Young SR, Bianchi R, Wong RK. Signaling mechanisms underlying group I mGluR-induced persistent AHP suppression in CA3 hippocampal neurons. Activation of group I metabotropic glutamate receptors (mGluRs) leads to a concerted modulation of spike afterpotentials in guinea pig hippocampal neurons including a suppression of both medium and slow afterhyperpolarizations (AHPs). Suppression of AHPs may be long-lasting, in that it persists after washout of the agonist. Here, we show that persistent AHP

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... uppression differs from short-term, transient suppression in that distinct and additional signaling processes are required to render the suppression persistent. Persistent AHP suppression followed DHPG application for 30 min, but not DHPG application for 5 min. Persistent AHP suppression was temperature dependent, occurring at 30 -31°C, but not at 25-26°C. Preincubation of slices in inhibitors of protein synthesis (cycloheximide or anisomycin) prevented the persistent suppression of AHPs by DHPG. Similarly, preincubation of slices in an inhibitor of p38 MAP kinase (SB 203580) prevented persistent AHP suppression. In contrast, a blocker of p42/44 MAP kinase activation (PD 98059) had no effect on persistent AHP suppression. Additionally, we show that the mGluR5 antagonist MPEP, but not the mGluR1 antagonist LY 367385, prevented DHPG-induced persistent AHP suppression. Thus persistent AHP suppression by DHPG in hippocampal neurons requires activation of mGluR5. In addition, activation of p38 MAP kinase signaling and protein synthesis are required to impart persistence to the DHPGactivated AHP suppression. PL, Pennefather PS. Metabotropic glutamate receptors coupled to IP 3 production mediate inhibition of I AHP in rat dentate granule neurons. J Neurophysiol 76: 2691-2700, 1996a. Abdul-Ghani MA, Valiante TA, Carlen PL, Pennefather PS. Tyrosine kinase inhibitors enhance a Ca 2ϩ -activated K ϩ current (I AHP ) and reduce I AHP suppression by a metabotropic glutamate receptor agonist in rat dentate granule neurones. Anwyl R. Metabotropic glutamate receptors: electrophysiological properties and role in plasticity. Brain Res Rev 29: 83-120, 1999. Anwyl R. Induction and expression mechanisms of postsynaptic NMDA receptor-independent homosynaptic long-term depression. Prog Neurobiol 78: 17-37, 2006. Arvanov VL, Holmes KH, Keele NB, Shinnick-Gallagher P. The functional role of metabotropic glutamate receptors in epileptiform activity induced by 4-aminopyridine in the rat amygdala slice. Brain Res 669: 140 -144, 1995. Banko JL, Hou L, Poulin F, Sonenberg N, Klann E. Regulation of eukaryotic initiation factor 4E by converging signaling pathways during metabotropic glutamate receptor-dependent long-term depression. J Neurosci 26: 2167-2173, 2006. Bianchi R, Wong RKS. Excitatory synaptic potentials dependent on metabotropic glutamate receptor activation in guinea-pig hippocampal pyramidal cells. J Physiol 487: 663-676, 1995. Bianchi R, Young SR, Wong RKS. Group I mGluR activation causes voltage-dependent and -independent Ca 2ϩ rises in hippocampal pyramidal cells. J Neurophysiol 81: 2903-2913, 1999. Bolshakov VY, Carboni L, Cobb MH, Siegelbaum SA, Belardetti F. Dual MAP kinase pathways mediate opposing forms of long-term plasticity at CA3-CA1 synapses. Nat Neurosci 3: 1107-1112, 2000. Bortolotto ZA, Fitzjohn SM, Collingridge GL. Roles of metabotropic glutamate receptors in LTP and LTD in the hippocampus. Curr Opin Neurobiol 9: 299 -304, 1999. Chuang SC, Bianchi R, Kim D, Shin HS, Wong RKS. Group I metabotropic glutamate receptors elicit epileptiform discharges in the hippocampus through PLC␤1 signaling. J Neurosci 21: 6387-6394, 2001. Chuang SC, Zhao W, Bauchwitz R, Yan Q, Bianchi R, Wong RKS. Prolonged epileptiform discharges induced by altered group I metabotropic glutamate receptor-mediated synaptic responses in hippocampal slices of a fragile X mouse model. J Neurosci 25: 8048 -8055, 2005. Chuang SC, Zhao W, Young SR, Conquet F, Bianchi R, Wong RKS. Activation of group I mGluRs elicits different responses in murine CA1 and CA3 pyramidal cells. J Physiol 541: 113-121, 2002. Cohen AS, Coussens CM, Raymond CR, Abraham WC. Long-lasting increase in cellular excitability associated with the priming of LTP induction in rat hippocampus. J Neurophysiol 82: 3139 -3148, 1999. Cooper EC, Aldape KD, Abosch A, Barbaro NM, Berger MS, Peacock WS, Jan YN, Jan LY. Colocalization and coassembly of two human brain M-type potassium channel subunits that are mutated in epilepsy. Proc Natl Acad Sci USA 97: 4914 -4919, 2000. Cuenda A, Rouse J, Doza YN, Meier R, Cohen P, Gallagher TF, Young PR, Lee JC. SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Lett 364: 229 -233, 1995. Desai MA, Conn PJ. Excitatory effects of ACPD receptor activation in the GROUP I mGluR-INDUCED PERSISTENT AHP SUPPRESSION J Neurophysiol • VOL 99 • MARCH 2008 • www.jn.org