Journal qfNeurochernistry zyxwvutsrqponm Raven Press, Ltd., New York zyxwvutsrqpon 0 zyxwvutsrq 199 I International Society zyxwvutsrqponm for Neurochernistry Enhanced Sensitivity of “Metabotropic” Glutamate Receptors After Induction of Long-Term Potentiation in Rat Hippocampus E. Aronica, *U. Frey, TM. Wagner, TH. Schroeder, TM. Krug, zyx “f. Ruthrich, M. V. Catania, F. Nicoletti, and *K. G. Reymann insfitute of Pharmacology, University zyxwvut of Catania, School ofMedicine, Catania, Italy; and *Institute o f Neurobiology and Brain Research, Academy of Sciences, and ?Institute of Pharmacology and Toxicolom, Medical Academy, Magdeburg, zyxwvu F.R.G. Abstract: Stimulation of [3H]inositol monophosphate ( [3H]InsP) formation by ibotenate or trans- 1 -aminocyclo- pentyl- 1,3-dicarboxylic acid (t-ACPD) in rat hippocampal slices was enhanced after tetanic stimulation of the SchaRer collaterals projecting to the CA 1 region (in vitro) or the per- forant pathway projecting to the dentate gyrus (in freely moving animals). This effect was observed 5 h (but not 2 h) after long-term potentiation (LTP) induction and was abol- ished if tetanic stimulation was performed in the presence of specific antagonists of N-methyl-D-aspartate receptors. The delayed increase in excitatory amino acid-induced poly- phosphoinositide (PPI) hydrolysis was accompanied by an enhanced responsivenessto norepinephrine, whereas the basal and carbamylcholine-stimulated [3H]InsP formation were unchanged. These results suggest that an increased activity of “metabotropic” glutamate receptors may contribute to the synaptic mechanisms enabling the late expression and or maintenance of LTP. Accordingly, LTP decayed more rapidly (within 5 h) in rats repeatedly injected with LiCl (60-120 mg/kg, i.p., for 10 days), a treatment that led to a reduced efficacy of ibotenate and norepinephrine in stimulating PPI hydrolysis in hippocampal slices. Key Words: Glutamate- Phosphoinositides-Long-term potentiation-Hippocam- pus. Aronica E. et al. Enhanced sensitivity of “metabotropic” glutamate receptors after induction of long-term potentiation in rat hippocampus. J. Neurochem. 57, 376-383 (1991). Specific excitatory amino acid (EAA) receptors cou- pled to polyphosphoinositide (PPI) hydrolysis (“me- tabotropic receptors”) have been described in the CNS (reviewed in Sladeczek et al., 1988). In brain slices, metabotropic receptors are activated by ibotenate, trans- 1 -aminocyclopentyl- 1,3-dicarboxylic acid (t- ACPD), quisqualate, or glutamate, but not by a-amino- zyxwv 3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA), N-methyl-D-aspartate (NMDA), or kainate, and selec- tively antagonized by 2-amino-3-phosphonopropion- ate, 2-amino-4-phosphonobutanoate (AP4), or serine- 0-phosphate (Nicoletti et al., 198646; Schoepp and Johnson, 1988, 1989; Palmer et al., 1989). The sensi- tivity of metabotropic receptors to EAAs is high during early postnatal life and then progressively declines with Received June 26, 1990: final revised manuscript received Decem- ber 5, 1990; accepted January 3, 1991. Address correspondence and reprint requests to Dr. F. Nicoletti at Institute of Pharmacology, University of Catania, School of Med- icine, viale A. Dona 6, 95 125 Catania, Italy. Abbreviations zyxwvutsrqpo used: t-ACPD, trans-aminocyclopentyl- 1,3-dicar- boxylic acid; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolpro- increasing age (Nicoletti et al., 1986b; Guiramand et al., 1989; Dudek t:t al., 1989; Schoepp and Hillman, 1990),suggesting that stimulation of PPI hydrolysis by glutamate is involved in developmental plasticity. In kitten visual cortex, ibotenate-stimulated PPI hydro- lysis is enhanced between 3 and 5 weeks after birth, a time that corresponds to the “critical” period for syn- aptic modification (Dudek and Bear, 1989).The tran- sient rise in ibotenate-stimulated PPI hydrolysis is abolished when kittens are reared in complete darkness (Dudek and Bear, 1989),suggestingthat changes in the sensitivity of metabotropic receptors are in relation to activity-dependeni modification of synaptic efficacy. In support of this hypothesis, we now report that the responsiveness of metabotropic receptors to EAAs is pionate; AP4, 2-amino-4-phosphonobutanoate; AP5, 2-amino-5- phosphonopentanoate; AP7, 2-amino-7-phosphonoheptanoate: EAA, excitatory amino acid; EPSP, excitatory postsynaptic potential; InsP, inositol monophospha te; InsP,, inositol trisphosphate; LTP, long- term potentiation; NMDA, N-methyla-aspartate; PKC, protein ki- nase C: PPI, polyphosphoinositide; PS, population spike. 3 76