title: Developmental α₂-adrenergic regulation of noradrenergic synaptic facilitation at cerebellar GABAergic synapses.
abstract: In the central nervous system, the normal development of neuronal circuits requires adequate temporal activation of receptors for individual neurotransmitters. Previous studies have demonstrated that α₂-adrenoceptor (α₂-AR) activation eliminates spontaneous action potentials of interneurons in the cerebellar molecular layer (MLIs) and subsequently reduces the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in Purkinje cells (PCs) after the second postnatal week. The magnitude of the α₂-adrenergic reduction in sIPSC frequency is enhanced during the third postnatal week because of an increase in firing-derived sIPSCs. However, little is known about the effects of α₂-AR activation by noradrenaline (NA) on cerebellar GABAergic synaptic transmission that is accompanied by the activation of other AR subtypes, α₁- and β-ARs. Here, we developmentally examined the roles of α₂-AR activation in the noradrenergic facilitation of sIPSCs in cerebellar PCs. Until the second postnatal week, when substantial inhibitory effects of α₂-ARs are absent, NA potentiated sIPSCs and maintained the increased sIPSC frequency, suggesting that NA causes long-lasting facilitation of GABAergic synaptic transmission through α₁- and β-AR activation. After the second postnatal week, NA transiently increased the sIPSC frequency, whereas blocking α₂-ARs sustained the noradrenergic sIPSC facilitation and increase in the firing rate of MLIs, suggesting that α₂-AR activation suppresses the noradrenergic facilitation of GABAergic synaptic transmission. The simultaneous activation of α₁- and β-ARs by their specific agonists mimicked the persistent facilitation of sIPSC frequency, which required extracellular signal-regulated kinase 1/2 activation. These findings indicate that NA acts as a neurotrophic factor that strengthens GABAergic synaptic transmission in the developing cerebellar cortex and that α₂-ARs temporally restrain the noradrenergic facilitation of sIPSCs after GABAergic synaptogenesis.
authors.affiliation: Laboratory for Motor Learning Control, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan; Obata Research Unit, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan. Electronic address: mhirono@mail.doshisha.ac.jp.
authors.forename: M
authors.initials: M
authors.lastname: Hirono
authors.affiliation: Laboratory for Motor Learning Control, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Nagao
authors.affiliation: Obata Research Unit, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Obata
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D018663:Adrenergic Agents / Q000494:pharmacology; D059331:Adrenergic Neurons / Q000187:drug effects / Q000378:metabolism*; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002531:Cerebellum / Q000166:cytology* / Q000254:growth & development; D004347:Drug Interactions; D005260:Female; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009287:Naphthyridines / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
chemical_list: D018663:Adrenergic Agents; D007546:Isoquinolines; D009287:Naphthyridines; C104875:RS 79948-197; D018341:Receptors, Adrenergic, alpha-2
keywords: ACSF; AR; BDNF; EGTA; ERK; HCN; HEPES; IPSC; ISP; MEK; MLI; NA; PC; PE; PKA; PKC; Purkinje cell; TTX; TrkB; adrenoceptor; artificial cerebrospinal fluid; brain-derived neurotrophic factor; cAMP; cerebellar cortex; cyclic adenosine monophosphate; ethylene glycol tetraacetic acid; extracellular signal-regulated kinase; hydroxyethyl piperazineethanesulfonic acid; hyperpolarization-activated cyclic nucleotide-gated; interneuron; interneuron in the molecular layer; isoproterenol; mIPSC; miniature inhibitory postsynaptic current; mitogen extracellular regulating kinase; noradrenaline; phenylephrine; protein kinase A; protein kinase C; sIPSC; spontaneous inhibitory postsynaptic current; synergistic effect; tetrodotoxin; tyrosine kinase B