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Regulation of sensorimotor gating via Disc1/Huntingtin-mediated Bdnf transport in the cortico-striatal circuit

Molecular Psychiatry volume 27, pages 1805–1815 (2022)Cite this article

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Abstract

Sensorimotor information processing underlies normal cognitive and behavioral traits and has classically been evaluated through prepulse inhibition (PPI) of a startle reflex. PPI is a behavioral dimension deregulated in several neurological and psychiatric disorders, yet the mechanisms underlying the cross-diagnostic nature of PPI deficits across these conditions remain to be understood. To identify circuitry mechanisms for PPI, we performed circuitry recording over the prefrontal cortex and striatum, two brain regions previously implicated in PPI, using wild-type (WT) mice compared to Disc1-locus-impairment (LI) mice, a model representing neuropsychiatric conditions. We demonstrated that the corticostriatal projection regulates neurophysiological responses during the PPI testing in WT, whereas these circuitry responses were disrupted in Disc1-LI mice. Because our biochemical analyses revealed attenuated brain-derived neurotrophic factor (Bdnf) transport along the corticostriatal circuit in Disc1-LI mice, we investigated the potential role of Bdnf in this circuitry for regulation of PPI. Virus-mediated delivery of Bdnf into the striatum rescued PPI deficits in Disc1-LI mice. Pharmacologically augmenting Bdnf transport by chronic lithium administration, partly via phosphorylation of Huntingtin (Htt) serine-421 and its integration into the motor machinery, restored striatal Bdnf levels and rescued PPI deficits in Disc1-LI mice. Furthermore, reducing the cortical Bdnf expression negated this rescuing effect of lithium, confirming the key role of Bdnf in lithium-mediated PPI rescuing. Collectively, the data suggest that striatal Bdnf supply, collaboratively regulated by Htt and Disc1 along the corticostriatal circuit, is involved in sensorimotor gating, highlighting the utility of dimensional approach in investigating pathophysiological mechanisms across neuropsychiatric disorders.

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Fig. 1: The prefrontal cortex and dorsomedial striatum in sensorimotor gating.
Fig. 2: Sensorimotor gating in Disc1 LI mice.
Fig. 3: Deficits in corticostriatal Bdnf transport in Disc1 LI mice.
Fig. 4: Lithium-mediated augmentation of Bdnf transport can rescue PPI deficits in Disc1 LI mice.
Fig. 5: Lithium upregulates Htt Ser-421 phosphorylation and enhances assembly of the Bdnf transport machinery in Disc1 LI mice.

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Acknowledgements

We thank Drs Francis Lee, Nicola Cascella, Deqiang Jing and Ravi Tharakan for discussion. We thank Drs Melissa Landek-Salgado, Pamela Talalay and Ann West for critical reading and Ms Yukiko Lema for organizing the paper and figures. We also thank Freeman Hrabowski, Robert and Jane Meyerhoff, and the Meyerhoff Scholarship Program (KDz).

Funding

This work was supported by NIH (MH-094268 Silvio O. Conte center, and MH-092443) (to AS), as well as foundation grants of Stanley (to AS), RUSK/S-R (to AS), NARSAD/BBRF (to AS, and HJ-P) and MSCRF (to AS). This work was also supported by NIH (R37MH073853 and R21MH099479) (to KDz); and DOD/CDMRP (W81XWH-11-1-0269) (to TT). We have uploaded a prior version of this paper on bioRxiv preprint server: https://doi.org/10.1101/497446.

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Author notes

  1. Diana Zala

    Present address: Institut de Psychiatrie et Neurosciences de Paris (IPNP), UMR_1266, INSERM, Université de Paris, Paris, France

  2. These authors contributed equally: Hanna Jaaro-Peled, Sunil Kumar.

  3. These authors jointly supervised this work: Kafui Dzirasa, Akira Sawa, Toshifumi Tomoda.

Authors and Affiliations

  1. Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Hanna Jaaro-Peled, Sun-Hong Kim, Sandra Zoubovsky, Beverly Huang, Soumya Narayan, Takatoshi Hikida, Koko Ishizuka & Akira Sawa

  2. Department of Psychiatry and Behavioral Sciences, Neurobiology, and Biomedical Engineering, Duke University Medical Center, Durham, NC, USA

    Sunil Kumar, Dalton Hughes, Brittany M. Katz, William C. Wetsel & Kafui Dzirasa

  3. Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, University of Toronto, Toronto, ON, Canada

    Akiko Sumitomo & Toshifumi Tomoda

  4. Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Akiko Sumitomo, Yuki Hirota-Tsuyada & Toshifumi Tomoda

  5. Department of Neurosciences, Beckman Research Institute of City of Hope, Duarte, CA, USA

    Yuki Hirota-Tsuyada, Rafael Flores III & Toshifumi Tomoda

  6. University Grenoble Alpes, INSERM, U1216, CHU Grenoble Alpes, Grenoble Institut Neuroscience, 38000, Grenoble, France

    Diana Zala, Julie Bruyere & Frédéric Saudou

  7. Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Zhipeng Hou & Susumu Mori

  8. Regeneron Pharmaceuticals, Tarrytown, NY, USA

    Aris N. Economides

  9. Departments of Bioengineering and Psychiatry and Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA

    Karl Deisseroth

  10. Jnana Therapeutics, Lexington, MA, USA

    Nicholas J. Brandon

  11. Laboratory for Protein Conformation Diseases, RIKEN Brain Science Institute, Wako, Japan

    Motomasa Tanaka

  12. Institute of Pharmaceutical Sciences, King’s College London, London, UK

    Miles D. Houslay

  13. Departments of Neuroscience, Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Akira Sawa

  14. Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Akira Sawa

  15. Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Akira Sawa

  16. Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Akira Sawa

Authors
  1. Hanna Jaaro-Peled
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  2. Sunil Kumar
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Contributions

HJ-P, KDz, ASa, and TT conceived the studies; HJ-P, SK, DH, ASu, S-HK, SZ, YH-T, DZ, JB, BMK, BH, RF, SN, and ZH carried out experiments and analyzed data; ANE contributed to the design of Disc1-LI mice; TH, WCW, KD, SM, NJB, MT, KI, MDH, and FS provided analytical tools; HJ-P, KDz, ASa, and TT wrote and edited the paper.

Corresponding authors

Correspondence to Kafui Dzirasa, Akira Sawa or Toshifumi Tomoda.

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Jaaro-Peled, H., Kumar, S., Hughes, D. et al. Regulation of sensorimotor gating via Disc1/Huntingtin-mediated Bdnf transport in the cortico-striatal circuit. Mol Psychiatry 27, 1805–1815 (2022). https://doi.org/10.1038/s41380-021-01389-3

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