mGlu1 potentiation enhances prelimbic somatostatin interneuron activity to rescue schizophrenia-like physiological and cognitive deficits
James Maksymetz,
Nellie E. Byun,
Deborah J. Luessen,
Brianna Li,
Robert L. Barry,
John C. Gore,
Colleen M. Niswender,
Craig W. Lindsley,
Max E. Joffe,
P. Jeffrey Conn
Affiliations
James Maksymetz
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA
Nellie E. Byun
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Deborah J. Luessen
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA
Brianna Li
Vanderbilt University, Nashville, TN 37232, USA
Robert L. Barry
Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Radiology & Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA
John C. Gore
Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Radiology & Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA
Colleen M. Niswender
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232, USA
Craig W. Lindsley
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
Max E. Joffe
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA
P. Jeffrey Conn
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232, USA; Corresponding author
Summary: 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.
