Dopaminergic and Antipsychotic Modulation of Cerebellar Microcircuits in Mice: Insights from High-Density MEA Recordings

Alterations in the dopaminergic system is a central hypothesis for the pathophysiology of schizophrenia (SZ), particularly for cognitive dysfunction. While the cerebellum has emerged as a critical node in cognitive networks, the physiological mechanisms by which dopamine regulates cerebellar circuits remain poorly understood. Lobule VI, strongly implicated in cognitive control and consistently altered in SZ, provides an optimal model to address this question. This work investigates dopaminergic modulation of cerebellar cortical activity using acute in vitro slices of lobule VI from C57BL/6 wild-type mice. High-density multielectrode array (HD-MEA) recordings were employed to examine three levels of circuit function: (i) Purkinje cell output, (ii) mossy fiber–evoked granule cell responses, and (iii) long-term plasticity at mossy fiber–granule cell synapses. Exogenous dopamine application and selective antagonists of D1-like (SCH23390) and D2-like (sulpiride) receptors were used to dissect receptor-specific mechanisms. Clozapine, an atypical antipsychotic with unique efficacy in treatment-resistant SZ, was tested to evaluate its modulatory effects on basal activity and synaptic plasticity. Finally, developmental regulation was assessed by comparing long-term plasticity between young (P18–23) and adult (P60) mice. Taken together, our results reveal three mechanisms shaping cerebellar circuit function. First, dopamine enhances Purkinje cell excitability in a concentration-dependent manner, consistent with a role in fine-tuning cerebellar output and cognitive flexibility. Second, clozapine broadly suppressed evoked and spontaneous activity, reflecting its capacity to rebalance excitatory–inhibitory dynamics. Third, high-frequency stimulation (HFS) uncovered an age-dependent shift in granular layer plasticity, highlighting developmental regulation of excitability. Together, these findings suggest that cerebellar function arises from the interplay of plasticity, neuromodulation, and pharmacological intervention, offering new insights into its role in schizophrenia.