susceptibility genes such as DTNBP1, DISC1, GAD67, NKCC1, and AKT1 converge in this pathway (45,50,51).…”

Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors

“…A key process regulating NMDAR activity is phosphorylation by NMDAR-associated kinases. Certain NMDAR-dependent functions, such as ventilation and locomotion, may be independent of NMDAR phosphorylation 4 , whereas phosphorylation-induced upregulation of NMDARs is critical for synaptic plasticity [5][6][7] .A prominent hypothesis for the pathophysiology of schizophrenia is that core symptoms such as hallucinations and cognitive deficits may be due to hypofunction of the NMDAR [8][9][10] . In support of this hypothesis, administering NMDAR-blocking drugs to otherwise normal adults elicits hallucinations and cognitive deficits 11 .…”

“…A prominent hypothesis for the pathophysiology of schizophrenia is that core symptoms such as hallucinations and cognitive deficits may be due to hypofunction of the NMDAR [8][9][10] . In support of this hypothesis, administering NMDAR-blocking drugs to otherwise normal adults elicits hallucinations and cognitive deficits 11 .…”