M1 acetylcholine receptors in somatostatin interneurons contribute to GABAergic and glutamatergic plasticity in the mPFC and antidepressant-like responses

Alterations in glutamatergic and GABAergic function in the medial prefrontal cortex (mPFC) are prevalent in individuals with major depressive disorder, resulting in impaired synaptic plasticity that compromises the integrity of signal transfer to limbic regions. Scopolamine, a non-selective muscarinic receptor antagonist, produces rapid antidepressant-like effects by targeting M1-type acetylcholine receptors (M1R) on somatostatin (SST) interneurons. So far, these effects have been investigated with relatively short-term manipulations, and long-lasting synaptic mechanisms involved in these responses are still unknown. Here, we generated mice with conditional deletion of M1R (M1(f/f)Sst(Cre+)) only in SST interneurons to determine the role of M1R in modulating long-term GABAergic and glutamatergic plasticity in the mPFC that leads to attenuation of stress-relevant behaviors. We have also investigated whether the molecular and antidepressant-like effects of scopolamine could be mimicked or occluded in male M1(f/f)Sst(Cre+) mice. M1R deletion in SST-expressing neurons occluded the rapid and sustained antidepressant-like effects of scopolamine, as well as scopolamine-induced increases in c-Fos(+)/CaMKII alpha cells and proteins necessary for glutamatergic and GABAergic function in the mPFC. Importantly, M1R SST deletion resulted in resilience to chronic unpredictable stress in behaviors relevant to coping strategies and motivation, and to a lesser extent, in behaviors relevant to avoidance. Finally, M1R SST deletion also prevented stress-induced impairments in the expression of GABAergic and glutamatergic markers in the mPFC. These findings suggest that the antidepressant-like effects of scopolamine result from modulation of excitatory and inhibitory plasticity via M1R blockade in SST interneurons. This mechanism could represent a promising strategy for antidepressant development.

Automated summary

Alterations in glutamatergic and GABAergic function in the medial prefrontal cortex (mPFC) play a role in major depressive disorder. Scopolamine, a muscarinic receptor antagonist, has rapid antidepressant-like effects by targeting M1-type acetylcholine receptors (M1R). In this study, M1R deletion in SST interneurons in the mPFC attenuates the antidepressant-like effects of scopolamine and impairs GABAergic and glutamatergic function. These findings suggest that modulation of excitatory and inhibitory plasticity via M1R blockade in SST interneurons could be a promising strategy for developing antidepressants.