mGluR1-mediated facilitation of long-term potentiation at inhibitory synapses on a cerebellar Purkinje neuron.
Synaptic plasticity has been studied extensively at excitatory synapses, whereas studies on plasticity at GABAergic inhibitory synapses have been limited. In the rat cerebellar cortex, postsynaptic depolarization of a Purkinje neuron (PN) induces long-term potentiation of GABA(A) receptor (GABA(A)R) responsiveness (termed rebound potentiation; RP). Induction of RP requires an increase in intracellular Ca(2+) concentration and resultant activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). We previously reported that GABA(B) receptor (GABA(B)R) activation coupled with depolarization suppresses RP induction by facilitating protein phosphatase 1 (PP-1)-mediated inhibition of CaMKII through down-regulation of cAMP-dependent protein kinase A (PKA) activity. Here, we examined the involvement of metabotropic glutamate receptor type 1 (mGluR1) in RP regulation. RP was monitored with the amplitudes of either the current responses to GABA or miniature inhibitory postsynaptic currents recorded from a PN in a primary culture or in a cerebellar slice. Inhibition of mGluR1 by an antagonist, 7(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate-ethyl-ester (CPCCOEt), prevented RP induction, which was abolished either by activation of adenylyl cyclase or by inhibition of PP-1. Furthermore, mGluR1 inhibition impaired depolarization-induced CaMKII activation. By contrast, activation of mGluR1 by the agonist (R,S)3,5-dihydroxyphenylglycine (DHPG) rescued RP induction from its suppression by GABA(B)R activation. The rescue was impaired either by inhibition of PKA or by facilitation of PP-1 activity. In addition, mGluR1 activation counteracted the GABA(B)R-mediated CaMKII inhibition. Taken together, these results suggest that mGluR1 activity counteracts GABA(B)R activity and contributes to RP induction through PKA activation, down-regulation of PP-1 and up-regulation of CaMKII.
Sugiyama
Yuko
Y
Department of Biophysics, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
Kawaguchi
Shin-ya
SY
Hirano
Tomoo
T
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D054645:Protein Phosphatase 1 / Q000378:metabolism; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*
C117789:7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester; D002867:Chromones; D018080:Receptors, GABA-B; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D008734:Methoxyhydroxyphenylglycol; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054645:Protein Phosphatase 1; C010117:3,4-dihydroxyphenylglycol