Potentiating M1 and mGlu1 receptors to modulate prefrontal cortical dysfunction in psychiatric diseases

Abstract

In psychiatric disorders including posttraumatic stress disorder (PTSD) and schizophrenia, dysfunction of the prefrontal cortex (PFC) is associated with cognitive and emotional deficits that involve aberrant afferent integration and intracortical processing. Current treatments for these disorders have limited efficacy, especially concerning PFC-dependent cognitive functions; therefore, there is a critical need to identify novel pharmacological mechanisms to restore PFC function in these disorders. We aimed to identify novel approaches that could be useful to reduce cortical hyperactivity, focusing on macrocircuit-level regulation of afferent drive and microcircuit-level modulation of inhibitory neurotransmission.

Stress-induced loss of fear extinction is thought to play a critical role in sustaining pathological fear in PTSD and the PFC is essential for fear extinction by integrating information from the ventral hippocampus (vHipp) and the basolateral amygdala (BLA). We identified that M1 muscarinic acetylcholine receptor activation induces an input-specific long-term depression of synaptic transmission at the vHipp- and BLA-inputs to the PFC and further demonstrated that an M1 positive allosteric modulator (PAM) enhances fear extinction in a preclinical model of PTSD. Intracortical processing involving inhibitory GABAergic interneurons is critical for proper PFC function and a consistent pathophysiological finding in schizophrenia is evidence of inhibitory interneuron dysfunction. We identified mGlu1 as a novel pharmacological target enriched in PFC GABAergic interneurons, and that activation of mGlu1 preferentially increases the activity of somatostatin (SST) interneurons to shift the PFC excitation-inhibition balance towards inhibition. We further demonstrated that an mGlu1 PAM reverses physiological and behavioral deficits in a preclinical model of schizophrenia, suggesting that targeted enhancement of mGlu1 function may rescue inhibitory deficits and lead to novel therapeutics for cognitive dysfunction in schizophrenia. Altogether, these data identify pharmacological mechanisms to reduce cortical hyperactivity and validate M1 and mGlu1 PAMs as novel treatments for PTSD and schizophrenia, respectively.