Abstract / Summary
Abstract Memory deficits are not only a major health problem during normal aging but also occur in individuals with Alzheimer’s disease and many other neurological and neurodegenerative conditions. The mechanisms that drive the onset and progression of memory impairment remain poorly understood, and the development of effective treatments has been challenging because most drug candidates and memory enhancers have failed to reliably reverse memory deficits in humans. Previously, we found that the memory-enhancing protein regulator of G-protein signaling 14 of 414 amino acids (RGS14 414 ) can reverse memory deficits through a 14–3-3ζ–BDNF–dependent upregulation of BDNF signaling. Here, we show that the RGS14 414 -induced increase in BDNF leads to a time-controlled activation of protein kinase Cα (PKCα), a downstream effector of BDNF. This short-lived PKCα activation triggers robust synaptic structural plasticity in excitatory pyramidal neurons. RGS14 414 expression in the perirhinal cortex increased PKCα levels for approximately two weeks, during which no improvement in object recognition memory (ORM) was observed. During this early phase, however, dendritic branching and the total number of dendritic spines increased by approximately twofold and remained elevated long after PKCα levels returned to baseline. Correspondingly, ORM enhancement emerged only during week three, when structural reorganization had already occurred and new synaptic connections were established. Knockdown of PKCα eliminated both dendritic growth and memory enhancement, demonstrating that PKCα is required for structural-plasticity–driven memory improvement. Moreover, PKCα was essential not only for enhancing multiple types of memory in young adult rats but also for rescuing recognition, spatial, and temporal memory in aged animals. These memory types represent core components of episodic memory that are primarily affected in patients with memory dysfunctions. Together, these findings identify PKCα as a key mediator of time-controlled neuronal structural plasticity and underscore the central role of synaptic remodelling in memory enhancement. They also highlight PKCα-dependent synaptic remodelling as a promising therapeutic target for memory deficits and other conditions associated with synaptic connectivity deficits.