This narrative review examines how dorsolateral prefrontal cortex (dlPFC) circuitry — particularly layer III pyramidal neuron microcircuits supporting working memory and top-down control — is disrupted across schizophrenia, major depressive disorder (MDD), Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD), drawing on postmortem, neuroimaging, genetics, and primate model data.
Convergent evidence shows that dlPFC layer III pyramidal neurons are a shared vulnerability hub: schizophrenia reduces dendritic spine density and alters inhibitory input balance; MDD impairs dlPFC pathways regulating the subgenual cingulate cortex; and AD/FTLD tau pathology selectively targets association cortex layer III circuits, driving executive dysfunction.
As a narrative review, it does not provide pooled effect sizes or systematic literature selection; findings from rhesus macaque and marmoset models may not fully translate to human disease; postmortem studies are subject to confounds (medication, agonal state, tissue quality).
dlPFC layer III circuits — modulated by NMDA receptors, cholinergic signaling, and calcium-cAMP pathways — represent a convergent therapeutic target across schizophrenia, MDD, and AD. Emerging strategies aimed at strengthening prefrontal network function (e.g., targeting recurrent excitation or spine stability) may benefit multiple diagnostic categories.
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