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Signal Attenuation as a Rat Model of Obsessive Compulsive Disorder
Published on: January 9, 2015
Increased Metabotropic Glutamate Receptor 5 Signaling Underlies Obsessive-Compulsive Disorder-like Behavioral and
Kristen K Ade1, Yehong Wan1, Harold C Hamann1
1Departments of Neurology, Duke University Medical Center, Durham, North Carolina; Neurobiology, Duke University Medical Center, Durham, North Carolina.
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.
Insights
Targeting type 5 metabotropic glutamate receptors (mGluR5) can effectively treat obsessive-compulsive disorder (OCD) related behaviors and striatal abnormalities. This study shows mGluR5 inhibition remedies circuit and behavioral issues in mouse models.
Area of Science:
- Neuroscience
- Molecular Biology
- Psychiatry
Background:
- Understanding the molecular mechanisms of obsessive-compulsive disorder (OCD) is crucial for developing effective treatments.
- While frontostriatal circuit hyperactivity is implicated in OCD, the specific molecular signaling pathways remain largely unknown.
- This study investigates the role of type 5 metabotropic glutamate receptors (mGluR5) in OCD-related behavioral and circuit abnormalities.
Purpose of the Study:
- To determine the role of mGluR5 in the behavioral and striatal circuit abnormalities observed in Sapap3 knockout (KO) mice, a model relevant to OCD.
- To explore the therapeutic potential of targeting mGluR5 for OCD-related phenotypes.
Main Methods:
- Sapap3 KO mice were treated with an mGluR5 antagonist to assess OCD-relevant behaviors (self-grooming, anxiety) and striatal activity.
- Two-photon calcium imaging was used to monitor striatal output pathways.
- Pharmacological and biochemical methods investigated constitutive mGluR5 signaling, and positive allosteric modulators were used to test mGluR5 sufficiency in wild-type mice.
Main Results:
- Excessive mGluR5 signaling was found to underlie OCD-like behaviors and striatal abnormalities in Sapap3 KO mice.
- Acute antagonism of mGluR5 corrected the increased and imbalanced striatal output in Sapap3 KO mice.
- Enhancing mGluR5 activity in wild-type mice recapitulated OCD-like behavioral phenotypes.
Conclusions:
- Increased mGluR5 signaling causally drives striatal output abnormalities and behaviors relevant to OCD.
- Acute inhibition of mGluR5 presents a tractable therapeutic strategy for rectifying circuit and behavioral abnormalities in OCD.
