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Increased Metabotropic Glutamate Receptor 5 Signaling Underlies Obsessive-Compulsive Disorder-like Behavioral and Striatal Circuit Abnormalities in Mice.

Publication ,  Journal Article
Ade, KK; Wan, Y; Hamann, HC; O'Hare, JK; Guo, W; Quian, A; Kumar, S; Bhagat, S; Rodriguiz, RM; Wetsel, WC; Conn, PJ; Dzirasa, K; Huber, KM; Calakos, N
Published in: Biol Psychiatry
October 1, 2016

BACKGROUND: Development of treatments for obsessive-compulsive disorder (OCD) is hampered by a lack of mechanistic understanding about this prevalent neuropsychiatric condition. Although circuit changes such as elevated frontostriatal activity are linked to OCD, the underlying molecular signaling that drives OCD-related behaviors remains largely unknown. Here, we examine the significance of type 5 metabotropic glutamate receptors (mGluR5s) for behavioral and circuit abnormalities relevant to OCD. METHODS: Sapap3 knockout (KO) mice treated acutely with an mGluR5 antagonist were evaluated for OCD-relevant phenotypes of self-grooming, anxiety-like behaviors, and increased striatal activity. The role of mGluR5 in the striatal circuit abnormalities of Sapap3 KO mice was further explored using two-photon calcium imaging to monitor striatal output from the direct and indirect pathways. A contribution of constitutive signaling to increased striatal mGluR5 activity in Sapap3 KO mice was investigated using pharmacologic and biochemical approaches. Finally, sufficiency of mGluR5 to drive OCD-like behavior in wild-type mice was tested by potentiating mGluR5 with a positive allosteric modulator. RESULTS: Excessive mGluR5 signaling underlies OCD-like behaviors and striatal circuit abnormalities in Sapap3 KO mice. Accordingly, enhancing mGluR5 activity acutely recapitulates these behavioral phenotypes in wild-type mice. In Sapap3 KO mice, elevated mGluR5 signaling is associated with constitutively active receptors and increased and imbalanced striatal output that is acutely corrected by antagonizing striatal mGluR5. CONCLUSIONS: These findings demonstrate a causal role for increased mGluR5 signaling in driving striatal output abnormalities and behaviors with relevance to OCD and show the tractability of acute mGluR5 inhibition to remedy circuit and behavioral abnormalities.

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Published In

Biol Psychiatry

DOI

EISSN

1873-2402

Publication Date

October 1, 2016

Volume

80

Issue

7

Start / End Page

522 / 533

Location

United States

Related Subject Headings

  • Thiazoles
  • Signal Transduction
  • Receptor, Metabotropic Glutamate 5
  • Pyridines
  • Psychiatry
  • Obsessive-Compulsive Disorder
  • Niacinamide
  • Nerve Tissue Proteins
  • Mice, Transgenic
  • Mice, Knockout
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Ade, K. K., Wan, Y., Hamann, H. C., O’Hare, J. K., Guo, W., Quian, A., … Calakos, N. (2016). Increased Metabotropic Glutamate Receptor 5 Signaling Underlies Obsessive-Compulsive Disorder-like Behavioral and Striatal Circuit Abnormalities in Mice. Biol Psychiatry, 80(7), 522–533. https://doi.org/10.1016/j.biopsych.2016.04.023
Ade, Kristen K., Yehong Wan, Harold C. Hamann, Justin K. O’Hare, Weirui Guo, Anna Quian, Sunil Kumar, et al. “Increased Metabotropic Glutamate Receptor 5 Signaling Underlies Obsessive-Compulsive Disorder-like Behavioral and Striatal Circuit Abnormalities in Mice.Biol Psychiatry 80, no. 7 (October 1, 2016): 522–33. https://doi.org/10.1016/j.biopsych.2016.04.023.
Ade KK, Wan Y, Hamann HC, O’Hare JK, Guo W, Quian A, et al. Increased Metabotropic Glutamate Receptor 5 Signaling Underlies Obsessive-Compulsive Disorder-like Behavioral and Striatal Circuit Abnormalities in Mice. Biol Psychiatry. 2016 Oct 1;80(7):522–33.
Ade, Kristen K., et al. “Increased Metabotropic Glutamate Receptor 5 Signaling Underlies Obsessive-Compulsive Disorder-like Behavioral and Striatal Circuit Abnormalities in Mice.Biol Psychiatry, vol. 80, no. 7, Oct. 2016, pp. 522–33. Pubmed, doi:10.1016/j.biopsych.2016.04.023.
Ade KK, Wan Y, Hamann HC, O’Hare JK, Guo W, Quian A, Kumar S, Bhagat S, Rodriguiz RM, Wetsel WC, Conn PJ, Dzirasa K, Huber KM, Calakos N. Increased Metabotropic Glutamate Receptor 5 Signaling Underlies Obsessive-Compulsive Disorder-like Behavioral and Striatal Circuit Abnormalities in Mice. Biol Psychiatry. 2016 Oct 1;80(7):522–533.
Journal cover image

Published In

Biol Psychiatry

DOI

EISSN

1873-2402

Publication Date

October 1, 2016

Volume

80

Issue

7

Start / End Page

522 / 533

Location

United States

Related Subject Headings

  • Thiazoles
  • Signal Transduction
  • Receptor, Metabotropic Glutamate 5
  • Pyridines
  • Psychiatry
  • Obsessive-Compulsive Disorder
  • Niacinamide
  • Nerve Tissue Proteins
  • Mice, Transgenic
  • Mice, Knockout