Disrupted inhibitory plasticity and homeostasis in Fragile X syndrome
Fragile X Syndrome (FXS) is a neurodevelopmental disorder instigated by the absence of a key translation regulating protein, Fragile X Mental Retardation Protein (FMRP). The loss of FMRP in the CNS leads to abnormal synaptic development, disruption of critical periods of plasticity, and an overall d...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-08-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996120302345 |
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| author | C.A. Cea-Del Rio A. Nunez-Parra S.M. Freedman J.K. Kushner A.L. Alexander D. Restrepo M.M. Huntsman |
| author_facet | C.A. Cea-Del Rio A. Nunez-Parra S.M. Freedman J.K. Kushner A.L. Alexander D. Restrepo M.M. Huntsman |
| author_sort | C.A. Cea-Del Rio |
| collection | DOAJ |
| description | Fragile X Syndrome (FXS) is a neurodevelopmental disorder instigated by the absence of a key translation regulating protein, Fragile X Mental Retardation Protein (FMRP). The loss of FMRP in the CNS leads to abnormal synaptic development, disruption of critical periods of plasticity, and an overall deficiency in proper sensory circuit coding leading to hyperexcitable sensory networks. However, little is known about how this hyperexcitable environment affects inhibitory synaptic plasticity. Here, we show that in vivo layer 2/3 of the primary somatosensory cortex of the Fmr1 KO mouse exhibits basal hyperexcitability and an increase in neuronal firing rate suppression during whisker activation. This aligns with our in vitro data that indicate an increase in GABAergic spontaneous activity, a faulty mGluR-mediated inhibitory input and impaired inhibitory plasticity processes. Specifically, we find that mGluR activation sensitivity is overall diminished in the Fmr1 KO mouse leading to both a decreased spontaneous inhibitory postsynaptic input to principal cells and a disrupted form of inhibitory long-term depression (I-LTD). These data suggest an adaptive mechanism that acts to homeostatically counterbalance the cortical hyperexcitability observed in FXS. |
| first_indexed | 2024-12-16T06:11:40Z |
| format | Article |
| id | doaj.art-d6842b0eab834f82902ec60cef08eb19 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-16T06:11:40Z |
| publishDate | 2020-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-d6842b0eab834f82902ec60cef08eb192022-12-21T22:41:23ZengElsevierNeurobiology of Disease1095-953X2020-08-01142104959Disrupted inhibitory plasticity and homeostasis in Fragile X syndromeC.A. Cea-Del Rio0A. Nunez-Parra1S.M. Freedman2J.K. Kushner3A.L. Alexander4D. Restrepo5M.M. Huntsman6Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States of America; CIBAP, Escuela de Medicina, Facultad de Ciencias Medicas, Universidad de Santiago de Chile, Santiago, Chile; University of Colorado, Anschutz Medical Campus, Aurora, CO, United States of AmericaDepartment of Cell and Developmental Biology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States of America; Department of Biology, Universidad de Chile, Santiago, ChileDepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States of AmericaDepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States of America; Department of Neurosurgery, School of Medicine, Anschutz Medical Campus, Aurora, CO, United States of AmericaDepartment of Neurosurgery, School of Medicine, Anschutz Medical Campus, Aurora, CO, United States of AmericaDepartment of Cell and Developmental Biology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States of AmericaDepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States of America; Department of Pediatrics, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States of America; Corresponding author at: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pediatrics School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, United States of America.Fragile X Syndrome (FXS) is a neurodevelopmental disorder instigated by the absence of a key translation regulating protein, Fragile X Mental Retardation Protein (FMRP). The loss of FMRP in the CNS leads to abnormal synaptic development, disruption of critical periods of plasticity, and an overall deficiency in proper sensory circuit coding leading to hyperexcitable sensory networks. However, little is known about how this hyperexcitable environment affects inhibitory synaptic plasticity. Here, we show that in vivo layer 2/3 of the primary somatosensory cortex of the Fmr1 KO mouse exhibits basal hyperexcitability and an increase in neuronal firing rate suppression during whisker activation. This aligns with our in vitro data that indicate an increase in GABAergic spontaneous activity, a faulty mGluR-mediated inhibitory input and impaired inhibitory plasticity processes. Specifically, we find that mGluR activation sensitivity is overall diminished in the Fmr1 KO mouse leading to both a decreased spontaneous inhibitory postsynaptic input to principal cells and a disrupted form of inhibitory long-term depression (I-LTD). These data suggest an adaptive mechanism that acts to homeostatically counterbalance the cortical hyperexcitability observed in FXS.http://www.sciencedirect.com/science/article/pii/S0969996120302345Inhibitory neurotransmissionPlasticityFragile X syndromeInterneuronsCortex |
| spellingShingle | C.A. Cea-Del Rio A. Nunez-Parra S.M. Freedman J.K. Kushner A.L. Alexander D. Restrepo M.M. Huntsman Disrupted inhibitory plasticity and homeostasis in Fragile X syndrome Neurobiology of Disease Inhibitory neurotransmission Plasticity Fragile X syndrome Interneurons Cortex |
| title | Disrupted inhibitory plasticity and homeostasis in Fragile X syndrome |
| title_full | Disrupted inhibitory plasticity and homeostasis in Fragile X syndrome |
| title_fullStr | Disrupted inhibitory plasticity and homeostasis in Fragile X syndrome |
| title_full_unstemmed | Disrupted inhibitory plasticity and homeostasis in Fragile X syndrome |
| title_short | Disrupted inhibitory plasticity and homeostasis in Fragile X syndrome |
| title_sort | disrupted inhibitory plasticity and homeostasis in fragile x syndrome |
| topic | Inhibitory neurotransmission Plasticity Fragile X syndrome Interneurons Cortex |
| url | http://www.sciencedirect.com/science/article/pii/S0969996120302345 |
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