Cognitive Dysfunction and Prefrontal Cortical Circuit Alterations in Schizophrenia: Developmental Trajectories.

Area of Science:

• Neuroscience
• Cognitive Science
• Psychiatry

Background:

• Schizophrenia (SZ) is associated with cognitive deficits, particularly in working memory (WM).
• WM impairments in SZ emerge during development and involve the dorsolateral prefrontal cortex (dlPFC).
• The dlPFC microcircuit, involving excitatory layer 3 pyramidal neurons and inhibitory parvalbumin basket cells (PVBCs), is critical for WM.

Purpose of the Study:

• To propose a developmental model explaining working memory (WM) impairments in schizophrenia (SZ).
• To integrate findings on neuronal alterations and developmental trajectories in the context of SZ.
• To elucidate the roles of excitatory and inhibitory neuronal circuits in WM deficits.

Main Methods:

• Review of postmortem human studies on dlPFC microcircuits in SZ.
• Analysis of studies on the postnatal development of pyramidal neurons and PVBCs in non-human primates.
• Synthesis of evidence to support or challenge a proposed developmental model.

Main Results:

• Alterations in both layer 3 pyramidal neurons and PVBCs are observed in SZ postmortem brains.
• Distinct postnatal developmental trajectories exist for pyramidal neurons and PVBCs.
• A model is proposed where early insults and adolescent synaptic pruning disrupt the excitatory-inhibitory balance in dlPFC, impairing WM development.

Conclusions:

• Genetic or environmental insults may affect excitatory signaling early in life, impacting WM and PVBC development.
• Adolescent synaptic pruning exacerbates excitatory deficits, overwhelming compensatory inhibition and hindering WM maturation in SZ.
• The proposed model integrates cellular, developmental, and circuit-level findings to explain WM impairments in schizophrenia.