Distinctive Molecular Mechanisms in Higher Cortical Circuits Confer Vulnerability to Mental Disorders
Year: 2026
Type: article
Abstract: In this article, we review the molecular differences across the cortical hierarchy in primates that expand in the dorsolateral prefrontal cortex (dlPFC) to generate working memory and top-down control but also confer vulnerability in mental disorders. Research on molecular mechanisms early in the primate cortical hierarchy, e.g., in the primary visual cortex (V1), are often in concert with rodent, e.g., neurotransmission relies greatly on AMPA receptors (AMPARs), while modulation with attention involves NMDA receptors (NMDARs) and cholinergic mechanisms. However, there are also significant differences in cortical specializations and cholinergic receptor localization between the rodent and the primate V1. In contrast to V1, the recurrent excitatory microcircuits in layer III of the primate dlPFC that generate working memory express many distinct mechanisms; neurotransmission depends on NMDARs and acetylcholine (and thus arousal state), not AMPARs; extended neuronal firing underlying working memory depends on magnified calcium signaling in spines; however, excessive cytosolic calcium reduces firing, with powerful mechanisms to take the dlPFC offline during uncontrollable stress and/or inflammation, e.g., opening potassium channels on spines to rapidly weaken connections. Regulation of these powerful mechanisms is lost due to inflammation and/or genetic insults (e.g., gain-of-function mutations in CACNA1C, loss of function in GRM3), which may interact to induce loss of dendritic spines and/or tau pathology, cognitive impairments, and reduced top-down control. Many of the genetic risks for schizophrenia weaken layer III dlPFC spine connections, suggesting that multiple genotypes would produce a shared phenotype. The review also suggests new therapeutic targets that can act to reduce inflammation, regulate calcium, and strengthen synaptic efficacy in the primate dlPFC.
Source: Biological Psychiatry
Institutions: Yale University, Duke University, Boston University
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,489
Awards: Bi-directional, task-dependent control of thalamic input gain, in layer 4c of the primary visual cortex, by the cholinergic and serotonergic neuromodulatory systems., Role of kynurenic acid in higher cognitive deficits: Mechanism and treatment strategies, Probing D2 and 5HT-2A mechanisms in early visual processing in V1, Prefrontal impairment with stress- NE receptor subtype mechanisms.
OpenAlex ID: W7165389901