Metabotropic glutamate receptor 1 (mGlu1) has a discrete distribution in the central nervous system restricted to neurons. Its expression undergoes important changes during development and in response to physiological and pathological modifications. Here, we have determined the structure of the mGlu1 gene and demonstrated that mGlu1 transcription takes places at alternative first exons. Moreover, we have identified active promoter regions upstream from the two most expressed first exons by means of luciferase reporter gene assays performed in primary cerebellar granule neurons. Targeted mutations of active elements constituting the core promoter and electrophoretic mobility shift assays demonstrated that the factors thyroid transcription factor-1 and CCAAT/enhancer-binding proteins beta act synergistically to promote mGlu1 transcription. We have also elucidated the molecular bases for the neuron-specific expression of mGlu1 identifying a neural restrictive silencing element and a regulatory factor for X box element, which suppressed mGlu1 expression in nonneuronal cells. These results reveal the molecular bases for cell- and context-specific expression of an important glutamate receptor critically involved in synaptogenesis, neuronal differentiation, synaptic transmission, and plasticity.