The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK

• 5-HT7R activation induces LTD of parallel fiber-Purkinje cell synapse.
• 5-HT7R-induced depression requires postsynaptic activation of PKC and MAPK.
• 5-HT7R activation blocks LTP induced by 1 Hz parallel fiber stimulation.
• 5-HT7R antagonist impairs LTD produced by PF stimulation plus PC depolarization.
• We provide a novel mechanism by which serotoninergic inputs shape cerebellar network.

The 5-HT7 receptor (5-HT7R) mediates important physiological effects of serotonin, such as memory and emotion, and is emerging as a therapeutic target for the treatment of cognitive disorders and depression. Although previous studies have revealed an expression of 5-HT7R in cerebellum, particularly at Purkinje cells, its functional role and signaling mechanisms have never been described. Using patch-clamp recordings in cerebellar slices of adult mice, we investigated the effects of a selective 5-HT7R agonist, LP-211, on the main plastic site of the cerebellar cortex, the parallel fiber-Purkinje cell synapse. Here we show that 5-HT7R activation induces long-term depression of parallel fiber-Purkinje cell synapse via a postsynaptic mechanism that involves the PKC-MAPK signaling pathway. Moreover, a 5-HT7R antagonist abolished the expression of PF-LTD, produced by pairing parallel fiber stimulation with Purkinje cell depolarization; whereas, application of a 5-HT7R agonist impaired LTP induced by 1 Hz parallel fiber stimulation. Our results indicate for the first time that 5-HT7R exerts a fine regulation of cerebellar bidirectional synaptic plasticity that might be involved in cognitive processes and neuropsychiatric disorders involving the cerebellum.

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