Cholecystokinin modulates corticostriatal transmission and plasticity in rodents.

Abstract

Recent findings have shifted the view of cholecystokinin (CCK) from being a cellular neuronal marker to being recognized as a crucial neuropeptide pivotal in synaptic plasticity and memory processes. Despite its now appreciated importance in various brain regions and abundance in the basal ganglia, its role in the striatum, which is vital for motor control, remains unclear. This study sought to fill this gap by performing a comprehensive investigation of the role of CCK in modulating striatal medium spiny neurons (MSN) membrane properties, as well as the secondary somatosensory cortex S2 to MSN synaptic transmission and plasticity in rodents. Using in-vivo optopatch-clamp recording in mice on identified medium spiny neurons (MSNs), we showed that the application of CCK receptor type 2 (CCK2R) antagonists decreases corticostriatal transmission in both direct and indirect pathway MSNs. Moving to an ex vivo rat preparation to maximize experimental access, we showed that CCK2R inhibition impacts MSN membrane properties by reducing spike threshold and rheobase, suggesting an excitability increase. Moreover, CCK modulates corticostriatal transmission mainly via CCK2R, and CCK2R blockage shifted spike-timing-dependent plasticity (STDP) from long-term potentiation to long-term depression. Our study advances the understanding of CCK's importance in modulating corticostriatal transmission. By showing how CCK2R blockade influences synaptic function and plasticity, we provide new insights into the mechanisms underlying striatal functions, opening new paths for exploring its potential relevance to neurological disorders involving basal ganglia related behaviors.Significance Statement Cholecystokinin (CCK) plays a critical role in synaptic plasticity and memory but completely unexplored in corticostriatal synapses and motor control. This study shows that blocking the CCK2 receptor (CCK2R) reduces postsynaptic potentials (EPSPs) and excitatory postsynaptic currents (EPSCs) in the motor striatum (in vivo and ex vivo) and disrupts corticostriatal spike-timing-dependent plasticity (STDP), shifting it from long-term potentiation (LTP) to long-term depression (LTD). These findings reveal CCK signaling as a key modulator of corticostriatal communication, capable of reversing the direction of synaptic plasticity. The results position CCK as a crucial regulator of synaptic and motor functions, with implications for understanding corticostriatal mechanisms.