Neuropharmacology. 2026 Apr 23. pii: S0028-3908(26)00166-8. [Epub ahead of print]
110993
The gut hormone glucagon-like peptide 1 (GLP-1) is a key contributor to the controls of food intake and reward processing. GLP-1 receptors (GLP-1R) are widely expressed throughout the central nervous system where their signaling alters neuronal excitability, resulting in suppressed food intake and reward. Recent studies have shown GLP-1R expression in Purkinje cells (PCs) within the cerebellum, a region gathering increasing appreciation for its role in sensory processing and appetitive behaviors. Importantly, the cerebellum responds to feeding signals and directly projects to key mesolimbic nuclei that initiate appetitive behaviors, including food intake. What remains unknown is if GLP-1Rs are expressed in other cell types of the cerebellum and the extent to which their activation produces neurophysiological changes. Here we combined RT-qPCR, RNAscope and immunohistochemistry with functional electrophysiology to map GLP-1R expression and signaling across the lobes and cell types of the cerebellar cortex of male/female C57BL/6N mice. We found that GLP-1Rs were nearly evenly expressed across all cerebellar lobes at the level of the vermis, as well as densely expressed in the deep cerebellar nuclei. At the cellular level, we found significant GLP-1R expression in granule cells (GCs) and GC-innervating mossy fibers, in addition to the previously reported expression in the PCs. Functionally, application of the GLP-1R agonist exendin-4 increased the frequency of spontaneous glutamate release on to the majority of recorded GCs and enhanced action potential firing in PCs. Together these results demonstrate broad expression of functional GLP-1R across cerebellar lobes which enhance synaptic transmission through the cerebellar cortex.
Keywords: Cerebellum; GLP-1R; Purkinje cell; exendin-4; glutamate; granule cell; mossy fiber