GPCR modulation of prefrontal cortex circuits
We investigate G protein-coupled receptors to identify breakthrough treatment for psychiatric disease.
What we do
The laboratory’s goal is to identify, scrutinize, and validate novel druggable targets for the treatment of alcohol use disorders, substance use disorders disorders, and other diseases. While the advent of optogenetics and sophisticated gene editing technology provides exciting opportunities for the development of next-generation psychiatric treatments, pharmacological approaches retain theoretical and practical advantages for the rapid delivery of new therapies. Our laboratory therefore aims to leverage contemporary neuroscience techniques to investigate how G protein-coupled receptors (GPCRs) regulate discrete prefrontal cortex circuits.
Researchers in our laboratory ask:
How do GPCRs regulate neuronal activity, synaptic plasticity, and animal behavior?
How do disease-relevant experiences usurp, impair, or modify synaptic plasticity mechanisms?
How can we leverage this information to identify new psychiatric treatments?
Our research approaches these questions from several angles. Trainees in the laboratory have opportunities to train extensively in whole-cell patch-clamp electrophysiology, optogenetics-assisted circuit mapping, in vivo biosensor-based imaging, and rodent behavioral techniques.
Recent Publicaions
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Parvalbumin interneuron mGlu 5 receptors govern sex differences in prefrontal cortex physiology and binge drinking.
Fabian CB, Jordan ND, Cole RH, Carley LG, Thompson SM, Seney ML, Joffe ME. Neuropsychopharmacology. 2024 May 21. doi: 10.1038/s41386-024-01889-0. Online ahead of print. PMID: 38773314
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Acute alcohol and chronic drinking bidirectionally regulate the excitability of prefrontal cortex vasoactive intestinal peptide interneurons.
Thompson SM, Fabian CB, Ferranti AS, Joffe ME. Neuropharmacology. 2023 Nov 1;238:109638. doi: 10.1016/j.neuropharm.2023.109638. Epub 2023 Jul 22. PMID: 37482180.
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Prefrontal cortex parvalbumin interneurons exhibit decreased excitability and potentiated synaptic strength after ethanol reward learning.
Ferranti AS, Johnson KA, Winder DG, Conn PJ, Joffe ME. Alcohol. 2022 Feb 26; 101:17-26. doi: 10.1016.j.alcohol.2022.02.003
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Acute stress redirects prefrontal cortex circuit function through mGlu 5 receptor plasticity on somatostatin-expressing interneurons.
Joffe ME†, Maksymetz J, Luschinger JR, Dogra S, Ferranti AS, Luessen DJ, Gallinger IM, Xiang Z, Branthwaite H, Melugin PR, Williford KM, Centanni SW, Shields BC, Lindsley CW, Calipari ES, Siciliano CA, Niswender CM, Tadross MR, Winder DG, and Conn PJ†. Neuron. 2022 Mar 16;110(6):1068-1083. (†: co-corresponding authors)
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mGlu1 potentiation enhances cortical somatostatin interneuron activity to rescue schizophrenia-like physiological and cognitive deficits.
Maksymetz J, Byun NE, Luessen DJ, Li B, Barry R, Gore JC, Niswender CM, Lindsley CW, Joffe ME, Conn PJ. Cell Reports. In press.
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mGlu2 and mGlu3 negative allosteric modulators divergently potentiate thalamocortical transmission and exert rapid antidepressant-like effects.
Joffe ME, Santiago CI, Oliver KH, Maksymetz J, Harris NA, Engers JL, Lindsley CW, Winder DG, Conn PJ. Neuron. 2020 Jan 8;105(1)46-59. pii: S0896-6273(19)30847-5. doi: 10.1016/j.neuron.2019.09.044. Epub 2019 Nov 14.
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Mechanisms underlying prelimbic prefrontal cortex mGlu3/mGlu5-dependent plasticity and reversal learning deficits following acute stress.
Joffe ME, Santiago CI, Stansley BJ, Maksymetz J, Gogliotti RG, Engers JL, Nicoletti F, Lindsley CW & Conn, PJ. Neuropharmacology. 2019 Jan;144:19-28. doi: 10.1016/j.neuropharm.2018.10.013.
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Metabotropic glutamate receptor subtype 3 gates acute stress-induced dysregulation of amygdala-cortical function.
Joffe ME, Santiago CI, Engers JL, Lindsley CW, Conn PJ. Molecular Psychiatry. 2019 Jun; 24(6):916-927. doi:10.1038/s41380-017-0015-z. Epub 2017 Dec 21.
