mGluR1 in cerebellar Purkinje cells is required for normal association of temporally contiguous stimuli in classical conditioning.

In metabotropic glutamate receptor-subtype 1 (mGluR1)-null (mGluR1-/-) mice, cerebellar long-term depression (LTD) and several forms of memory are impaired. However, because mGluR1 is expressed in various brain regions in wild-type mice, it has been difficult to identify which type of memory depends on mGluR1 expressed in a given brain region. Furthermore, severe ataxia in mGluR1-/- mice complicated interpretation of the data from non-cerebellum-dependent tasks. We have generated mGluR1-rescue mice, which express mGluR1 only in Purkinje cells (PCs) of their cerebellum, by introducing the mGluR1alpha transgene into mGluR1-/- mice under the control of a PC-specific promoter. The mGluR1-rescue mouse has normal LTD and displays no apparent ataxia. Therefore, this mouse is the first animal model in which effects of mGluR1 deficiency outside PCs can be studied without cerebellar dysfunction. We used three eyeblink conditioning paradigms with different temporal specificities between conditioned stimulus (CS) and unconditioned stimulus (US). Delay conditioning, in which CS and US coterminate, was impaired in mGluR1-/- mice but normal in mGluR1-rescue mice. However, both strains of mice displayed severe impairment in trace conditionings, in which a stimulus-free interval of 250 or 500 ms intervened between CS and US. We also examined social transmission of food-preference and novel-object-recognition memory tests. In these tasks, mGluR1-rescue mice showed normal short-term but impaired long-term memory. We conclude that mGluR1 in PCs is indispensable for normal learning of association of temporally contiguous stimuli in associative conditioning. In contrast, mGluR1 in other cell types is required for associating discontiguous stimuli and long-term memory formation in nonspatial hippocampus-dependent learning.