Contribution of Hippocampal and Extra-Hippocampal NR2B-Containing NMDA Receptors to Performance on Spatial Learning Tasks

Abstract

Controversy revolves around the differential contribution of NR2A- and NR2B-containing NMDA receptors, which coexist in principal forebrain neurons, to synaptic plasticity and learning in the adult brain. Here, we report genetically modified mice in which the NR2B subunit is selectively ablated in principal neurons of the entire postnatal forebrain or only the hippocampus. NR2B ablation resulted in smaller NMDA receptor-mediated EPSCs with accelerated decay kinetics, as recorded in CA1 pyramidal cells. CA3-to-CA1 field LTP remained largely unaltered, although a pairing protocol revealed decreased NMDA receptor-mediated charge transfer and reduced cellular LTP. Mice lacking NR2B in the forebrain were impaired on a range of memory tasks, presenting both spatial and nonspatial phenotypes. In contrast, hippocampus-specific NR2B ablation spared hippocampus-dependent, hidden-platform water maze performance but induced a selective, short-term, spatial working memory deficit for recently visited places. Thus, both hippocampal and extra-hippocampal NR2B containing NMDA receptors critically contribute to spatial performance.

Hippocampal synaptic plasticity, spatial memory and anxiety

“…Whereas ablation of the GluN2B subunit in both hippocampus and cortex impaired watermaze learning 49 (but importantly had no effect on the visible platform control task), deletion restricted to just the hippocampus had no effect 67 . Thus, these data clearly demonstrate that NMDARs either elsewhere in the extended hippocampal formation, such as the entorhinal cortext 73 or subiculum 5 , or across the wider cortical mantle, are necessary for spatial memory performance.…”

“…Notably, the deficit in Grin1 ΔDGCA1 mice during spatial reversal testing reflects their increased perseveration to the old platform location. This is evident by the greater time spent in the training quadrant during the transfer test (which was performed in extinction), conducted at the end of the initial watermaze acquisition training ( Figure 2b, Transfer Test; see also 67 ).…”

Reciprocal signalling between NR2 subunits of the NMDA receptor and neuregulin1 and their role in schizophrenia

“…While human post-mortem data supports that NMDARs and their subunits are altered in schizophrenia, whether they be increased or decreased in brain regional 1908, displayed increased locomotor activity (10-30mg/kg) and impaired response inhibition (1-10mg/kg) but no disruption to PPI (1-10mg/kg) (Higgins et al, 2003). A recent study has shown that there are deficits in both spatial and non-spatial memory following a forebrain-specific deletion of NR2B, whereas hippocampal-restricted deletion of NR2B induces a selective working memory deficit (von Engelhardt et al, 2008). Mice with a complete knockout of NR2B die shortly after birth and therefore cannot undergo behavioural analysis.…”

GluN2B-Containing NMDA Receptors Promote Wiring of Adult-Born Neurons into Olfactory Bulb Circuits

“…pAAV-double floxed mCherry was a kind gift from K. Deisseroth and AAV was produced as previously described (Monory et al, 2006). Conditional knock-out (KO) mice for Grin2B (GluN2B fl/fl ) (von Engelhardt et al, 2008) and Grin1 (GluN1 fl/fl ) (Niewoehner et al, 2007), heterozygous lacZ reporter (B6-gt(ROSA) 26SOR lacZ) mice (Soriano, 1999), and Grin2A (GluN2A Ϫ/Ϫ ) KO mice (Sakimura et al, 1995) were bred in a C57BL/6N background (Charles River). Mice of either sex were used.…”