EFFECT OF JUVENILE SOCIAL ISOLATION ON EXCITABILITY OF PREFRONTAL PYRAMIDAL CELLS WITH DIFFERENT SUBCORTICAL AXONAL PROJECTIONS

Social experience during development is critical for the maturation of the prefrontal cortex (PFC), yet how juvenile social isolation (JSI) affects specific prefrontal output circuits remains unclear. This study examined whether JSI differentially alters the intrinsic and synaptic properties of layer 5 (L5) mPFC pyramidal cells according to their subcortical projection targets. Using retrograde neuronal tracing in mice, L5 mPFC pyramidal cells projecting to the mediodorsal thalamus (MD), striatum (STR), or pontine nuclei (PON) were identified. Whole-cell patch-clamp recordings were performed to characterize intrinsic membrane properties and excitatory synaptic inputs under group-housed and JSI conditions. Under control conditions, pyramidal cells projecting axon to the PON exhibited prominent hyperpolarization-activated currents, lower input resistance, higher intrinsic excitability, and stronger excitatory synaptic inputs compared with pyramidal cells projecting axons to the MD and STR. JSI affects the development of L5 pyramidal cells based on their projection target. Pyramidal cells projecting axons to the MD, particularly those with prominent h-current, showed increased excitability, reflected by reduced rheobase and a steeper spike frequency–current curve. In contrast, JSI selectively reduced action potential–dependent excitatory synaptic inputs onto pyramidal cells projecting axons to the pontine nuclei, without significantly affecting their intrinsic membrane properties. Pyramidal cells projecting axons to the STR were largely unaffected by JSI. These findings indicate that JSI affects the intrinsic membrane properties and excitatory synaptic inputs of medial L5 mPFC pyramidal cells in a projection-dependent manner.