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Group III metabotropic glutamate receptor-mediated, chemically induced long-term depression differentially affects

Katja Naie¹, Sabine Gundimi, Herbert Siegmund

¹Synaptic Plasticity Research Group, Johannes Mueller Institute for Physiology, Charité, Berlin, Germany.

European Journal of Pharmacology

|March 21, 2006

Abstract:

In vivo, activation of group III metabotropic glutamate (mGlu) receptors leads to a reduction of basal synaptic transmission in the hippocampus, and depending on the experimental conditions in vitro, leads to neuroprotection or neurotoxicity. Here, the cellular response to cerebral application of L(+)-2-amino-4-phosphonobutanoic acid (AP4) was investigated in the CA1 region and dentate gyrus of freely moving rats. Drugs were applied via the lateral ventricle, and electrophysiological measurements were obtained via chronically implanted electrodes. AP4 produced a slowly developing depression of evoked responses in both hippocampal regions which lasted for over 4 h. Effects could be reversed by application of high frequency tetanus. Histological evaluation, 4 h or 7 d, following a single, acute AP4 injection into the lateral cerebral ventricle showed that AP4-mediated synaptic depression either amplified (CA1) or attenuated (dentate gyrus) excitotoxic neuronal death, strongly depending on the sub-region investigated. Effects were long-lasting, being still evident 7 days after AP4 application. In both hippocampal areas, the effects obtained were subtle, however, with the CA1 region being more potently affected. Interestingly, effects in the dentate gyrus comprised a slight enhancement of live cell number coupled with deterioration in cell area, suggesting that cell proliferation triggered by group III mGlu receptor activation may have masked neurotoxic effects mediated by activation of this receptor. These results show that although AP4 induces a slow-onset synaptic depression in both sub-regions, cell viability is differentially influenced by activation of group III mGlu receptors in the CA1 region and dentate gyrus.

Insights

Activation of group III metabotropic glutamate (mGlu) receptors with L(+)-2-amino-4-phosphonobutanoic acid (AP4) in rats caused long-lasting synaptic depression. AP4 differentially affected neuronal death in the hippocampus, with CA1 being more affected than the dentate gyrus.

Area of Science:

Neuroscience
Neuropharmacology
Cellular Biology

Background:

Group III metabotropic glutamate (mGlu) receptors modulate synaptic transmission.
In vitro studies show varied effects of group III mGlu receptor activation, including neuroprotection and neurotoxicity.
In vivo effects on synaptic transmission and cell viability in specific hippocampal sub-regions require further investigation.

Purpose of the Study:

To investigate the in vivo cellular and synaptic responses to L(+)-2-amino-4-phosphonobutanoic acid (AP4), a group III mGlu receptor agonist, in the rat hippocampus.
To determine the long-term effects of AP4 on synaptic transmission and neuronal viability in the CA1 region and dentate gyrus.
To elucidate the differential impact of group III mGlu receptor activation on excitotoxicity in distinct hippocampal sub-regions.

Main Methods:

Cerebral application of AP4 via the lateral ventricle in freely moving rats.
Electrophysiological recordings using chronically implanted electrodes to measure evoked responses.
Histological evaluation of neuronal survival and cell morphology at 4 hours and 7 days post-injection.

Main Results:

AP4 induced a slow-onset, long-lasting depression of evoked synaptic transmission in both the CA1 region and dentate gyrus.
AP4-mediated synaptic depression differentially modulated excitotoxic neuronal death: amplified in CA1 and attenuated in the dentate gyrus.
Effects were long-lasting, evident up to 7 days post-application, with the CA1 region showing greater sensitivity.

Conclusions:

Group III mGlu receptor activation by AP4 leads to sustained synaptic depression in the hippocampus.
Activation of group III mGlu receptors differentially influences neuronal viability in the CA1 region and dentate gyrus, suggesting region-specific roles.
Potential cell proliferation in the dentate gyrus may mask or counteract neurotoxic effects observed in the CA1 region.

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