Emotional memory processing, such as fear memory, engages a large neuronal network of brain regions including the cerebellum. However, the molecular and cellular mechanisms of the cerebellar cortex modulating the fear memory network is largely unknown. Here, we illustrate a novel mechanism by which synaptic signaling in cerebellar Purkinje cells (PCs) via STAT3 regulates long-term fear memory. Firstly, we generated PC-specific STAT3 knockout (STAT3PKO) mice. Transcriptome analyses revealed that STAT3 deletion results in transcriptional changes that lead to an increase in the expression of glutamate receptors. The amplitude of AMPA receptor-mediated excitatory postsynaptic currents at parallel fiber to PC synapses was larger in STAT3PKO mice than in wild-type littermates. Conditioning at the parallel fiber induced long-term depression of parallel fiber-PC synapses in STAT3PKO mice while the same manipulation induced long-term potentiation in wild-type littermates. Interestingly, STAT3PKO mice showed an aberrantly enhanced long-term fear memory. Neuronal activity in fear-related regions increased in fear-conditioned STAT3PKO mice. Our data suggest that STAT3-dependent molecular regulation in PCs is indispensable for proper expression of fear memory processing.
bioRxiv Subject Collection: Neuroscience