GluN1 hypomorph mice exhibit wide-ranging behavioral alterations

Abstract

The psychotomimetic effects of N-methyl-d-aspartate receptor (NMDA) antagonists such as ketamine and phencyclidine suggest a role for reduced NMDA receptor-mediated neurotransmission in schizophrenia. GluN1 'hypomorph' (GluN1(hypo) ) mice exhibit reduced NMDA receptor expression and have been suggested as a mouse model of schizophrenia. However, NMDA receptors are ubiquitous and are implicated in many physiological and pathological processes. The GluN1(hypo) mice have a global reduction of NMDA receptors and the consequences of such a global manipulation are likely to be wide-ranging. We therefore assessed GluN1(hypo) mice on a battery of behavioral tests, including tests of naturalistic behaviors, anxiety and cognition. GluN1(hypo) mice exhibited impairments on all tests of cognition that we employed, as well as reduced engagement in naturalistic behaviors, including nesting and burrowing. Behavioral deficits were present in both spatial and non-spatial domains, and included deficits on both short- and long-term memory tasks. Results from anxiety tests did not give a clear overall picture. This may be the result of confounds such as the profound hyperactivity seen in GluN1(hypo) mice, although hyperactivity cannot account for all of the results obtained. When viewed against this background of far-reaching behavioral abnormalities, the specificity of any one behavioral deficit is inevitably called into question. Indeed, the present data from GluN1(hypo) mice are indicative of a global impairment rather than any specific disease. The deficits seen go beyond what one would expect from a mouse model of schizophrenia, thus questioning their utility as a selective model of this disease.

Figure 1. Time spent socially interacting for GluN1

^hypo(HYPO) and WT mice split into male (a) and female (b) mice. In the social interaction task, GluN1^hypo mice show a deficit in social behavior that is driven by differences between male mice (a) and not female mice (b). This group difference was not diminished by habituation to the testing environment but did increase social activity in all mice. Time spent socially interacting is expressed as mean ± SEM.

Figure 2. Time spent in aggressive encounters for male GluN1

^hypo(HYPO) and WT mice. In the social interaction task, male GluN1^hypo showed less aggressive behavior than WT mice. This was most apparent following habituation to the testing environment as a result of habituation leading to a large increase in aggressive behavior in the WT mice but not in the HYPO mice, with both groups showing very little aggressive behavior when not habituated to the testing context. Time spent in aggressive encounters is expressed as mean ± SEM.

Figure 3. Performance of GluN1

^hypo(HYPO) and WT mice in discrete trial spontaneous alternation (a) and the spatial novelty Y-maze (b) tasks. In the spontaneous alternation task (a), WT mice show a high level of performance while GluN1^hypo mice were at chance levels. In the spatial novelty Y-maze (b), the GluN1^hypo mice once again showed deficits compared to the WT mice. Spontaneous alternation is expressed as median and IQR, spatial novelty Y-maze as mean ± SEM of the novelty preference ratio, defined as time spent in novel arm/(time spent in novel arm + time spent in other arm). *P < 0.05 WT vs. HYPO.

Figure 4. Performance of GluN1

^hypo(HYPO) and WT mice during the test phase of the novel object recognition task. GluN1^hypo mice were significantly impaired compared to WT mice. Performance is expressed as mean ± SEM of preference ratio, defined as time spent exploring novel object/(time spent exploring novel object + time spent exploring familiar object). *P < 0.05 WT vs. HYPO.

Figure 5. Performance of GluN1

^hypo(HYPO) and WT mice in the spatial reference Y-maze (a, mean ± SEM) and visual discrimination (b, mean ± SEM) tasks. GluN1^hypo mice failed to acquire either the spatial or non-spatial associative long-term memory task.