The different effects of over-expressing murine NMDA receptor 2B subunit in the forebrain on conditioned taste aversion

Abstract

The glutamate transmission system and the N-methyl-d-aspartate receptor (NMDA-R), in particular its 2B subunit (NR2B), have been reported to be possibly related to taste memory as a result of treatment with NMDA antagonists and agonists. In order to further study the role of the NR2B subunit in gustation memory, we applied four different taste aversive tasks to observe the behavior of a transgenic mice model in which the NR2B subunit was specifically over-expressed in the forebrain. We found that in both short- and long-term conditioned taste aversion (CTA) experiments, mice with forebrain expression of the NR2B transgene (Tg) showed significantly enhanced CTA 2 days after training. However, both the Tg and the wild-type (Wt) mice shared the same level of aversive memory on the 30th day after training. In both fast and slow extinction experiments, Tg mice maintained a higher CTA memory than that of control mice in most extinction trials. The third experiment, which involved testing the memory for familiar taste, demonstrated that NR2B augmentation had no benefit on the latent inhibition (LI) of CTA. In addition, the last experiment (two-taste LI) showed a suppression of enhanced CTA in Tg mice when the mice were exposed to both novel and familiar tastes. These data suggested that forebrain NR2B over-expression had different effects on gustatory learning and memory. The transgenic animals were only sensitive to novel but not familiar tastes, and up-regulation of NR2B resulted in enhanced CTA function for only a short period of time.

Introduction

Taste-recognition memory, which is an important acquired skill that contributes to animal survival, is one of the memory systems that have attracted recent attention in the scientific community. Conditioned taste aversion (CTA) is reported to be a useful behavior paradigm for the experimental evaluation of taste memory (Bermudez-Rattoni, 2004, Garcia et al., 1955, Welzl et al., 2001). Several lines of evidence from pharmacological approaches have pointed out that neuronal N-methyl-d-aspartate (NMDA) receptors are involved in the formation of taste memory. One research group has indicated that the establishment of CTA induces long-lasting tyrosine phosphorylation of NMDA receptor 2B subunit, which is the regulatory subunit of NMDA receptor, and that the antagonist of tyrosine kinase could block the formation of aversive memory, including CTA (Rosenblum et al., 1997). Moreover, novel taste exposure could induce intracellular redistribution of NR2A and NR2B subunits in the insular cortex (Nunez-Jaramillo et al., 2008) and the injection of carbacholine could increase the tyrosine levels of NR2B subunit and induce serine phosphorylation (Rosenblum et al., 1995). When given saccharin sodium or sucrose with different concentrations, all animal groups showed increased phosphorylation in the NMDA receptor subunits. Furthermore, after repeated doses of saccharin with the same concentration, the levels of serine phosphorylation of NR2A and NR2B subunits decreased dramatically (Nuñez-Jaramillo, 2003). However, a detailed account of the role of NMDA receptor and its subunits in CTA remains unclear.

Given that the administration of antagonists and agonists may lead to unexpected side effects (Aguado et al., 1997) and thus interfere with experimental results, we instead examined the forebrain of transgenic NR2B mice to further study the influence of NR2B in CTA. Previous research on NR2B transgenic mice using in situ hybridization has shown that NR2B mRNA levels were increased in the forebrain cortex (including insular cortex), the amygdala and the hippocampus (Cao et al., 2007, Tang et al., 1999). Moreover, the NR2B transgenic mice showed significantly better results in a variety of learning and memory behavioral tasks than the control mice (Cao et al., 2007, Tang et al., 1999, White & Youngentob, 2004). Based on the classical understanding of CTA as well as on our data on memory extinction and latent inhibition (LI), we will further discuss the comprehensive effects of forebrain NR2B expression on taste memory.