PKCΑ-DEPENDENT STRUCTURAL REMODELING OF PERIRHINAL CORTEX PYRAMIDAL NEURONS UNDERLIES MEMORY ENHANCEMENT AND REVERSAL OF MEMORY DEFICITS

Memory deficits are a major health problem during normal aging and are also prominent in Alzheimer’s disease and other neurological and neurodegenerative conditions. Despite extensive efforts, effective treatments remain limited, as most memory-enhancing strategies have failed to reliably reverse cognitive impairment. Previously, we identified the memory-enhancing protein regulator of G-protein signaling 14 of 414 amino acids (RGS14₄₁₄) as a factor capable of reversing memory deficits through a 14-3-3ζ–BDNF–dependent upregulation of BDNF signaling. Here, we demonstrate that RGS14₄₁₄-induced BDNF elevation leads to time-controlled activation of protein kinase Cα (PKCα), a downstream effector of BDNF signaling. RGS14₄₁₄ expression in the perirhinal cortex selectively increased PKCα levels for approximately two weeks, during which no improvement in object recognition memory (ORM) was detected. However, this early phase was marked by a robust increase in dendritic branching and spine density in excitatory pyramidal neurons, which persisted long after PKCα levels returned to baseline. Memory enhancement emerged only during the third week, coinciding with the establishment of sustained structural reorganization. Importantly, PKCα knockdown abolished both dendritic remodeling and memory enhancement, indicating that PKCα-dependent structural plasticity is required for memory improvement. Beyond ORM, PKCα was essential for enhancing multiple memory modalities in young adult rats and for rescuing recognition, spatial, and temporal memory deficits in aged animals. Together, these findings identify PKCα as a critical mediator of time-regulated neuronal structural plasticity and highlight PKCα-dependent synaptic remodeling as a promising therapeutic target for memory deficits associated with aging and neurological disease.