RAPID COMMUNICATION Loss of Long-Lasting Potentiation Mediated by Group III mGluRs in Amygdala Neurons in Kindling-Induced Epileptogenesis

Neugebauer, Volker, N. Bradley Keele, and Patricia Shinnicklong-term effects of seizures, including intractable epilepsies Gallagher. Loss of long-lasting potentiation mediated by group and memory disorders (Sutula et al. 1995). III mGluRs in amygdala neurons in kindling-induced epileptogenThe G-protein coupled metabotropic glutamate receptors esis. J. Neurophysiol. 78: 3475–3478, 1997. Long-lasting modi(mGluRs) consist of eight subtypes, which, on the basis of fications of synaptic transmission can be induced in the amygdala sequence homology, signal transduction mechanisms, and by electrical stimulation as done in the long-term potentiation pharmacological profile, are classified into groups I, II, and (LTP) model of learning and memory and the kindling model of III (Knöpfel et al. 1995; Pin and Duvoisin 1995). Postsynepilepsy. The present study reports for the first time a long-lasting aptically, group I mGluRs are up-regulated in kindled basopotentiation (LLP) of synaptic transmission that is induced pharlateral amygdala (BLA) neurons whereas group II mGluRs macologically by the activation of group III metabotropic glutamate receptors (mGluRs) in basolateral amygdala (BLA) neurons. are downregulated (Holmes et al. 1996). Presynaptically, In whole cell voltage-clamp mode, BLA neurons were recorded activation of groups II and III mGluRs depresses synaptic in brain slices from control rats and rats with amygdala-kindled transmission in control BLA neurons; in kindled neurons seizures. The group III mGluR agonist L-2-amino-4-phosphonobuthis inhibitory effect is enhanced 30-fold (Neugebauer et tyrate (L-AP4, 10 mM) induced LLP of monosynaptic excitatory al. 1997). postsynaptic currents (EPSCs) evoked by electrical stimulation in Here we report a novel pharmacologically induced form the lateral amygdala (maximum 258 { 50% of predrug control; of long-lasting potentiation (LLP) of excitatory synaptic means { SE) in control (n Å 7) but not in kindled neurons transmission in the BLA after the activation of group III but (nÅ 6). LLP was measured 15 min after the superfusion of L-AP4, not group II mGluRs. Importantly, this pharmacologically lasted for ú45 min, and was not accompanied by postsynaptic induced LLP is lost in kindled neurons. Although it is presmembrane changes. L-AP4 induced LLP was prevented by the group III mGluR antagonist (S)-2-methyl-2-amino-4-phosphonoently unclear how this form of LLP relates to the established butyrate (MAP4; 100 mM, n Å 6) but not the group II mGluR LTP model of learning and memory, the loss of pharmacoantagonist (2S,3S,4S)-2-methyl-2-carboxycyclopropylglycine logically induced LLP in kindled neurons may be relevant (MCCG; 100 mM, nÅ 3). LLP was not observed after superfusion for the learning and memory deficits in kindled animals and of the group II mGluR agonist (2S,3S,4S)-2-(carboxycyclopropatients with epilepsies. pyl)glycine (L-CCG; 1.0 and 10 mM) in either control (n Å 13) or kindled (n Å 10) neurons. If the underlying mechanisms and