BEHAVIORAL REGULATION OF SMITH-MAGENIS SYNDROME THROUGH DOPAMINERGIC NEURON MODULATION

SMS is due to chromosome 17p11.2 half-deletions which contains multiple genes including the developmentally regulated GTP-binding protein 2 (DRG2). DRG2 is expressed in all cells, with the highest concentrations found in the brain such as dopamine neuron. we previous reports that DRG2 was associated with physical developmental delay, motor coordination and motor deficit dopamine dependent neurological function. We recently demonstrate that DRG2 KO mice exhibit sleep disturbances, aggression, obsessive-compulsive behavior and hyperactivity. These behavioral phenotype are strongly suggests abnormalities in dopamine reward/impulse control circuits, similar to behavioral characteristics observed in SMS patients. In this study, we aimed to elucidate how DRG2 regulates dopamine circuits and its association with SMS. First, we confirmed that dopamine and epinephrine levels were significantly reduced in the striatum (Str) region, and that dopamine secretion was significantly impaired when the substantia nigra region of DRG2 KO mice was stimulated with electrode. DRG2 KO mice which suggest that DRG2 depletion results in nigrostriatal dopaminergic dysfunction. Indeed, the the behavioral motor deficiency in DRG2 KO mice was significantly rescued by treatment with L-DOPA, a dopamine precursor, in the striatum. We further investigated BDNF was significantly decreased in hypothalamus and substantia nigra (SN) of DRG2 KO mice. BDNF deficiency is associated with behavioral changes due to dopaminergic dysfunction. Our data indicate that dopamine secretion regulation via DRG2 occurs through reduced BDNF, providing a clue that well explains the various behavioral abnormalities observed in SMS patients.