M1 muscarinic receptors modulate fear-related inputs to the prefrontal cortex: Implications for novel treatments of posttraumatic stress disorder

Abstract Background The prefrontal cortex (PFC) integrates information from multiple inputs to exert “top down” control allowing for appropriate responses in a given context. In psychiatric disorders such as posttraumatic stress disorder (PTSD), PFC hyperactivity is associated with inappropriate fear in safe situations. We previously reported a form of muscarinic acetylcholine receptor (mAChR)-dependent long-term depression (LTD) in the PFC that we hypothesize is involved in appropriate fear responding and could serve to reduce cortical hyperactivity following stress. However, it is unknown if this LTD occurs at fear-related inputs. Methods Using optogenetics with extracellular and whole-cell electrophysiology, we assessed the effect of mAChR activation on the synaptic strength of specific PFC inputs. We used selective pharmacological tools to assess the involvement of M 1 mAChRs in conditioned fear extinction in control mice and in the stress-enhanced fear learning (SEFL) model. Results M 1 mAChR activation induced LTD at inputs from the ventral hippocampus and basolateral amygdala but not the mediodorsal nucleus of the thalamus. We found that systemic M 1 mAChR antagonism impaired contextual fear extinction. Treatment with an M 1 PAM enhanced contextual fear extinction consolidation in SEFL-conditioned mice. Conclusions M 1 mAChRs dynamically modulate synaptic transmission at two PFC inputs whose activity is necessary for fear extinction and M 1 mAChR function is required for proper contextual fear extinction. Furthermore, an M 1 PAM enhanced the consolidation of fear extinction in the SEFL model suggesting M 1 PAMs may provide a novel treatment strategy to facilitate exposure therapy in the clinic for the treatment of PTSD.