State-dependent cAMP sensitivity of presynaptic function underlies metaplasticity in a hippocampal feedforward inhibitory circuit.
At hippocampal mossy fiber (MF)-st. lucidum interneuron (SLIN) synapses, mGluR7 serves as a metaplastic switch controlling bidirectional plasticity. mGluR7 activation during high-frequency stimulation (HFS) triggers presynaptic LTD due to persistent P/Q-type Ca(2+) channel inhibition. However, following mGluR7 internalization HFS produces presynaptic LTP. Surprisingly, LTP is not a simple molecular reversal of Ca(2+) channel depression. Rather, mGluR7 activation/internalization controls plasticity polarity by gating cAMP sensitivity of release. While naive surface mGluR7 expressing MF-SLIN synapses are insensitive to cAMP elevation, synapses that have internalized mGluR7 robustly potentiate following cAMP increases. Moreover, MF-SLIN LTP requires adenylate cyclase (AC) and protein kinase A (PKA) activities. We also discovered an association between mGluR7 and RIM1alpha, an active zone molecule required for AC/PKA-dependent presynaptic LTP. Importantly, the mGluR7-RIM1alpha interaction is regulated by mGluR7 activation, and mice lacking RIM1alpha are deficient in MF-SLIN LTP. We conclude that state-dependent cAMP sensitivity controlled by mGluR7-RIM1alpha interactions underlies MF-SLIN metaplasticity.
Pelkey
Kenneth A
KA
Laboratory of Cellular and Synaptic Neurophysiology, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA. pelkeyk2@mail.nih.gov
Topolnik
Lisa
L
Yuan
Xiao-Qing
XQ
Lacaille
Jean-Claude
JC
McBain
Chris J
CJ
D000818:Animals; D000831:Animals, Newborn; D000873:Anthracenes / Q000494:pharmacology; D001703:Biophysics; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000172:deficiency; D006624:Hippocampus / Q000166:cytology*; D047468:Immunoprecipitation / Q000379:methods; D007546:Isoquinolines / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000187:drug effects*; D011422:Propionates / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects* / Q000502:physiology
C520117:2,3-didecyloxyanthracene; C114785:2-amino-4-phosphono-propinate; D000873:Anthracenes; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D011422:Propionates; D018094:Receptors, Metabotropic Glutamate; C491490:Rims1 protein, mouse; D013449:Sulfonamides; C102719:metabotropic glutamate receptor 7; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D002118:Calcium