GABAergic Interneurons: Implications for Understanding Schizophrenia and Bipolar Disorder

There is an urgent need to improve the pharmacotherapy of schizophrenia despite the introduction of important new medications. New treatment insights may come from appreciating the therapeutic implications of model psychoses. In particular, basic and clinical studies have employed the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, ketamine, as a probe of NMDA receptor contributions to cognition and behavior. These studies illustrate a translational neuroscience approach for probing mechanistic hypotheses related to the neurobiology and treatment of schizophrenia and other disorders. Two particular pathophysiologic themes associated with schizophrenia, the disturbance of cortical connectivity and the disinhibition of glutamatergic activity may be modeled by the administration of NMDA receptor antagonists. The purpose of this review is to consider the possibility that agents that attenuate these two components of NMDA receptor antagonist response may play complementary roles in the treatment of schizophrenia.

NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development.

Emerging principles of altered neural circuitry in schizophrenia.

Context Chondroitin sulfate proteoglycans (CSPGs), a main component of the brain extracellular matrix, regulate developmental and adult neural functions that are highly relevant to the pathogenesis of schizophrenia. Such functions, together with marked expression of CSPGs in astrocytes within the normal human amygdala and evidence of a disruption of astrocytic functions in this disease, point to involvement of CSPG-glial interactions in schizophrenia. Hypothesis Chondroitin sulfate proteoglycan–related abnormalities involve glial cells and extracellular matrix pericellular aggregates (perineuronal nets) in the amygdala and entorhinal cortex of subjects with schizophrenia. Design Postmortem case-control study. Setting The Translational Neuroscience Laboratory at McLean Hospital, Harvard Medical School. Specimens were obtained from the Harvard Brain Tissue Resource Center at McLean Hospital. Participants Two separate cohorts of healthy control (n = 15; n = 10) and schizophrenic (n = 11; n = 10) subjects and a cohort of subjects with bipolar disorder (n = 11). Interventions Quantitative, immunocytological, and histological postmortem investigations. Main Outcome Measures Numerical densities of CSPG-positive glial cells and perineuronal nets, glial fibrillary acidic protein-positive astrocytes, and total numbers of parvalbumin-positive neurons in the deep amygdala nuclei and entorhinal cortex. Results In schizophrenia, massive increases in CSPG-positive glial cells were detected in the deep amygdala nuclei (419%-1162%) and entorhinal cortex (layer II; 480%-1560%). Perineuronal nets were reduced in the lateral nucleus of the amygdala and lateral entorhinal cortex (layer II). Numerical densities of glial fibrillary acidic protein-positive glial cells and total numbers of parvalbumin-positive neurons were unaltered. Changes in CSPG-positive elements were negligible in subjects with bipolar disorder. Conclusions Marked changes in functionally relevant molecules in schizophrenia point to a pivotal role for extracellular matrix–glial interactions in the pathogenesis of this disease. Disruption of these interactions, unsuspected thus far, may represent a unifying factor contributing to disturbances of neuronal migration, synaptic connectivity, and GABAergic, glutamatergic, and dopaminergic neurotransmission in schizophrenia. The lack of CSPG abnormalities in bipolar disorder points to a distinctive aspect of the pathophysiology of schizophrenia in key medial temporal lobe regions.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/210547/yoa90062_155_166.pdf

Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia.

The anterior cingulate cortex (ACC) is a functionally heterogeneous region involved in diverse cognitive and emotional processes that support goal-directed behaviour. Structural magnetic resonance imaging (MRI) and neuropathological findings over the past two decades have converged to suggest abnormalities in the region may represent a neurobiological basis for many of the clinical manifestations of schizophrenia. However, while each approach offers complimentary information that can provide clues regarding underlying patholophysiological processes, the findings from these 2 fields are seldom integrated. In this article, we review structural neuroimaging and neuropathological studies of the ACC, focusing on the unique information they provide. The available imaging data suggest grey matter reductions in the ACC precede psychosis onset in some categories of high-risk individuals, show sub-regional specificity, and may progress with illness duration. The available post-mortem findings indicate these imaging-related changes are accompanied by reductions in neuronal, synaptic, and dendritic density, as well as increased afferent input, suggesting the grey matter differences observed with MRI arise from alterations in both neuronal and non-neuronal tissue compartments. We discuss the potential mechanisms that might facilitate integration of these findings and consider strategies for future research.

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Anatomical Abnormalities of the Anterior Cingulate Cortex in Schizophrenia: Bridging the Gap Between Neuroimaging and Neuropathology

Gluatamtergic fibers have been immunocytochemically localized in the entorhinal cortex of postmortem schizophrenic brains. The density of small caliber vertical fibers was higher in schizophrenics than controls, with no significant increase in the number of large caliber fibers. Increased glutamatergic fiber density has been previously reported in the cingulate cortex. It is proposed that increases in glutamatergic fibers from the amygdala may be responsible for these changes and that they may play a central role in the pathophysiology of schizophrenia.

D. Longson

Papers

Increased density of entorhinal glutamate-immunoreactive vertical fibers in schizophrenia.

Specific increase in size of lamina II pyramidal cells in the entorhinal cortex in schizophrenia