Signaling-Biased 5-HT6R Antagonism Rescues Cognition Deficit in Mice

摘要

The 5-HT6 receptor(5-HT6R) is closely implicated in cognitive function. Antagonists targeting 5-HT6R have shown therapeutic efficacy against cognitive deficits. However, preclinical studies indicate that 5-HT6R antagonists carry a risk of inducing anxiety-like behaviors. This may reflect region-specific functional heterogeneity of 5-HT6R, but the biological basis of this heterogeneity remains unclear. Here we investigated the physiological functions of 5-HT6R by manipulating 5-HT6R expression in cognition-associated, receptor-enriched brain areas. In disease models of Alzheimer's disease and schizophrenia, 5-HT6R mRNA and protein are elevated in the medial prefrontal cortex(mPFC) and dorsal CA1(dCA1). Region-targeted neuronal overexpression of 5-HT6R in the mPFC, but not in dCA1, precipitates cognitive deficits. Mechanistically, supraphysiological 5-HT6R expression in mPFC neurons disrupts primary cilium morphology and function via a ciliary cAMP-PKA signaling axis, culminating in dysregulation of brain-derived neurotrophic factor(BDNF) expression. By contrast, 5-HT6R expression in the nucleus accumbens(NAc) promotes anxiety-like behaviors through cAMP-PKA-independent mechanisms. A compound term CZL-24 was therefore screened for as a Gs signaling-baised 5-HT6R antagonist. CZL-24 significantly ameliorated either spatial memory or novel objects recognition in 5 XFAD mice without leading anxiety-like behaviors. This study delineated the regionally discrete, function-specific roles of 5-HT6R and discovered signaling-biased antagonism for AD therapy.