Excitatory effects of ACPD receptor activation in the hippocampus are mediated by direct effects on pyramidal cells and blockade of synaptic inhibition

Abstract

1. Phosphoinositide hydrolysis-linked excitatory amino acid (EAA) receptors (ACPD receptors) are selectively activated by the glutamate analogue trans-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD). Regional analysis of trans-ACPD-induced phosphoinositide hydrolysis indicates that this response is greater in the hippocampus than in other brain regions. Therefore we designed a series of studies aimed at testing the hypothesis that activation of this receptor modulates synaptic function in the hippocampal region. 2. We report that trans-ACPD dramatically altered field population spikes at each of the three major synapses in the hippocampal trisynaptic circuit at concentrations that are effective in activating phosphoinositide hydrolysis. At the perforant path-dentate gyrus synapse, bath application of trans-ACPD resulted in a decrease in the amplitude of field population spikes. In contrast, trans-ACPD markedly enhanced field population spike amplitude at the mossy fiber-CA3 synapse and the Schaffer collateral-CA1 synapse. In area CA1, but not area CA3, trans-ACPD also induced generation of multiple population spikes. 3. Simultaneous field potential recordings from the s. pyramidale and s. radiatum in area CA1 revealed that the effect of trans-ACPD on population spikes in this region was not accompanied by an increase in the initial slope of the field EPSP. This suggests that the effect of trans-ACPD was not mediated by a presynaptic action but must be mediated by direct effects on CA1 pyramidal cells or by a decrease in synaptic inhibition. 4. trans-ACPD had a number of direct excitatory effects on CA1 pyramidal cells. These included 1) cell depolarization (with an increase in input resistance), 2) inhibition of the slow afterhyperpolarization, and 3) blockade of spike frequency adaptation. trans-ACPD also had effects on CA1 pyramidal cells that were not excitatory in nature. These included an increase in the threshold for initiation of calcium spikes and an increase in interspike interval during prolonged current injection. None of these effects were mimicked by an ACPD analogue that does not activate the ACPD receptor (trans-methanoglutamate), nor were they blocked by kynurenate, a nonselective EAA receptor antagonist that does not block the ACPD receptor.(ABSTRACT TRUNCATED AT 400 WORDS)

Plasticity of Intrinsic Excitability during Long-Term Depression Is Mediated through mGluR-Dependent Changes inIhin Hippocampal CA1 Pyramidal Neurons

“…Previous reports of mGluR activation on CA1 pyramidal neuron excitability examined the changes in intrinsic properties during agonist application (Desai and Conn, 1991;Gereau and Conn, 1995). In contrast, we report persistent effects up to 30 min after either 3 Hz stimulation or DHPG application.…”

“…In contrast, we report persistent effects up to 30 min after either 3 Hz stimulation or DHPG application. Metabotropic glutamate receptor agonists can increase excitability by inhibiting several intrinsic potassium conductances including I AHP and I leak (Charpak et al, 1990;Desai and Conn, 1991;Gereau and Conn, 1995). Although we cannot exclude the possibility that the spike afterhyperpolarization is reduced, changes in I AHP cannot explain our results because I AHP does not contribute to any of the electrophysiological parameters altered after 3 Hz stimulation.…”

NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin

“…Phosphoinositide hydrolysis in cortical and hippocampal slices was measured as previously described (Desai and Conn, 1991;Conn and Wilson, 1991). Briefly, 300 m cross-chopped slices were labeled with [ 3 H]-inositol and agonist-induced accumulation of radioactivity in inositol phosphates during a 15-min incubation was measured.…”

Multiple Actions of 1S,3R-ACPD in Modulating Endogenous Synaptic Transmission to Spinal Respiratory Motoneurons

“…This is apparent in examining the effects of a broad spectrum agonist, trans-(Ϯ)-1-aminocyclopentane-1,3-dicarboxylic acid (trans-ACPD), on neuronal function. In hippocampal neurons, trans-ACPD increases neuronal excitability (Charpak et al, 1990;Desai and Conn, 1991) by inhibiting several K ϩ conductances, including a voltage-gated, a Ca 2ϩ -activated, and a Ba 2ϩ -sensitive tonically activated K ϩ conductance (Charpak et al, 1990;Guerineau et al, 1994). Activation of mGluRs can also attenuate synaptic transmission in, for example, hippocampus (Koerner and Cotman, 1981;Yamamoto et al, 1983;Forsythe and Clements, 1990;Baskys and Malenka, 1991;Gereau and Conn, 1995), nucleus of the tractus solitarius , cerebellum (Llano and Marty, 1995), and striatum (Lovinger and McCool, 1995); the responsible mGluRs may be located presynaptically.…”