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Abstract:
Stress-induced psychiatric disorders, such as depression, have recently
been linked to changes in glutamate transmission in the central nervous
system. Glutamate signaling is mediated by a range of receptors,
including metabotropic glutamate receptors (mGluRs). In particular,
mGluR subtype 5 (mGluR5) is highly implicated in stress-induced
psychopathology. The major scaffold protein Homer1 critically interacts
with mGluR5 and has also been linked to several psychopathologies. Yet,
the specific role of Homer1 in this context remains poorly understood.
We used chronic social defeat stress as an established animal model of
depression and investigated changes in transcription of Homer1a and
Homer1b/c isoforms and functional coupling of Homer1 to mGluR5. Next, we
investigated the consequences of Homer1 deletion, overexpression of
Homer1a, and chronic administration of the mGluR5 inverse agonist CTEP
(2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-
yl)ethynyl)pyridine) on the effects of chronic stress. In mice exposed
to chronic stress, Homer1b/c, but not Homer1 a, mRNA was upregulated
and, accordingly, Homer1/mGluR5 coupling was disrupted. We found a
marked hyperactivity behavior as well as a dysregulated hypothalamic
pituitary adrenal axis activity in chronically stressed Homer1 knockout
(KO) mice. Chronic administration of the selective and orally
bioavailable mGluR5 inverse agonist, CTEP, was able to recover
behavioral alterations induced by chronic stress, whereas overexpression
of Homer1a in the hippocampus led to an increased vulnerability to
chronic stress, reflected in an increased physiological response to
stress as well as enhanced depression-like behavior. Overall, our
results implicate the glutamatergic system in the emergence of
stress-induced psychiatric disorders, and support the Homer1/mGluR5
complex as a target for the development of novel antidepressant agents.
