Insights into the pharmacology of depression

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Science Translational Medicine  07 Oct 2015:
Vol. 7, Issue 308, pp. 308ec171
DOI: 10.1126/scitranslmed.aad3628

Clinical depression affects nearly 20 million Americans each year and has created a global market for antidepressants that, last year, exceeded $10 billion. Serotonin reuptake inhibitors (SSRIs) are most commonly prescribed, despite questions about their efficacy, mechanism of action, and well-documented safety concerns in adolescents. The mechanisms that underlie both depression and the drugs used to treat this potentially debilitating condition remain unresolved. Now, new insights by Lee et al. link depressive symptoms in mice to the regulation of metabotropic glutamate receptor 5 (mGluR5) activity by the serotonin regulator protein S100A10 (p11).

Lee et al. found that p11 binding increases cell surface localization of mGluR5 through a newly discovered interaction with its cytoplasmic tail. The authors then knocked out mGluR5 and p11 specifically in either glutamatergic (excitatory) or GABAergic (inhibitory) neurons. They found that mGluR5 and p11 play opposite roles in these distinct neuronal cell types; depression-like behaviors resulted from deletion of either mGluR5 or p11 in glutamatergic neurons, whereas antidepressant-like behaviors resulted from loss of either mGluR5 or p11 in GABAergic neurons. Most critically, p11 was required for the antidepressant-like effect of mGluR5 antagonism in GABAergic neurons.

These findings suggest a new method by which mGluR5 antagonism could achieve antidepressant-like activity. The fast-acting effects of mGluR5 antagonists might reflect altered synaptic transmission at GABAergic inputs to glutamatergic neurons; this speedy mechanism is in contrast to SSRIs, which produce therapeutic effects only after chronic treatment for several weeks. Furthermore, it is worth noting that mGluR5 activity is also a therapeutic target for schizophrenia, fragile X syndrome, and levodopa-induced dyskinesias in Parkinson’s disease. The new work demonstrates that cell-type specificity may be critical when targeting mGluR5 activity for future therapeutics.

K.-W. Lee et al., Alteration by p11 of mGluR5 localization regulates depression-like behaviors. Mol. Psychiatry 10.1038/mp.2015.132 (2015). [Abstract]

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