Hippocampal alpha 7 nicotinic ACh receptors contribute to modulation of depression-like behaviour in C57BL/6J mice

BACKGROUND AND PURPOSE Clinical studies have identified links between cholinergic signalling and depression in human subjects. Increased cholinergic signalling in hippocampus also increases behaviours related to anxiety and depression in mice, which can be reversed by ACh receptor antagonists. EXPERIMENTAL APPROACH As the alpha 7 subunit of the nicotinic ACh receptor (nAChR) is highly expressed in hippocampus, we determined whether blocking alpha 7 nAChRs could reverse the effects of increased ACh signalling in anxiety- and depression-related behaviours in mice. KEY RESULTS Administration of the alpha 7 nAChR agonist GTS-21 had no effect in tail suspension or forced swim tests. Conversely, the alpha 7 nAChR antagonist methyllycaconitine (MLA) induced significant antidepressant-like effects in male mice in these paradigms, consistent with previous studies, but this was not observed in female mice. MLA also decreased physostigmine-induced c-fos immunoreactivity (a marker of neuronal activity) in hippocampus. Local knockdown of alpha 7 nAChRs in hippocampus had no effect on its own but decreased a subset of depression-like phenotypes induced by physostigmine in male mice. Few effects of alpha 7 nAChR knockdown were observed in depression-like behaviors in female mice, possibly due to a limited response to physostigmine. There was no significant effect of hippocampal alpha 7 nAChR knockdown on anxiety-like phenotypes in male mice. However, a modest increase in anxiety-like behavior was observed in female mice infused with a scrambled control vector in response to physostigmine administration, that was not seen after alpha 7 nAChR knockdown in the hippocampus. CONCLUSIONS AND IMPLICATIONS These results suggest that ACh signalling through alpha 7 nAChRs in the hippocampus contributes to regulation of a subset of depression-like behaviours when ACh is increased, as can occur under stressful conditions. These studies also provide evidence for sex differences that may be relevant for treatments of mood disorders based on cholinergic signalling.