Abstract
Synaptic long-term depression (LTD) is believed to underlie critical mnemonic processes in the adult hippocampus. The roles of the metabotropic and ionotropic actions of glutamate in the induction of synaptic LTD by electrical low-frequency stimulation (LFS) in the living adult animal is poorly understood. Here we examined the requirement for metabotropic glutamate (mGlu) and NMDA receptors in LTD induction in anaesthetized adult rats. LTD induction was primarily dependent on NMDA receptors and required the involvement of both the ion channel function and GluN2B subunit of the receptor. Endogenous mGlu5 receptor activation necessitated the local application of relatively high doses of either competitive or non-competitive NMDA receptor antagonists to block LTD induction. Moreover, boosting endogenous glutamate activation of mGlu5 receptors with a positive allosteric modulator lowered the threshold for NMDA receptor-dependent LTD induction by weak LFS. The present data provide support in the living animal that NMDA receptor-dependent LTD is boosted by endogenously released glutamate activation of mGlu5 receptors. Given the predominant perisynaptic location of mGlu5 receptors, the present findings emphasize the need to further evaluate the contribution and mechanisms of these receptors in NMDA receptor-dependent synaptic plasticity in the adult hippocampus in vivo.
Highlights
Elucidation of the mechanisms of long-term potentiation (LTP) and long-term depression (LTD) provide a means of understanding synaptic plasticity processes that are believed to underlie information storage processes in learning and memory[1,2,3]
Of electrically evoked field excitatory postsynaptic potentials by low-frequency stimulation (LFS), consisting of 900 high-intensity pulses at 1 Hz, was not blocked by standard systemic doses of either NMDA receptor (NMDAR) or mGlu5R antagonists when applied alone[19], we wondered if both types of receptors needed to be blocked simultaneously
Consistent with our previous finding[19], using a dose (10 mg/kg, i.p.) of the competitive NMDAR antagonist CPP known to completely inhibit synaptic LTP in the CA1 area[22], the application of LFS after injection of CPP induced robust and stable synaptic LTD similar in magnitude to that induced in control, vehicle-injected rats (Fig. 1a,b)
Summary
Elucidation of the mechanisms of long-term potentiation (LTP) and long-term depression (LTD) provide a means of understanding synaptic plasticity processes that are believed to underlie information storage processes in learning and memory[1,2,3]. The ability of the ion channel of the NMDAR to conduct Ca2+ currents over prolonged periods was considered fundamental for the induction of NMDAR-dependent LTD by the standard low-frequency conditioning stimulation protocol (LFS, 1 Hz). A major other form of synaptically evoked hippocampal LTD, usually induced by paired-pulse LFS, is mGluR-dependent and has been reported to operate via distinct signaling pathways[7,8,9] This apparent dichotomy may only be valid under conditions where either one or other of these glutamate receptors is activated alone[9,10]. The GluN2B subunit and a functional ion channel in NMDARs were obligatory for such LTD induction in vivo
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