Neuroscience

Countering Impaired Cognition

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Science  26 Oct 2012:
Vol. 338, Issue 6106, pp. 444
DOI: 10.1126/science.338.6106.444-c

Cognitive impairment is a cardinal feature of many psychiatric disorders, including schizophrenia. Blockade of 5-HT6 receptors is a potential strategy for correcting the cognitive deficits of schizophrenia and other central nervous system disorders. However, the molecular mechanisms underlying the deleterious impact of 5-HT6 receptors on cognitive function are still unknown. Using an unbiased proteomic approach to find protein partners and signaling mechanisms engaged by 5-HT6 receptors, Meffre et al. identified several members of the mammalian target of rapamycin (mTOR) signaling complex. mTOR has been implicated in the cognitive impairment associated with a number of genetic disorders. 5-HT6 receptor stimulation activated mTOR-dependent signaling, and the mTOR inhibitor rapamycin reversed some of the disruptive effects induced by a 5-HT6 receptor agonist in a recognition memory paradigm and in a social interaction test. In two developmental rodent models of schizophrenia, 5-HT6 receptor–elicited activation of the mTOR pathway was detected in the prefrontal cortex of adult rats, and rapamycin mimicked 5-HT6 antagonists in reversing the accompanying cognitive deficits. These results provide new insights into the molecular substrates mediating the negative impact of 5-HT6 receptors on cognition and into cellular events underlying cognitive deficits in schizophrenia.

EMBO Mol. Med. 4, 1043 (2012).

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