Shalini Dogra1, Branden J Stansley1, Zixiu Xiang1, Weilun Qian2, Rocco G Gogliotti3, Ferdinando Nicoletti4, Craig W Lindsley5, Colleen M Niswender6, Max E Joffe7, P Jeffrey Conn8. 1. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee. 2. Vanderbilt University, Nashville, Tennessee. 3. Molecular Pharmacology and Neuroscience Department, Loyola University Chicago, Maywood, Illinois. 4. IRCCS Neuromed, Pozzilli, Italy; Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy. 5. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Department of Chemistry, Vanderbilt University, Nashville, Tennessee; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee; Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, Tennessee. 6. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee; Vanderbilt Kennedy Center, Vanderbilt University, Nashville, Tennessee. 7. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee; Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, Tennessee. Electronic address: max.joffe@vanderbilt.edu. 8. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee; Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, Tennessee; Vanderbilt Kennedy Center, Vanderbilt University, Nashville, Tennessee. Electronic address: jeff.conn@vanderbilt.edu.
Abstract
BACKGROUND: Polymorphisms in GRM3, the gene encoding the mGlu3 metabotropic glutamate receptor, are associated with impaired cognition and neuropsychiatric disorders such as schizophrenia. Limited availability of selective genetic and molecular tools has hindered progress in developing a clear understanding of the mechanisms through which mGlu3 receptors regulate synaptic plasticity and cognition. METHODS: We examined associative learning in mice with trace fear conditioning, a hippocampal-dependent learning task disrupted in patients with schizophrenia. Underlying cellular mechanisms were assessed using ex vivo hippocampal slice preparations with selective pharmacological tools and selective genetic deletion of mGlu3 receptor expression in specific neuronal subpopulations. RESULTS: mGlu3 receptor activation enhanced trace fear conditioning and reversed deficits induced by subchronic phencyclidine. Mechanistic studies revealed that mGlu3 receptor activation induced metaplastic changes, biasing afferent stimulation to induce long-term potentiation through an mGlu5 receptor-dependent, endocannabinoid-mediated, disinhibitory mechanism. Selective genetic deletion of either mGlu3 or mGlu5 from hippocampal pyramidal cells eliminated effects of mGlu3 activation, revealing a novel mechanism by which mGlu3 and mGlu5 interact to enhance cognitive function. CONCLUSIONS: These data demonstrate that activation of mGlu3 receptors in hippocampal pyramidal cells enhances hippocampal-dependent cognition in control and impaired mice by inducing a novel form of metaplasticity to regulate circuit function, providing a clear mechanism through which genetic variation in GRM3 can contribute to cognitive deficits. Developing approaches to positively modulate mGlu3 receptor function represents an encouraging new avenue for treating cognitive disruption in schizophrenia and other psychiatric diseases.
BACKGROUND: Polymorphisms in GRM3, the gene encoding the mGlu3 metabotropic glutamate receptor, are associated with impaired cognition and neuropsychiatric disorders such as schizophrenia. Limited availability of selective genetic and molecular tools has hindered progress in developing a clear understanding of the mechanisms through which mGlu3 receptors regulate synaptic plasticity and cognition. METHODS: We examined associative learning in mice with trace fear conditioning, a hippocampal-dependent learning task disrupted in patients with schizophrenia. Underlying cellular mechanisms were assessed using ex vivo hippocampal slice preparations with selective pharmacological tools and selective genetic deletion of mGlu3 receptor expression in specific neuronal subpopulations. RESULTS: mGlu3 receptor activation enhanced trace fear conditioning and reversed deficits induced by subchronic phencyclidine. Mechanistic studies revealed that mGlu3 receptor activation induced metaplastic changes, biasing afferent stimulation to induce long-term potentiation through an mGlu5 receptor-dependent, endocannabinoid-mediated, disinhibitory mechanism. Selective genetic deletion of either mGlu3 or mGlu5 from hippocampal pyramidal cells eliminated effects of mGlu3 activation, revealing a novel mechanism by which mGlu3 and mGlu5 interact to enhance cognitive function. CONCLUSIONS: These data demonstrate that activation of mGlu3 receptors in hippocampal pyramidal cells enhances hippocampal-dependent cognition in control and impaired mice by inducing a novel form of metaplasticity to regulate circuit function, providing a clear mechanism through which genetic variation in GRM3 can contribute to cognitive deficits. Developing approaches to positively modulate mGlu3 receptor function represents an encouraging new avenue for treating cognitive disruption in schizophrenia and other psychiatric diseases.
