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12. Vagus nerve stimulation for stroke rehabilitation: Neural substrates, neuromodulatory effects and therapeutic implications.

Author

Schambra, Heidi M. and Hays, Seth A.

Subjects
*VAGUS nerve stimulation, *NEURAL stimulation, *STROKE rehabilitation, *STROKE, *NEUROMODULATION
Abstract

Paired vagus nerve stimulation (VNS) has emerged as a promising strategy to potentiate recovery after neurological injury. This approach, which combines short bursts of electrical stimulation of the vagus nerve with rehabilitation exercises, received approval from the US Food and Drug Aministration in 2021 as the first neuromodulation‐based therapy for chronic stroke. Because this treatment is increasingly implemented in clinical practice, there is a need to take stock of what we know about this approach and what we have yet to learn. Here, we provide a survey on the foundational basis of VNS therapy for stroke and offer insight into the mechanisms that underlie potentiated recovery, focusing on the principles of neuromodulatory reinforcement. We discuss the current state of observations regarding synaptic reorganization in motor networks that are enhanced by VNS, and we propose other prospective loci of neuromodulation that should be evaluated in the future. Finally, we highlight the future opportunities and challenges to be faced as this approach is increasingly translated to clinical use. Collectively, a clearer understanding of the mechanistic basis of VNS therapy may reveal ways to maximize its benefits. [ABSTRACT FROM AUTHOR]

Published
2024
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19. Selective Disruption of Metabotropic Glutamate Receptor 5-Homer Interactions Mimics Phenotypes of Fragile X Syndrome in Mice

Author

Guo, Weirui, Molinaro, Gemma, Collins, Katie A, Hays, Seth A, Paylor, Richard, Worley, Paul F, Szumlinski, Karen K, and Huber, Kimberly M

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Intellectual and Developmental Disabilities (IDD), Genetics, Rare Diseases, Pediatric, Autism, Basic Behavioral and Social Science, Fragile X Syndrome, Brain Disorders, Neurosciences, Behavioral and Social Science, Mental Health, 2.1 Biological and endogenous factors, Aetiology, Neurological, Mental health, Animals, Carrier Proteins, Fragile X Mental Retardation Protein, Gene Knock-In Techniques, Homer Scaffolding Proteins, In Vitro Techniques, MAP Kinase Signaling System, Mice, Mice, Inbred C57BL, Mice, Knockout, Neocortex, Phenotype, Receptor, Metabotropic Glutamate 5, Seizures, Sensory Gating, fragile X syndrome, Homer, LTD, mGluR5, protein synthesis, UP states, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

Altered function of the Gq-coupled, Group 1 metabotropic glutamate receptors, specifically mGlu5, is implicated in multiple mouse models of autism and intellectual disability. mGlu5 dysfunction has been most well characterized in the fragile X syndrome mouse model, the Fmr1 knock-out (KO) mouse, where pharmacological and genetic reduction of mGlu5 reverses many phenotypes. mGlu5 is less associated with its scaffolding protein Homer in Fmr1 KO mice, and restoration of mGlu5-Homer interactions by genetic deletion of a short, dominant negative of Homer, H1a, rescues many phenotypes of Fmr1 KO mice. These results suggested that disruption of mGlu5-Homer leads to phenotypes of FXS. To test this idea, we examined mice with a knockin mutation of mGlu5 (F1128R; mGlu5(R/R)) that abrogates binding to Homer. Although FMRP levels were normal, mGlu5(R/R) mice mimicked multiple phenotypes of Fmr1 KO mice, including reduced mGlu5 association with the postsynaptic density, enhanced constitutive mGlu5 signaling to protein synthesis, deficits in agonist-induced translational control, protein synthesis-independent LTD, neocortical hyperexcitability, audiogenic seizures, and altered behaviors, including anxiety and sensorimotor gating. These results reveal new roles for the Homer scaffolds in regulation of mGlu5 function and implicate a specific molecular mechanism in a complex brain disease.Significance statementAbnormal function of the metabotropic, or Gq-coupled, glutamate receptor 5 (mGlu5) has been implicated in neurodevelopmental disorders, including a genetic cause of intellectual disability and autism called fragile X syndrome. In brains of a mouse model of fragile X, mGlu5 is less associated with its binding partner Homer, a scaffolding protein that regulates mGlu5 localization to synapses and its ability to activate biochemical signaling pathways. Here we show that a mouse expressing a mutant mGlu5 that cannot bind to Homer is sufficient to mimic many of the biochemical, neurophysiological, and behavioral symptoms observed in the fragile X mouse. This work provides strong evidence that Homer-mGlu5 binding contributes to symptoms associated with neurodevelopmental disorders.

Published
2016

42. Contributors

Author

Abdelmalek, Mohab, Abd-Elsayed, Alaa, Adler, Emerald P, Ardell, Jeffrey L., Bautista, Alexander, Bennett, Samuel, Blake, Justyna, Bremner, J. Douglas, Chakravarthy, Krishnan, Chitneni, Ahish, Covalin, Alejandro, Czura, Christopher J., Das, Undurti N., De Ridder, Dirk, Elberson, Brooke, Elmati, Praveen Reddy, Erb, Matt, Errico, J.P., Farley, Josiah, Farmer, Adam D, Fatimah, Mozawalla, Feoktistov, Alexander, Fritz, Jason R., Garg, Shuchita, Goadsby, P.J., Gottfried-Blackmore, Andres, Gurel, Nil Z., Hadaya, Joseph, Halaris, Angelos, Hanscom, David, Hays, Seth A., Huston, Jared M., Ibrahim, Marco, Inan, Omer T., Jain, Esha, Jones, Eric, Khodaparast, Navid, Kilgard, Michael P., Kimmell, Samuel, Kinfe, Thomas M., Mathis, Keisa W., McReavy, Blake, Mehta, Puja K., Mogilevski, Tamara, Moreno-Ajona, D., Ng, Wan-Fai, Nguyen, Linda, Oehlermarx, Whitman, Palys, Viktoras, Park, Jeanie, Patel, Nishil, Petersen, Erika, Pinto, Ines Figueiredo, Porges, Stephen W., Rafter, Daniel, Rangon, Claire-Marie, Rennaker, Robert L., 2nd, Russo, Marc A., Samadani, Uzma, Samanta, Debopam, Shehata, Peter, Shiferaw, Barnabas, Simon, Bruce J., Singh, Omesh, Smith, Trozalla, Staats, Peter S., Tarn, Jessica, Turner, Ryan, Vandenbussche, N., Vanneste, Sven, Washburn, Stephanie N., Wigginton, Jane G., Wittbrodt, Matthew T., Woodbury, Anna, and Yadala, Sisira

Published
2025
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