Neurobiology of Schizophrenia Onset

Abstract

The clinical symptoms and cognitive and functional deficits of schizophrenia typically begin to gradually emerge during late adolescence and early adulthood. Recent findings suggest that disturbances of a specific subset of inhibitory neurons that contain the calcium-binding protein parvalbumin (PV), which may regulate the course of postnatal developmental experiencedependent synaptic plasticity in the cerebral cortex, including the prefrontal cortex (PFC), may be involved in the pathogenesis of the onset of this illness. Specifically, converging lines of evidence suggest that oxidative stress, extracellular matrix (ECM) deficit and impaired glutamatergic innervation may contribute to the functional impairment of PV neurons, which may then lead to aberrant developmental synaptic pruning of pyramidal cell circuits during adolescence in the PFC. In addition to promoting the functional integrity of PV neurons, maturation of ECM may also play an instrumental role in the termination of developmental PFC synaptic pruning; thus, ECM deficit can directly lead to excessive loss of synapses by prolonging the course of pruning. Together, these mechanisms may contribute to the onset of schizophrenia by compromising the integrity, stability, and fidelity of PFC connectional architecture that is necessary for reliable and predictable information processing. As such, further characterization of these mechanisms will have implications for the conceptualization of rational strategies for the diagnosis, early intervention, and prevention of this debilitating disorder. KeywordsCerebral cortex; Critical period; Dendritic spines; Extracellular matrix; GABA; Gamma band oscillation; Oxidative stress; Parvalbumin; Schizophrenia; Synaptic pruning Schizophrenia is a complex, prevalent, and extremely debilitating brain disorder affecting approximately 1% of the population worldwide. It is defined by a constellation of positive (i.e., delusions and hallucinations) and negative (i.e., affective flattening, avolition, alogia, anergia, and anhedonia) symptoms. In addition, patients exhibit prominent cognitive deficits, such as disturbances in executive functions, working memory, and attention. Together, these symptoms and cognitive deficits render the individuals inflicted with the

Neural ECM in addiction, schizophrenia, and mood disorder

“…Manifestation of these clinical symptoms generally occurs during late adolescence or early adulthood and parallels or shortly follows maturation of brain areas that underlie the cognitive functions that are affected in schizophrenia, such as the PFC (Lewis and Levitt, 2002;Marenco and Weinberger, 2000;Woo, 2013). This has led to the hypothesis that impaired maturation of neural circuits (i.e., synaptic pruning and stabilization of neural connections) is a major cause of this disorder (Woo, 2013).…”

“…Research into the neurobiological underpinnings of psychiatric disorders points to impaired neurodevelopmental and adult neural plasticity processes, such as cell migration, synaptogenesis, synaptic pruning, and LTP (Bambico and Belzung, 2013;Russo et al, 2010;Woo, 2013). The growing evidence that the ECM is an important regulator of neuronal adaptation and plasticity (Dityatev et al, 2010;Gundelfinger et al, 2010) suggests that abnormal ECM composition and turnover might underlie development and progression of psychiatric disorders.…”

“…Accordingly, postmortem studies have identified several deficits in synaptic connectivity in the PFC of schizophrenia subjects (Woo, 2013) including a reduced expression of synaptic proteins (Glantz and Lewis, 1997;Halim et al, 2003), a reduced density of dendritic spines on pyramidal cells (Garey et al, 1998;Kolluri et al, 2005;Lewis and Gonzalez-Burgos, 2008), and compromised inhibition of pyramidal cells by parvalbumin-expressing GABAergic interneurons (Lewis et al, 2012;Woo, 2013). As a consequence of an altered balance between excitatory neurotransmission and inhibitory neurotransmission, the strength of interneuron firing might be insufficient to generate gamma-frequency oscillations in the PFC , which are thought critical for cognitive function (Sun et al, 2011;Woo, 2013). Hence, reduced gamma oscillations in schizophrenia patients resulting from impaired maturation of neural circuits are thought to be a core defect underlying this psychiatric disorder.…”

“…Manifestation of these clinical symptoms generally occurs during late adolescence or early adulthood and parallels or shortly follows maturation of brain areas that underlie the cognitive functions that are affected in schizophrenia, such as the PFC (Lewis and Levitt, 2002;Marenco and Weinberger, 2000;Woo, 2013). This has led to the hypothesis that impaired maturation of neural circuits (i.e., synaptic pruning and stabilization of neural connections) is a major cause of this disorder (Woo, 2013). Accordingly, postmortem studies have identified several deficits in synaptic connectivity in the PFC of schizophrenia subjects (Woo, 2013) including a reduced expression of synaptic proteins (Glantz and Lewis, 1997;Halim et al, 2003), a reduced density of dendritic spines on pyramidal cells (Garey et al, 1998;Kolluri et al, 2005;Lewis and Gonzalez-Burgos, 2008), and compromised inhibition of pyramidal cells by parvalbumin-expressing GABAergic interneurons (Lewis et al, 2012;Woo, 2013).…”

“…This hints to a large brain area in which the ECM and in particular PNNs are affected in schizophrenia. Abnormal development of PNNs in schizophrenia might underlie impaired synaptic pruning and prolonged neural plasticity due to lack of synaptic stabilization (Woo, 2013). Furthermore, a reduced ion buffer capacity of the ECM due to reduced expression of PNNs might interfere with normal neurotransmission of fast-spiking inhibitory neurons (Bitanihirwe and Woo, 2014).…”