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.

Genome-wide association analyses of post-traumatic stress disorder and its symptom subdomains in the Million Veteran Program

“…For example, acetylcholine receptor antagonists could be considered given their association in cMAP with PLEKHM1 . In a recent rodent study, the muscarinic receptor antagonist, scopolamine, augmented extinction in conjunction with exposure 64 (although other studies suggest that positive allosteric modulation of M1 muscarinic activity enhances contextual fear conditioning) 65 . These results together suggest that a therapeutic role for cholinergic modulation in PTSD and other fear-related conditions, possibly in concert with exposure therapy, should be investigated.…”

Plasticity in Prefrontal Cortex Induced by Coordinated Synaptic Transmission Arising from Reuniens/Rhomboid Nuclei and Hippocampus

“…2015 ) and of HPC synapses onto both L2/3 and L5 pyramidal cells ( Wang and Yuan 2009 ; Ghoshal et al. 2017 ; Maksymetz et al. 2019 ).…”

“…It is possible that the relatively slow bath application of CCh used in the present study does not capture the effects of rapidly desensitizing nAChRs. However, muscarinic-LTD is also absent in MD projections to mPFC L5 ( Maksymetz et al. 2019 ), therefore suggesting that insensitivity to muscarinic LTD may be a feature of thalamic inputs to mPFC.…”

Plasticity in prefrontal cortex induced by coordinated nucleus reuniens and hippocampal synaptic transmission

“…Cholinergic modulation of NRe and HPC synapses onto mPFC cells was strikingly different. Previous data have shown cholinergic activation of mPFC with CCh produces depression of locally evoked excitatory transmission (Caruana et al 2011, Huang & Hsu 2010, Martin et al 2015 and of HPC synapses onto both L2/3 and L5 pyramidal cells (Ghoshal et al 2017, Maksymetz et al 2019, Wang & Yuan 2009). Here we find that lower concentrations of CCh than used in the above studies acting via M2 muscarinic receptors produced acute depression of HPC input to L5 pyramidal cells.…”

“…It is plausible that the relatively slow bath application of CCh used in the present study does not capture the effects of rapidly desensitising nAChRs. Muscarinic-LTD is also absent in MD projections to mPFC L5 (Maksymetz et al 2019), suggesting that insensitivity to muscarinic LTD may be a feature of thalamic inputs to mPFC.…”