Genetic Enhancement of Memory and Long-Term Potentiation but Not CA1 Long-Term Depression in NR2B Transgenic Rats

Abstract

One major theory in learning and memory posits that the NR2B gene is a universal genetic factor that acts as rate-limiting molecule in controlling the optimal NMDA receptor's coincidence-detection property and subsequent learning and memory function across multiple animal species. If so, can memory function be enhanced via transgenic overexpression of NR2B in another species other than the previously reported mouse species? To examine these crucial issues, we generated transgenic rats in which NR2B is overexpressed in the cortex and hippocampus and investigated the role of NR2B gene in NMDA receptor-mediated synaptic plasticity and memory functions by combining electrophysiological technique with behavioral measurements. We found that overexpression of the NR2B subunit had no effect on CA1-LTD, but rather resulted in enhanced CA1-LTP and improved memory performances in novel object recognition test, spatial water maze, and delayed-to-nonmatch working memory test. Our slices recordings using NR2A- and NR2B-selective antagonists further demonstrate that the larger LTP in transgenic hippocampal slices was due to contribution from the increased NR2B-containing NMDARs. Therefore, our genetic experiments suggest that NR2B at CA1 synapses is not designated as a rate-limiting factor for the induction of long-term synaptic depression, but rather plays a crucial role in initiating the synaptic potentiation. Moreover, our studies provide strong evidence that the NR2B subunit represents a universal rate-limiting molecule for gating NMDA receptor's optimal coincidence-detection property and for enhancing memory function in adulthood across multiple mammalian species.

The rat perirhinal cortex: A review of anatomy, physiology, plasticity, and function

“…As the NR2A subunit is associated with LTP and the NR2B subunit is associated with LTD (Massey et al, 2004;Toyoda et al, 2005;Bartlett et al, 2007;Yashiro and Philpot, 2008), this implies that both perirhinal LTPand LTD-like processes are required for the formation of object recognition memories. Furthermore, transgenic overexpression of the NR2B subunit in hippocampal and cortical neurons enhances performance in an object recognition task yet does not promote LTD in the area CA1 (Wang et al, 2009) which is a conflicting finding compared to the majority of research in this area. There are a large number of molecular mechanisms involved in object recognition memory that are correlated with LTD including L-type voltage-dependent Ca 2+ channels (Seoane et al, 2009), CREB (Warburton et al, 2005), muscarinic cholinergic receptors (Warburton et al, 2003;Massey et al, 2008), GABA receptors (Wan et al, 2004) mGlu receptors (Barker et al, 2006a;Moult et al, 2006), NMDA receptors (Cho et al, 2000Roberts et al, 2009;, kainate receptors (Barker et al, 2006a;Park et al, 2006;Holman et al, 2007) and AMPA receptor internalisation (Griffiths et al, 2008).…”

Life Extension Factor Klotho Prevents Mortality and Enhances Cognition in hAPP Transgenic Mice

“…Interestingly, transgenic overexpression of GluN2B (Tang et al, 1999;Wang et al, 2009) or increasing the surface expression of GluN2B by disrupting its phosphorylation by cyclin-dependent kinase 5 (Hawasli et al, 2007;Plattner et al, 2014) in mice or rats enhanced both synaptic and cognitive functions, possibly by delaying deactivation of NMDARs and increasing the summation of synaptic current and calcium influx (Yashiro and Philpot, 2008;Wang et al, 2009;Foster et al, 2010). These studies suggest that the GluN2B subunit gates and optimizes coincidence detection by NMDARs, a process that leads to enhanced synaptic potentiation (Tsien, 2000).…”

Importance of the GluN2B carboxy-terminal domain for enhancement of social memories

“…The N-methyl-D-aspartate (NMDA) receptor is known to play a crucial role in multiple forms of learning and memory including object recognition memory, emotional memory, social memory, extinction memory, and spatial memory Tonegawa et al 1996;Tsien et al 1996;Rampon et al 2000a,b;Szapiro et al 2003;Cui et al 2004Cui et al , 2005Li and Tsien 2009;Wang et al 2009;Kuang et al 2010;Zimmerman and Maren 2010;Mei et al 2011;Zhang et al 2013). …”