Study Overview

A recent study published in JAMA Psychiatry delves into the molecular mechanisms influencing layer III pyramidal cells in the dorsolateral prefrontal cortices (dlPFC) of both humans and nonhuman primates. The research identified key calcium-related proteins highly expressed in these neurons, including CALB1 (calbindin), CACNA1C (L-type calcium channel Cav1.2), GRIN2B (NMDA receptor GluN2B), and KCNN3 (SK3 potassium channel). These proteins are crucial for neuronal function, and their dysregulation can contribute to cognitive impairment. The study emphasises that excessive actions of L-type calcium channels (LTCC), driven by β1-adrenoceptor (β1-AR) stimulation, significantly reduce neuronal firing. Conversely, blocking LTCC or β1-AR helps protect working memory performance from stress-induced impairment.

Key Findings

The findings reveal a potent mechanism through which stress impairs cognitive function in the dlPFC, highlighting why variants in CACNA1C are linked to increased risk of cognitive disorders. Both loss-of-function and gain-of-function variants in CACNA1C were found to be detrimental to prefrontal cortex function, thus raising the risk of neuropsychiatric disorders. The study also focused on the connectivity, protein expression, physiology, and cognitive behaviour of these neurons in macaques, revealing that protecting neurons with heightened calcium signalling is vital for maintaining healthy cognitive function.

Implications for Cognitive Disorders

In addition to the functional implications, the study discusses the impact of various genetic variants and neurodevelopmental insults on the pathology of layer III dlPFC pyramidal cells in conditions such as schizophrenia and Alzheimer’s disease. The role of calcium-related proteins like LTCC Cav1.2, GRIN2B, and KCNN3 in neuronal function and cognitive abilities was thoroughly examined, emphasising the importance of these proteins in the context of neuropsychiatric health. Funded by National Science Foundation grants and other sources, this research provides significant insights into the molecular underpinnings of cognitive impairment and suggests potential therapeutic targets for mitigating the effects of stress on cognitive function.

Source: JAMA Psychiatry