Cholecystokinin exerts a major control on corticostriatal synapse and motor behavior

Cholecystokinin (CCK) is a neuropeptide detected and produced at high concentrations in the brain. To date it was mainly used as a neuronal marker of neuronal subtypes and its role as a neuromodulator was poorly known. However, few studies showed that it could be an essential neuromodulator in various brain structures, playing a role on synaptic plasticity and memory consolidation. In order to better understand the processes by which CCK impacts plasticity, we focus our attention on the striatum, a nucleus involved in procedural learning and motor behavior, with a rich expression of CCK receptor type 2 (CCK2R). By using in-vivo and ex-vivo electrophysiological approaches, we show that CCK is involved in the corticostriatal synaptic transmission and has a key role in its plasticity. Using in-vivo optopatch-clamp of identified MSNs, we observe a decrease of corticostriatal synaptic transmission after an injection of CCK2R antagonist, leading to a reduction of evoked excitatory post synaptic potential recorded on both MSNs populations (direct and indirect pathways). In addition, we evaluate the impact of CCK2R antagonist on corticostriatal synaptic plasticity using Spike Timing Dependent Plasticity (STDP) protocols on MSNs of acute rat brain slices. Results demonstrate that the CCK2R antagonist is able to reverse the corticostriatal synaptic plasticity (i.e. LTP protocol leads to LTD). Finally, we evaluate the effect of CCK2R antagonist on the motor behavior of juvenile rats challenged with different locomotor tests and show a sex-dependent impairment of motor behavior. Overall, our results demonstrate that CCK and its receptor CCK2R are essential for inputs processing encoding in the corticostriatal network with consequences on motor activity. Significant statementCholecystokinin (CCK) is considered to be one of the most abundant neuropeptides in the brain but its role as a neuromodulator is not well understood. In our study we investigate its role on the corticostriatal transmission which is a well characterized synapse highly involved in motor and cognitive functions. Here, we show that CCK2R is crucial for the corticostriatal synaptic transmission and plasticity. Indeed, CCK binding on CCK2R is essential for LTP induction by STDP. Finally, we demonstrate that the blockage of CCK2R affects corticostriatal synaptic transmission and motor ability in male rats.