Year: 2026
Type: review
Abstract: Impaired activation of cortical circuits might contribute to working memory deficits in schizophrenia. In this disorder, layer 3 pyramidal neurons (L3PNs) of the prefrontal cortex (PFC), primary visual cortex (V1), and posterior parietal cortex (PPC)-3 cortical areas essential for working memory-display alterations that may impair network activity. We review evidence suggesting that L3PN morphology and physiology differ significantly across the PFC, PPC, and V1 in primates. These differences are much less pronounced in rodents, suggesting a primate-enhanced regional variability that may be the substrate for area-specific L3PN vulnerability in schizophrenia. PFC L3PNs exhibit larger dendrites with a higher spine density and thus have substantially more excitatory synapses than V1 or PPC L3PNs. Furthermore, the PFC contains a unique stripe-like connectivity system mediated by the horizontal axon collaterals of L3PNs that might support robust recurrent excitation and thus the mnemonic persistent activity thought to contribute to working memory storage. Physiologically, PFC L3PNs display higher spontaneous excitatory postsynaptic current (sEPSC) frequency and amplitude, indicating functionally more potent individual synapses in PFC than in V1 L3PNs. Although sEPSC differences are less pronounced between PPC and PFC L3PNs, the greater spine density in PFC suggests stronger excitatory drive in PFC L3PNs. We conclude by identifying open questions that are relevant for understanding schizophrenia pathophysiology: 1) What are the sources of synaptic input on L3PNs in each area? 2) What is the significance of dendritic spine density differences across areas? and 3) Do NMDA receptor-mediated synaptic currents differ in strength between L3PNs in the PFC, PPC, and V1?
Source: Biological Psychiatry
Institutions: University of Pittsburgh, Consejo Superior de Investigaciones Científicas, Centro de Neurociencias Cajal, Universidad Politécnica de Madrid, Göttingen Campus Institut für Dynamic biologischer Netzwerke, University of Göttingen, Western University, Fields Institute for Research in Mathematical Sciences, Universitätsmedizin Göttingen, Boston University
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,489
Funders: National Science Foundation, Ministerio de Ciencia, Innovación y Universidades, Deutsche Forschungsgemeinschaft, Western University, Alliance de recherche numérique du Canada, National Institutes of Health, Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, European Regional Development Fund, Agencia Estatal de Investigación, National Institute on Aging, National Institute of Mental Health, National Eye Institute, National Institute of Neurological Disorders and Stroke, Compute Ontario
Awards: CRCNS: Age-related changes to cortical dynamics underlying working memory, Prefrontal-cingulate functional networks in aging monkeys: neural circuit substrates of cognitive aging, G410571670, G451917667, NEURONEX: The fabric of the primate neocortex and the origin of mental representations. From transcriptomics to single neurons and neuronal networks., G5030982119, NEURONEX: The fabric of the primate neocortex and the origin of mental representations. From transcriptomics to single neurons and neuronal networks., Corticale Netzwerke in Primaten und der Ursprung mentaler Repräsentationen von Transcriptomics zu Einzelneuronen und neuronalen Netzwerken, G5967599077, Mechanisms of Age-related Cognitive Decline in the Rhesus Monkey, G7054016415, G7838019746, G9000378222, G9000378425, G9000380739, G9000383419, Circuit structure and dynamics in prefrontal-limbic networks, Spatiotemporal patterns of neural activity and their role in perception, Traveling Waves in Neocortical Circuits: Mechanisms, Computational Roles in Sensory Processing, and Impact on Sensory Perception, Multiscale modeling and empirical studies of normal and pathological brain aging, G929308097
OpenAlex ID: W7204604545