Diversity of Layer 3 Pyramidal Neuron Properties Across Areas of the Primate Neocortex

Impaired activation of cortical circuits might contribute to working memory deficits in schizophrenia. In this disorder, layer 3 pyramidal neurons (L3PNs) of the prefrontal (PFC), primary visual (V1) and posterior parietal (PPC) cortices, three 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 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 higher spine density, thus 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 post-synaptic 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: i) What are the sources of synaptic input on L3PNs in each area?, ii) What is the significance of dendritic spine density differences across areas?, and iii) Do NMDAR-mediated synaptic currents differ in strength between L3PNs in PFC, PPC, and V1?