Hippocampal NMDA receptors are important for behavioural inhibition but not for encoding associative spatial memories

Abstract

The idea that an NMDA receptor (NMDAR)-dependent long-term potentiation-like process in the hippocampus is the neural substrate for associative spatial learning and memory has proved to be extremely popular and influential. However, we recently reported that mice lacking NMDARs in dentate gyrus and CA1 hippocampal subfields (GluN1ΔDGCA1 mice) acquired the open field, spatial reference memory watermaze task as well as controls, a result that directly challenges this view. Here, we show that GluN1ΔDGCA1 mice were not impaired during acquisition of a spatial discrimination watermaze task, during which mice had to choose between two visually identical beacons, based on extramaze spatial cues, when all trials started at locations equidistant between the two beacons. They were subsequently impaired on test trials starting from close to the decoy beacon, conducted post-acquisition. GluN1ΔDGCA1 mice were also impaired during reversal of this spatial discrimination. Thus, contrary to the widely held belief, hippocampal NMDARs are not required for encoding associative, long-term spatial memories. Instead, hippocampal NMDARs, particularly in CA1, act as part of a comparator system to detect and resolve conflicts arising when two competing, behavioural response options are evoked concurrently, through activation of a behavioural inhibition system. These results have important implications for current theories of hippocampal function.

G Protein-Gated K + Channel Ablation in Forebrain Pyramidal Neurons Selectively Impairs Fear Learning

“…Moreover, genetic ablation of GluN1-containing NMDARs in forebrain pyramidal neurons correlates with decreased GIRK2 protein levels in cortical synaptic membranes (5). And, similar to our observations in CaMKII-Cre(+): Girk2 flox/flox mice, loss of GluN1-containing NMDAR channels in forebrain pyramidal neurons leaves spatial learning and memory in intact, but impairs other forms of hippocampal-dependent cognition (80, 81). Altogether, these data suggest that the deficit in contextual fear learning seen in CaMKII-Cre(+): Girk2 flox/flox mice may reflect in part alterations in NMDAR levels and/or function.…”

Human Hippocampal Dynamics during Response Conflict

“…Furthermore, conflicts can occur on the response level. Animal experiments showed a role of the hippocampus for inhibition of prevailing response tendencies and suppression of automatic stimulus-response mappings [14][15][16][17], potentially related to increased theta oscillations (3)(4)(5)(6)(7)(8) [18]. In humans, a recent fMRI study demonstrated hippocampal involvement in approach-avoidance conflicts [19].…”

“…Animal experiments indicate that the hippocampus plays a role in the inhibition of established response patterns [14][15][16][17][18].…”

Hippocampal synaptic plasticity, spatial memory and anxiety

“…There was no deficit in the Grin1 ΔDGCA1 mice during this acquisition phase. However, they were then subsequently impaired during probe trials starting from close to the decoy beacon (S-trials) 52 . Thus, Grin1 ΔDGCA1 mice are unable to use the spatial information provided by the extramaze cues to inhibit a conditioned, but inappropriate, behavioural tendency to approach any beacon that looks correct.…”