This paper reviews the molecular differences across the cortical hierarchy in primates that expand in dorsolateral prefrontal cortex (dlPFC) to generate working memory and top-down control, but which confer vulnerability in mental disorders. Research on molecular mechanisms early in the primate cortical hierarchy, e.g. in primary visual cortex (V1), are often in concert with rodent, e.g. neurotransmission relies greatly on AMPAR, while modulation with attention involves NMDAR and cholinergic mechanisms. However, there are also significant differences in cortical specializations and cholinergic receptor localization between rodent and primate V1. In contrast to V1, the recurrent excitatory microcircuits in layer III of primate dlPFC that generate working memory express many distinct mechanisms: neurotransmission depends on NMDAR and acetylcholine (and thus arousal state), not AMPAR; 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 “off-line” 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.
The dorsolateral prefrontal cortex (dlPFC) has recently advanced across mammalian evolution and subserves our highest order cognitive functions, such as working memory and abstract thought, and the executive functions, including top-down control (
1,
2). This remarkable cortical area dysfunctions in most mental disorders, while the primary visual cortex (V1) is generally more resilient (
3,
4,
5). What are the molecular features that distinguish these distinct cortical areas that are at opposite ends of the cortical hierarchy, and how might they relate to their differences in resilience? We have been learning that layer III of the dlPFC expresses specialized molecular mechanisms necessary for generating higher cognition and for coordinating cognitive state with arousal state, a process termed Dynamic Network Connectivity (
6,
7). However, these same mechanisms confer vulnerability to dysfunction and degeneration if not tightly regulated (
8,
9). Revealing these molecular actions will be key to understanding the functional consequences of genetic and inflammatory insults, and for developing informed strategies for treatments. The following reviews what is currently known about the molecular mechanisms governing V1 vs. the dlPFC, with the overarching goal of elucidating the characteristics that render layer III of the dlPFC so susceptible to malfunction and degeneration in mental disorders.
