The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK.
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.
Department of Pharmacy, University of Naples Federico II, Naples, Italy.
Pellegrino
P
Lippiello
Department of Neuroscience, University of Torino, Torino, Italy; Neuroscience Institute Cavalieri Ottolenghi (NICO), Torino, Italy.
Eriola
E
Hoxha
Institute of Genetics and Biophysics "Adriano Buzzati Traverso", CNR, Naples, Italy.
Luisa
L
Speranza
Department of Pharmacy, University of Naples Federico II, Naples, Italy; Institute of Genetics and Biophysics "Adriano Buzzati Traverso", CNR, Naples, Italy.
Floriana
F
Volpicelli
Department of Pharmacy, University of Naples Federico II, Naples, Italy.
Angela
A
Ferraro
Department of Pharmacy - Drug Science, University of Bari "A. Moro", Italy.
Marcello
M
Leopoldo
Department of Pharmacy - Drug Science, University of Bari "A. Moro", Italy.
Enza
E
Lacivita
Department of Pharmacy, University of Naples Federico II, Naples, Italy; Institute of Genetics and Biophysics "Adriano Buzzati Traverso", CNR, Naples, Italy.
Carla
C
Perrone-Capano
Department of Neuroscience, University of Torino, Torino, Italy; Neuroscience Institute Cavalieri Ottolenghi (NICO), Torino, Italy.
Filippo
F
Tempia
Department of Pharmacy, University of Naples Federico II, Naples, Italy. Electronic address: maria.miniaci@unina.it.
Maria Concetta
MC
Miniaci
D000818:Animals; D002525:Cerebellar Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; C573815:N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide; D010879:Piperazines; D011985:Receptors, Serotonin; D018490:Serotonin Agents; C104425:serotonin 7 receptor; D011493:Protein Kinase C; D020930:MAP Kinase Kinase Kinases
5-HT7 receptor; Cerebellum; Long-term depression; Purkinje cell; Serotonin; Synaptic transmission