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Nicotine consumption through smoking affects anxious states in humans. However, the precise role of nicotinic acetylcholine receptor (nAChR) circuitry in the regulation of anxiety remains elusive. The Lynx protein Lypd6 is highly enriched in synaptic loci and has been previously identified as an endogenous inhibitor of neuronal nAChR function in vitro. Here, we investigate the effect of Lypd6 in anxiety-related behaviour and examine the molecular underpinnings of its function in the brain. We employ the marble burying (MB) and elevated zero maze (EZM) tests in Lypd6 knock-out (KO) and wild-type (WT) mice and find that loss of Lypd6 leads to decreased digging behaviour in the MB test and increased time spent in the open area in the EZM test. Moreover, we demonstrate that acute nicotine administration reduces digging in the MB test in both KO and WT mice and further accentuates the inherent genotype difference. Using in vitro electrophysiology in dorsal raphe nuclei (DRN) neurons from Lypd6 KO mice, we show that nicotine-evoked whole-cell currents are enhanced in the absence of Lypd6. Collectively, these data are the first to indicate the involvement of Lypd6 in circuits associated with anxiety and suggest that a possible underlying neurobiological mechanism is the modulation of cholinergic responses in the DRN.Genetic deletion of Lypd6 results in reduced anxiety-like behaviour in two anxiety-related tests.Acute nicotine administration accentuates the inherent genotype difference in the marble burying test.Nicotine-evoked whole-cell currents in dorsal raphe nuclei are enhanced in the absence of Lypd6.