Lack of the glycine alpha 2 receptor impairs reward-motivated behavior and striatal signal integration

Distinct developmental pathologies, including autism spectrum disorder and schizophrenia, exhibit impaired reward-motivated behavior. Key to proper reward-motivated behavior is the integration of dopaminergic and glutamatergic inputs to the striatum. The glycine alpha 2 receptor (GlyRα2) is the single functionally expressed glycine receptor in adult striatum, and is therefore ideally positioned to modulate striatal behavior and cellular signal integration. Here, we report excessive appetitive conditioning in GlyRα2 knockout animals. We next show that depletion of GlyRα2 enhances dopamine-induced increases in the activity of putative dopamine D1-expressing striatal projection neurons, while not affecting dopamine neuron activity. These in vivo behavioral changes are tied to enhanced striatal activation in GlyRα2 KO mice, since we found excessive locomotor responses to amphetamine in GlyRα2 KO mice that correlate with immediate early gene c-fos expression in the dorsal striatum. 3-D modeling revealed activation of cell ensembles in the striatum in response to D-amphetamine, an increase in number of cells but no shift in intercell distance histograms, in agreement with unaltered dopamine release, in GlyRα2 KO mice. Taken together, we show that depletion of GlyRα2 impairs reward-motivated behavior and altered striatal signal integration. This sheds important light onto the cellular mechanisms that underlie reward function, and pave the way towards novel therapeutics for the treatment of e.g. schizophrenia and autism spectrum disorder. ### Competing Interest Statement The authors have declared no competing interest.