Unique Molecular Regulation of Higher-Order Prefrontal Cortical Circuits: Insights into the Neurobiology of Schizophrenia

ACS Chemical Neuroscience
Dibyadeep Datta, Amy F T Arnsten

Abstract

Schizophrenia is associated with core deficits in cognitive abilities and impaired functioning of the newly evolved prefrontal association cortex (PFC). In particular, neuropathological studies of schizophrenia have found selective atrophy of the pyramidal cell microcircuits in deep layer III of the dorsolateral PFC (dlPFC) and compensatory weakening of related GABAergic interneurons. Studies in monkeys have shown that recurrent excitation in these layer III microcircuits generates the precisely patterned, persistent firing needed for working memory and abstract thought. Importantly, excitatory synapses on layer III spines are uniquely regulated at the molecular level in ways that may render them particularly vulnerable to genetic and/or environmental insults. Glutamate actions are remarkably dependent on cholinergic stimulation, and there are inherent mechanisms to rapidly weaken connectivity, e.g. during stress. In particular, feedforward cyclic adenosine monophosphate (cAMP)-calcium signaling rapidly weakens network connectivity and neuronal firing by opening nearby potassium channels. Many mechanisms that regulate this process are altered in schizophrenia and/or associated with genetic insults. Current data suggest that the...Continue Reading

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Citations

Aug 21, 2020·Proceedings of the National Academy of Sciences of the United States of America·Guoping FengJohn H Morrison
Aug 9, 2019·Neurobiology of Learning and Memory·Thomas C Foster
Nov 4, 2020·Translational Psychiatry·Caroline F ZinkKristin L Bigos
Feb 25, 2021·Scientific Reports·Marissa A SmailRobert E McCullumsmith
May 14, 2021·Molecular Psychiatry·Megan RoussyJulio C Martinez-Trujillo

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