Abstract
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.
Keywords
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Article Info
Publication History
Published online: May 13, 2016
Accepted:
April 29,
2016
Received in revised form:
April 29,
2016
Received:
September 30,
2015
Identification
Copyright
© Society of Biological Psychiatry, 2016.
