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The involvement of metabotropic glutamate receptors in the induction of long-term potentiation in the medial frontal cortex of the rat

Morris, Shanida Helena; (1999) The involvement of metabotropic glutamate receptors in the induction of long-term potentiation in the medial frontal cortex of the rat. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Activity-dependent changes in the efficacy of synaptic transmission in the medial frontal cortex, namely long-term potentiation (LTP) and long-term depression (LTD), can persist for tens of minutes or hours and may be the neural basis of learning and memory. Glutamate is the principle excitatory neurotransmitter in the CNS. It acts on both ionotropic receptors that directly gate ion channels, and on metabotropic receptors (mGluRs) that exert their effects indirectly through second messenger cascades. I have investigated the involvement of mGluRs in the induction of LTP in the medial frontal cortex in vitro. The medial frontal cortex receives inputs from hippocampal regions in which neurones fire at theta frequencies when rats move in or explore their environment. We first established that repetitive bursts of stimulation at theta frequencies were an effective conditioning paradigm for inducing LTP. Intracellular recordings were made from layer V cells. Test shocks were applied to the layer I/II border. The involvement of mGluRs was investigated using the broad-spectrum antagonist (R,S)-α-methyl-4-carboxyphenylglycine (MCPG). This drug reduced the incidence of LTP at layer V synapses indicating mGluR involvement in LTP induction. We demonstrated that mGluRs were located on layer V cells in the medial frontal cortex by bath application of mGluR agonists. All produced excitatory effects in layer V cells, even when synaptic transmission was blocked using the GABAB agonist, baclofen. We investigated the effect of MCPG on test and conditioned responses. The drug had no significant effect on either. It was seen, however, to reduce the amplitude of a NMDA receptor mediated EPSP isolated using 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), low Mg2+ and higher stimulus intensities than those used in LTP induction. This suggests that the block of LTP induction by MCPG is unlikely to be the consequence of modulation of layer V electrophysiology. Activation of group I mGluRs leads to the production of IP3, which facilitates the release of Ca2+ from intracellular stores. In Ca2+ imaging experiments, intracellular Ca2+ was monitored in both hippocampal and medial frontal cortical neurones in culture using the indicator Fura-2. Application of selective group I agonists raised intracellular Ca2+, even in zero Ca2+ medium. This rise was inhibited by both MCPG and the group I specific antagonist (S)-4-carboxyphenylglycine (S-4CPG). These observations suggest the effect of MCPG on the incidence of LTP is, at least in part, the result of its ability to dampen the IP3-mediated rise in [Ca2+] triggered by mGluR activation. The effect of the group I specific agonist DHPG on the induction of LTP was then investigated. TBS alone produced no net change in the field response in layer V of medial frontal cortex in vitro. DHPG alone reversibly reduced the field response. TBS in conjunction with bath application of DHPG produced LTP of the field response. Activation of group I mGluRs therefore facilitates the induction of LTP in prelimbic cortex.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The involvement of metabotropic glutamate receptors in the induction of long-term potentiation in the medial frontal cortex of the rat
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Frontal cortex
URI: https://discovery.ucl.ac.uk/id/eprint/10103511
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