Authors: Julie L Engers; Katrina A Bollinger; Rebecca L Weiner; Alice L Rodriguez; Madeline F Long; Megan M Breiner; Sichen Chang; Sean R Bollinger; Michael Bubser; Carrie K Jones; Ryan D Morrison; Thomas M Bridges; Anna L Blobaum; Colleen M Niswender; P Jeffrey Conn; Kyle A Emmitte; Craig W Lindsley Journal: ACS Med Chem Lett Date: 2017-08-15 Impact factor: 4.345
Authors: A Ghoshal; J M Rook; J W Dickerson; G N Roop; R D Morrison; N Jalan-Sakrikar; A Lamsal; M J Noetzel; M S Poslusney; M R Wood; B J Melancon; S R Stauffer; Z Xiang; J S Daniels; C M Niswender; C K Jones; C W Lindsley; P J Conn Journal: Neuropsychopharmacology Date: 2015-06-25 Impact factor: 7.853
Authors: K J Gregory; E J Herman; A J Ramsey; A S Hammond; N E Byun; S R Stauffer; J T Manka; S Jadhav; T M Bridges; C D Weaver; C M Niswender; T Steckler; W H Drinkenburg; A Ahnaou; H Lavreysen; G J Macdonald; J M Bartolomé; C Mackie; B J Hrupka; M G Caron; T L Daigle; C W Lindsley; P J Conn; C K Jones Journal: J Pharmacol Exp Ther Date: 2013-08-21 Impact factor: 4.030
Authors: Rocco G Gogliotti; Rebecca K Senter; Jerri M Rook; Ayan Ghoshal; Rocio Zamorano; Chrysa Malosh; Shaun R Stauffer; Thomas M Bridges; Jose M Bartolome; J Scott Daniels; Carrie K Jones; Craig W Lindsley; P Jeffrey Conn; Colleen M Niswender Journal: Hum Mol Genet Date: 2016-03-02 Impact factor: 6.150
Authors: Kimberly M Lovell; Andrew S Felts; Alice L Rodriguez; Daryl F Venable; Hyekyung P Cho; Ryan D Morrison; Frank W Byers; J Scott Daniels; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley; Kyle A Emmitte Journal: Bioorg Med Chem Lett Date: 2013-05-17 Impact factor: 2.823
Authors: Sheryl Anne D Vermudez; Aditi Buch; Kelly Weiss; Rocco G Gogliotti; Colleen M Niswender Journal: Neuropharmacology Date: 2022-03-03 Impact factor: 5.250
Authors: Deborah J Luessen; Isabel M Gallinger; Anthony S Ferranti; Daniel J Foster; Bruce J Melancon; Craig W Lindsley; Colleen M Niswender; Jeffrey Conn Journal: Neuropsychopharmacology Date: 2022-05-28 Impact factor: 8.294
Authors: Max E Joffe; James Maksymetz; Joseph R Luschinger; Shalini Dogra; Anthony S Ferranti; Deborah J Luessen; Isabel M Gallinger; Zixiu Xiang; Hannah Branthwaite; Patrick R Melugin; Kellie M Williford; Samuel W Centanni; Brenda C Shields; Craig W Lindsley; Erin S Calipari; Cody A Siciliano; Colleen M Niswender; Michael R Tadross; Danny G Winder; P Jeffrey Conn Journal: Neuron Date: 2022-01-18 Impact factor: 17.173
Authors: Dibyadeep Datta; Shannon N Leslie; Elizabeth Woo; Nishita Amancharla; Ayah Elmansy; Miguel Lepe; Adam P Mecca; Barbara S Slusher; Angus C Nairn; Amy F T Arnsten Journal: Front Aging Neurosci Date: 2021-11-15 Impact factor: 5.750