Loss of GluN2B-Containing NMDA Receptors in CA1 Hippocampus and Cortex Impairs Long-Term Depression, Reduces Dendritic Spine Density, and Disrupts Learning

Abstract

NMDA receptors (NMDARs) are key mediators of certain forms of synaptic plasticity and learning. NMDAR complexes are heteromers composed of an obligatory GluN1 subunit and one or more GluN2 (GluN2A-GluN2D) subunits. Different subunits confer distinct physiological and molecular properties to NMDARs, but their contribution to synaptic plasticity and learning in the adult brain remains uncertain. Here, we generated mice lacking GluN2B in pyramidal neurons of cortex and CA1 subregion of hippocampus. We found that hippocampal principal neurons of adult GluN2B mutants had faster decaying NMDAR-mediated EPSCs than nonmutant controls and were insensitive to GluN2B but not NMDAR antagonism. A subsaturating form of hippocampal long-term potentiation (LTP) was impaired in the mutants, whereas a saturating form of LTP was intact. An NMDAR-dependent form of long-term depression (LTD) produced by low-frequency stimulation combined with glutamate transporter inhibition was abolished in the mutants. Additionally, mutants exhibited decreased dendritic spine density in CA1 hippocampal neurons compared with controls. On multiple assays for corticohippocampal-mediated learning and memory (hidden platform Morris water maze, T-maze spontaneous alternation, and pavlovian trace fear conditioning), mutants were impaired. These data further demonstrate the importance of GluN2B for synaptic plasticity in the adult hippocampus and suggest a particularly critical role in LTD, at least the form studied here. The finding that loss of GluN2B was sufficient to cause learning deficits illustrates the contribution of GluN2B-mediated forms of plasticity to memory formation, with implications for elucidating NMDAR-related dysfunction in disease-related cognitive impairment.

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

“…Recent findings that LTP and LTD are mediated by activation of GluN2A-and GluN2B-containing NMDARs (17,18) suggested the potential utility of GluN2-preferential antagonists to probe the functional roles of LTP and LTD in spatial memory. This possibility is supported further by transgenic data showing that selective knockout of the GluN2A subunit or deletion of its carboxyl tail impairs LTP (12,29), whereas knocking out the GluN2B subunit produces a deficit in LTD (14,30). Nonetheless, contradictory results challenge these findings (31,32).…”

“…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)(11)(12) or LTD (13)(14)(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).…”

“…Recent attempts using transgenic mice with deficits in either LTP (10)(11)(12) or LTD (13)(14)(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.…”

Prenatal inhibition of the tryptophan–kynurenine pathway alters synaptic plasticity and protein expression in the rat hippocampus

“…The importance of this may lie in the requirement for a specific balance between these subunits, with a shift in their relative expression occurring progressively throughout development. The balance between these two subunits is critical in regulating neuronal function and early brain development (Brigman et al, 2010;McKay et al, 2012;Rammes et al, 2009) as well as cell viability and degeneration (Hardingham and Bading, 2010).…”

Epistatic and Independent Effects on Schizophrenia-Related Phenotypes Following Co-disruption of the Risk Factors Neuregulin-1 × DISC1

“…Post-mortem studies have shown decreased GluN1 protein expression in the prefrontal cortex of schizophrenia cases, 34 and dysregulation of NMDA receptor formation and function in the hippocampus during development has been linked with the pathogenesis of schizophrenia. 35 Antipsychoticsensitive hyperactivity and PPI deficits have also been observed in mice having reduced expression of GluN1. 36 Emerging evidence suggests inhibition of NMDAR activity reduces activity in the PI3/AKT pathway, and that decreased NRG1/ErbB4 signaling may contribute to schizophrenia via modulation of this pathway.…”