PT  - JOURNAL ARTICLE
AU  - Hanna Jaaro-Peled
AU  - Sunil Kumar
AU  - Dalton Hughes
AU  - Sun-Hong Kim
AU  - Sandra Zoubovsky
AU  - Yuki Hirota-Tsuyada
AU  - Diana Zala
AU  - Akiko Sumitomo
AU  - Julie Bruyere
AU  - Brittany M. Katz
AU  - Beverly Huang
AU  - Rafael Flores III
AU  - Soumya Narayan
AU  - Zhipeng Hou
AU  - Aris N. Economides
AU  - Takatoshi Hikida
AU  - William C. Wetsel
AU  - Karl Deisseroth
AU  - Susumu Mori
AU  - Nicholas J. Brandon
AU  - Motomasa Tanaka
AU  - Koko Ishizuka
AU  - Miles D. Houslay
AU  - Frédéric Saudou
AU  - Kafui Dzirasa
AU  - Akira Sawa
AU  - Toshifumi Tomoda
TI  - The cortico-striatal circuit regulates sensorimotor gating via Disc1/Huntingtin-mediated Bdnf transport
AID  - 10.1101/497446
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 497446
4099  - http://biorxiv.org/content/early/2018/12/14/497446.short
4100  - http://biorxiv.org/content/early/2018/12/14/497446.full
AB  - Sensorimotor information processing that underlies normal cognitive and behavioral traits is dysregulated across a subset of neurological and psychiatric disorders. The cross-disease deficit in sensorimotor gating poses a unique opportunity to integrate hierarchical findings at molecular, cellular, through circuitry levels to obtain an in-depth mechanistic understanding of this process that contributes to brain physiology and pathophysiology beyond categorical segmentation of brain disorders. Based on circuitry recording with wild-type mice, we demonstrated that the cortico-striatal projection mediates sensorimotor gating responses during prepulse inhibition (PPI) task. We also found that these circuitry responses were disrupted in Disc1 locus-impairment (LI) mice, a model representing neuropsychiatric conditions. Thus, we hypothesized that Disc1-mediated molecular and cellular machinery along the cortico-striatal circuit may regulate sensorimotor gating. Anatomical and biochemical analyses of Disc1-LI mice revealed attenuated Bdnf transport along the cortico-striatal circuit. Pharmacologically augmenting Bdnf transport by chronic lithium administration, in part via Ser-421 phosphorylation of Huntingtin (Htt) and its integration into the motor machinery, restored the striatal Bdnf levels and PPI deficits in Disc1-LI mice, suggesting that the Bdnf transport attenuation mechanistically underlies the circuitry and behavioral deficits. These results also shed light on a novel mechanism and utility of lithium that is currently used as a major mood stabilizer in clinical settings. Collectively, the present study illustrates integrative biological mechanisms for sensorimotor gating, underscoring the cross-disease nature of this behavioral dimension and translational utility of the findings under the era of precision medicine in brain disorders.