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 the 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.

Fig. 1. DISC1 Regulates Many Aspects of Neuroplasticity During Development and Adulthood

(A) Disrupted in schizophrenia 1 (DISC1) is located in the postsynaptic density (PSD) of excitatory cortical neurons. It directly interacts with the anchoring molecule PSD 95 kDa (PSD95) and kalirin-7 (Kal-7), a GDP/GTP exchange factor for the small G protein Rac1, a well-known regulator of spine morphology and plasticity. This complex is modulated by N-methyl-d-aspartate receptor (NMDAR)-dependent activity, which regulates Rac-1 mediated changes in spine morphology. (B) DISC1 regulates proliferative activity during development and in the adult hippocampus via modulation of the canonical Wnt/β-catenin signaling pathways. DISC1 directly binds to, and inhibits the activity of glycogen synthase-3β (GSK3β). This consequently increases the cytosolic concentration of β-catenin, potentiates Wnt3a signaling, and increases cell proliferation. (C) DISC1 is part of the centrosome, where it anchors other proteins such as pericentriolar material 1 (PCM1), nudE-like 1 (NDEL1), lissencephaly 1 (LIS1), Bardet-Biedl syndrome protein 4 (BBS4), and ninein to the dynein motor complex. DISC1 is important for proper functioning of this complex, which is critical for neuronal migration and neurite outgrowth. (D) In the postnatal hippocampus, through its interaction with the actin binding protein, girdin, DISC1 regulates neuronal positioning and migration, as well as axonal development. DISC1 modulates neurogenesis in the dentate gyrus of the adult hippocampus, a brain region that retains the capacity to produce neurons throughout adulthood. DISC1 controls the timing of integration, dendritic arborization, and soma size of the newborn neurons. It does this by binding to, and inhibiting KIAA1212 (also known as girdin), an activator of Akt. This leads to reduced Akt signaling and reduced activation of its downstream substrate, mammalian target of rapamycin (mTOR).

Fig. 2. Dysbindin and Neuregulin1/ErbB4 regulate multiple neurotransmitter systems

(A) Glutamatergic transmission is modulated both pre- and postsynaptically by neuregulin-1 (NRG1) and dysbindin. In the presynaptic neuron, dysbindin increases glutamate release, while postsynaptically it inhibits the surface expression of NR2A, but not NR2B, subunit containing N-methyl-d-aspartate receptors (NMDARs). The mechanism underlying these trafficking effects is unknown. ErbB4 interacts and co-localizes with the scaffolding protein postsynaptic density 95 kDa (PSD95). NRG1 through ErbB4 signaling suppresses the induction and expression of long-term potentiation (LTP) at glutamatergic synapses in the hippocampus. Recent evidence suggests that NRG1/ErbB4 signaling most critically impacts glutamatergic transmission onto GABAergic interneurons, namely those expressing parvalbumin (PV+). (B) With respect to dopaminergic signaling, dysbindin negatively regulates the surface expression of dopamine type-2 (D2), but not D1 receptors by affecting recycling and insertion, rather than endocytosis. NRG1 stimulates hippocampal dopamine release, however the mechanism is unknown. (C) ErbB4 is present in the presynaptic terminals of GABAergic interneurons and stimulation of these presynaptic receptors by NRG1 enhances activity-dependent GABA release through presently unidentified mechanisms. In PV+ chandelier and basket cells, ErbB4 is also localized to axon terminals and PSDs that receive glutamatergic input. Furthermore, evidence suggests that NRG1/ErbB4 signaling in PV+ interneurons is important for synchronizing pyramidal cell activity in several brain regions.