ABSTRACT
Evidence for prefrontal cortical (PFC) GABAergic dysfunction is one of the most consistent findings in schizophrenia and may contribute to cognitive deficits. Recent studies suggest that the mGlu1 subtype of metabotropic glutamate receptor regulates cortical inhibition; however, understanding the mechanisms through which mGlu1 positive allosteric modulators (PAMs) regulate PFC microcircuit function and cognition is essential for advancing these potential therapeutics toward the clinic. We report a series of electrophysiology, optogenetic, pharmacological magnetic resonance imaging, and animal behavior studies demonstrating that activation of mGlu1 receptors increases inhibitory transmission in the prelimbic PFC by selective excitation of somatostatin-expressing interneurons (SST-INs). An mGlu1 PAM reverses cortical hyperactivity and concomitant cognitive deficits induced by N-methyl-d-aspartate (NMDA) receptor antagonists. Using in vivo optogenetics, we show that prelimbic SST-INs are necessary for mGlu1 PAM efficacy. Collectively, these findings suggest that mGlu1 PAMs could reverse cortical GABAergic deficits and exhibit efficacy in treating cognitive dysfunction in schizophrenia.
Subject(s)
Antipsychotic Agents/pharmacology , Behavior, Animal/drug effects , Cognition/drug effects , Cognitive Dysfunction/drug therapy , Excitatory Amino Acid Agonists/pharmacology , Glycine/analogs & derivatives , Interneurons/drug effects , Prefrontal Cortex/drug effects , Receptors, Metabotropic Glutamate/agonists , Resorcinols/pharmacology , Schizophrenia/drug therapy , Schizophrenic Psychology , Somatostatin/metabolism , Animals , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/physiopathology , Cognitive Dysfunction/psychology , Disease Models, Animal , Female , GABAergic Neurons/drug effects , GABAergic Neurons/metabolism , Glycine/pharmacology , Interneurons/metabolism , Male , Memory, Short-Term/drug effects , Mice, Inbred C57BL , Mice, Transgenic , Neural Inhibition/drug effects , Prefrontal Cortex/metabolism , Prefrontal Cortex/physiopathology , Rats, Sprague-Dawley , Receptors, Metabotropic Glutamate/metabolism , Schizophrenia/metabolism , Schizophrenia/physiopathology , Somatostatin/geneticsABSTRACT
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, PFC hyperactivity is associated with inappropriate fear in safe situations. We previously reported a form of muscarinic acetylcholine receptor (mAChR)-dependent long-term depression 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 whether this long-term depression 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 M1 mAChRs in conditioned fear extinction in control mice and in the stress-enhanced fear-learning model. RESULTS: M1 mAChR activation induced long-term depression at inputs from the ventral hippocampus and basolateral amygdala but not from the mediodorsal nucleus of the thalamus. We found that systemic M1 mAChR antagonism impaired contextual fear extinction. Treatment with an M1 positive allosteric modulator enhanced contextual fear extinction consolidation in stress-enhanced fear learning-conditioned mice. CONCLUSIONS: M1 mAChRs dynamically modulate synaptic transmission at two PFC inputs whose activity is necessary for fear extinction, and M1 mAChR function is required for proper contextual fear extinction. Furthermore, an M1 positive allosteric modulator enhanced the consolidation of fear extinction in the stress-enhanced fear-learning model, suggesting that M1 positive allosteric modulators may provide a novel treatment strategy to facilitate exposure therapy in the clinic for the treatment of posttraumatic stress disorder.
