Hippocampal long-term depression is required for the consolidation of spatial memory

Abstract

Although NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD) of glutamatergic transmission are candidate mechanisms for long-term spatial memory, the precise contributions of LTP and LTD remain poorly understood. Here, we report that LTP and LTD in the hippocampal CA1 region of freely moving adult rats were prevented by NMDAR 2A (GluN2A) and 2B subunit (GluN2B) preferential antagonists, respectively. These results strongly suggest that NMDAR subtype preferential antagonists are appropriate tools to probe the roles of LTP and LTD in spatial memory. Using a Morris water maze task, the LTP-blocking GluN2A antagonist had no significant effect on any aspect of performance, whereas the LTD-blocking GluN2B antagonist impaired spatial memory consolidation. Moreover, similar spatial memory deficits were induced by inhibiting the expression of LTD with intrahippocampal infusion of a short peptide that specifically interferes with AMPA receptor endocytosis. Taken together, our findings support a functional requirement of hippocampal CA1 LTD in the consolidation of long-term spatial memory.hippocampus | learning and memory | long-term potentiation | AMPA receptor endocytosis | Morris water maze T he hippocampus plays crucial roles in encoding and consolidating memory (1, 2). Activity-dependent plasticity of hippocampal glutamatergic synapses, particularly NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) and longterm depression (LTD), has been proposed as the primary cellular substrate for fulfilling these cognitive functions (3, 4). Indeed, formation of long-term spatial memory in the Morris water maze (MWM) can be impaired by preventing NMDAR activation using either pharmacological or genetic approaches (5-7). However, blocking NMDARs affects both LTP and LTD (8, 9), making it hard to attribute the observed spatial memory deficits to selective disruption of either LTP or LTD. Recent attempts using transgenic mice with deficits in either LTP (10-12) or LTD (13-15) have achieved some success in delineating the contribution of these two opposing forms of plasticity in memory formation. However, results obtained from transgenic studies are equivocal, perhaps because of structural alterations and/or functional compensatory changes at synapses that often arise after prolonged genetic alterations (14). Thus, determining the exact roles of hippocampal LTP and/or LTD in spatial memory requires new experimental approaches that enable acute, selective inhibition of LTP or LTD in freely moving animals.Evidence accumulated from recent studies suggests that GluN2A-and GluN2B-containing NMDARs preferentially contribute to the induction of hippocampal LTP and LTD in vitro (12,16,17) and in vivo (18). For example, the GluN2A preferential antagonist NVP-AAM077 (NVP) (19) and the GluN2B-specific antagonist Ro25-6981 (Ro) (20) selectively inhibit LTP and LTD, respectively, in anesthetized rats (18,21). If such GluN2 subunitselective requirements for LTP and LTD can be shown in freely moving ...

Cofilin under control of β-arrestin-2 in NMDA-dependent dendritic spine plasticity, long-term depression (LTD), and learning

“…solidation (46). These findings suggest that changes in LTD may underlie the impaired spatial learning in β-arrestin-2 KO mice.…”

Inhibition of learning and memory by general anesthetics

“…94,100 The opposite process, long-term depression of synaptic strength, is also necessary and is normally involved in memory storage. 101,102 Both the strengthening and weakening of synapses between neurons are involved in the reshaping of the neural network and the encoding of a novel engram. 103 Anesthetics modify a wide variety of neurotransmitter systems that influence synaptic plasticity, including the glutamatergic, GABAergic, cholinergic, and serotonergic neurotransmitter systems, among others.…”

Long-term potentiation decay and memory loss are mediated by AMPAR endocytosis

“…In order to make the correlation of electrophysiological characterizations more relevant to behavioral analyses of memory maintenance, we studied both decaying LTP and nondecaying LTP using an in vivo model of hippocampal synaptic plasticity in freely moving adult rats (20,21). Schaffer collateral stimulation-induced field excitatory postsynaptic potentials (fEPSPs) were recorded from the CA1 region.…”