Glial Clusters and Psychopathology: Exploring Reduced Counts With a Person’s Diagnosis of Schizophrenia or Bipolar Disorder and Finding Novel Cluster Morphology

Abstract

Schizophrenia (SZ) and Bipolar Disorder (BD) are both severe psychiatric disorders that permanently alter a person’s life by afflicting their cognitive and emotional faculties. Over the course of a person’s life, the symptoms might vary in severity, but the changes in neurological determinants of their cognitive and emotional function keep a biological score. Deficits in functional connectivity unique to the two disorders have been associated with alterations in the extracellular matrix (ECM), a loose chemical substance that acts as a chemical medium for cells to communicate and build structural and functional networks, as well as performing a host of other functions. Aside from the ECM itself being a structure found throughout the brain, various tightly organized aggregates of the ECM have been studied due to their potential role in regulating neuronal activity, which then has downstream effects on cognitive and emotional function. Previous investigations from our lab have found novel ECM structures called 6-sulfated chondroitin (CS-6) glial clusters, which consist of 6-sulfated structures associated with glial cells. Findings from these investigations indicate glial clusters may be involved in synaptic regulation. We previously reported marked reductions of these clusters in the amygdalae of persons diagnosed with SZ or BD compared to healthy people. Informed by these findings, we theorized that glial clusters may be involved in the cognitive and emotional processing deficits suffered by people with psychotic disorders, and sought to extend findings from the amygdala to the mediodorsal thalamic nucleus (MDTN) to find quantifiable evidence to support this theory. The MDTN was chosen due to its numerous, reciprocal axonal connections with the prefrontal cortex, where imaging studies have shown marked reductions in functional activity and connectivity in persons with SZ and BD. We hypothesized cluster counts would be decreased in the MDTN of persons with either a psychiatric diagnosis of SZ or BD compared to controls. Quantification of CS56 immunoreactive clusters in the MDTN showed significant reductions for total number in persons with a diagnosis of SZ or BD compared to control, and for numerical density as well, with no change in volume of the nucleus between groups. During the current investigation, high resolution microscopic imaging of the clusters stained by immunoreaction to CS56 (a CS-6 specific antibody) also led us to find distinctions in morphology, indicating heterogeneity not previously seen. We detail our classification system which revealed four novel morphological cluster types: a tendril type, a diffuse type, a densely diffuse type, and a fourth type called type-4. Discovery of morphological characteristics for clusters provides new avenues for researching neuropathological development in psychotic disorders, and findings of cluster reductions indicates a potential role for this ECM structure in the network disruptions resulting in cognitive and emotional deficits for persons with SZ and BD.