MULTIPLE BEHAVIORAL ANOMALIES IN GLUR2 MUTANT MICE EXHIBITING ENHANCED LTP

We have previously disrupted the ionotropic glutamate receptor type 2 gene (GluR2) using gene targeting in embryonic stem cells and generate d mice which lacked the GluR2 gene product. Neurophysiological analyse s of these mice showed a markedly enhanced long-term potentiation (LTP ) and a 9-fold increase in kainate induced Ca2+ permeability in the hi ppocampus. Here, we analyze the behavioral and neuroanatomical consequ ences of GluR2 deficiency in homozygous null mutant and age-matched li ttermate control mice. We show that despite unaltered gross brain morp hology, several aspects of behavior were abnormal in the mutants. Obje ct exploration, rearing, grooming and locomotion were altered in the n ovel arena. Eye-closure reflex, motor performance on the rotating rod and spatial and non-spatial learning performance in the water maze wer e also abnormal in the mutants. These abnormalities together with the widespread expression pattern of GluR2 in most excitatory CNS pathways suggest that the absence of GluR2 leads to neurological phenotypes as sociated with not only the hippocampus but several other brain regions potentially including the cortex and cerebellum. We speculate that Gl uR2 mutant mice suffer from an overall non-specifically increased exci tability that may alter cognitive functions ranging from stimulus proc essing to motivation and learning. (C) 1998 Elsevier Science B.V. All rights reserved.