Novel CS-6 Cluster Microenvironments: The Effect of Fear Conditioning Influencing the Number, Morphology, and Synaptic Activation of CS-6 Clusters

Abstract

Worldwide, over 50 million suffer with schizophrenia. The deficits associated with schizophrenia are severe, persistent, and largely complex; these effects cause an individual to endure severe cognitive impairments and impede their ability to properly function in daily tasks. These deficits range from emotional, cognitive, memory (verbal and non-verbal), behavior, perception (including hallucinations and deviations to reality), movement disorders, and various other impairments. Schizophrenia is undoubtedly a convoluted and multifaceted disorder in that it has been amalgamated with other disorders and has presentation of various symptoms (e.g., egodisturbances, passivity phenomena, auditory hallucinations, and delusions) (Northoff, 2015). Given the biological complexity, elucidating the fundamental aspects of schizophrenia along with dissecting the underlying mechanisms is of great importance. In uncovering this, the brain’s extracellular matrix (ECM), is an essential constituent of the brain that initiates chemical and mechanical signals, orchestrates tissue and cellular organization and functions (Naba, et al., 2016). In addition to providing biochemical cues, ECMs also empower signaling cascades that dictate cell survival, cell propagation, stem cell states, and differentiation (Campbell & Humphries, 2011; Rozario & DeSimone 2010; Wickström, et al., 2011). Increasing evidence has suggested that the brain ECM is implicated in the pathophysiology of several brain disorders and critically involved in the regulation of synaptic plasticity (Dzyubenko, et al., 2016; Pantazopoulos & Berretta, 2016). Of specific interest, schizophrenia has been notably linked through studies in genetics, animal models, and human postmortem studies in the pathophysiology of schizophrenia (Pantazopoulos, et al., 2013; Berretta, 2012; Pantazopoulos, et al., 2010; Mauney, et al., 2013; Buxbaum, et al., 2008; Muhleisen, et al., 2012; So, et al., 2010). Throughout the developmental stages, the brains ECM, including one of its primary components, chondroitin sulfate proteoglycans (CSPGs), play critical roles in synaptogenesis, neuronal migration and connectivity, synaptic development, and axonal outgrowth (Frischknecht & Gundelfinger, 2012; Bandtlow & Zimmerman, 2000; Curran & D’Arcangelo, 1998; Zimmerman, et al., 2008; Dityatev & Schachner, 2006; Dityatev, et al., 2010). Interestingly, developing data and research from our group and others have shown that these very CSPGs may play a central role in the pathophysiology of psychiatric disorders, specifically schizophrenia (Pantazopoulos & Berretta, 2016). Moreover, our group has revealed that systematized perisynaptic ECM structures enriched in CSPGs, mainly perineuronal nets (PNNs), have diminished counts in various regions throughout the brains of people with schizophrenia and bipolar disorder (Pantazopoulos, et al., 2010; Pantazopoulos, et al., 2015). Within this context, recent findings have pointed to CS-6 clusters, a novel form of ECM/CSPG aggregate, to be markedly reduced within the amygdala of individuals with schizophrenia (Pantazopoulos, 2015). Accounting for the fact that these CS-6 clusters play a critical role in synaptic plastic mechanisms, our aim is to test our hypothesis using a fear conditioning paradigm. Our main goal of the proposed studies is to ultimately investigate and provide evidence that these CS-6 cluster microenvironments have a linkage to experience-induced active sites of structural synaptic plasticity which contribute to dendritic spine pathology in schizophrenia. Our findings will shed light on the precise nature of CS-6 clusters, a unique ECM structure abundant throughout the cortical and subcortical brain regions. Additionally, we expect that an affirmative finding will illuminate an unknown mechanism which potentially plays a major role in regulating synaptic plasticity within segregated microenvironments. Ultimately, these results will allow a tool to analyze how experience affects groups of adjacent synapses and in process reveal compelling insight on the prospective contribution of CS-6 cluster density/volume to the pathophysiology of several brain disorders, including schizophrenia and bipolar disorder.