Disrupted inhibitory plasticity and homeostasis in Fragile X syndrome. 2020

C A Cea-Del Rio, and A Nunez-Parra, and S M Freedman, and J K Kushner, and A L Alexander, and D Restrepo, and M M Huntsman
Department 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 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.

UI MeSH Term Description Entries
D009433 Neural Inhibition The function of opposing or restraining the excitation of neurons or their target excitable cells. Inhibition, Neural
D009473 Neuronal Plasticity The capacity of the NERVOUS SYSTEM to change its reactivity as the result of successive activations. Brain Plasticity,Plasticity, Neuronal,Axon Pruning,Axonal Pruning,Dendrite Arborization,Dendrite Pruning,Dendritic Arborization,Dendritic Pruning,Dendritic Remodeling,Neural Plasticity,Neurite Pruning,Neuronal Arborization,Neuronal Network Remodeling,Neuronal Pruning,Neuronal Remodeling,Neuroplasticity,Synaptic Plasticity,Synaptic Pruning,Arborization, Dendrite,Arborization, Dendritic,Arborization, Neuronal,Arborizations, Dendrite,Arborizations, Dendritic,Arborizations, Neuronal,Axon Prunings,Axonal Prunings,Brain Plasticities,Dendrite Arborizations,Dendrite Prunings,Dendritic Arborizations,Dendritic Prunings,Dendritic Remodelings,Network Remodeling, Neuronal,Network Remodelings, Neuronal,Neural Plasticities,Neurite Prunings,Neuronal Arborizations,Neuronal Network Remodelings,Neuronal Plasticities,Neuronal Prunings,Neuronal Remodelings,Neuroplasticities,Plasticities, Brain,Plasticities, Neural,Plasticities, Neuronal,Plasticities, Synaptic,Plasticity, Brain,Plasticity, Neural,Plasticity, Synaptic,Pruning, Axon,Pruning, Axonal,Pruning, Dendrite,Pruning, Dendritic,Pruning, Neurite,Pruning, Neuronal,Pruning, Synaptic,Prunings, Axon,Prunings, Axonal,Prunings, Dendrite,Prunings, Dendritic,Prunings, Neurite,Prunings, Neuronal,Prunings, Synaptic,Remodeling, Dendritic,Remodeling, Neuronal,Remodeling, Neuronal Network,Remodelings, Dendritic,Remodelings, Neuronal,Remodelings, Neuronal Network,Synaptic Plasticities,Synaptic Prunings
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D005600 Fragile X Syndrome A condition characterized genotypically by mutation of the distal end of the long arm of the X chromosome (at gene loci FRAXA or FRAXE) and phenotypically by cognitive impairment, hyperactivity, SEIZURES, language delay, and enlargement of the ears, head, and testes. INTELLECTUAL DISABILITY occurs in nearly all males and roughly 50% of females with the full mutation of FRAXA. (From Menkes, Textbook of Child Neurology, 5th ed, p226) FRAXA Syndrome,FRAXE Syndrome,Martin-Bell Syndrome,Fra(X) Syndrome,Fragile X Mental Retardation Syndrome,Fragile X-F Mental Retardation Syndrome,Mar (X) Syndrome,Marker X Syndrome,Mental Retardation, X-Linked, Associated With Fragile Site Fraxe,Mental Retardation, X-Linked, Associated With Marxq28,X-Linked Mental Retardation and Macroorchidism,FRAXA Syndromes,FRAXE Syndromes,Fragile X Syndromes,Marker X Syndromes,Martin Bell Syndrome,Syndrome, FRAXA,Syndrome, FRAXE,Syndrome, Fragile X,Syndrome, Marker X,Syndrome, Martin-Bell,Syndromes, FRAXA,Syndromes, FRAXE,Syndromes, Fragile X,Syndromes, Marker X,X Linked Mental Retardation and Macroorchidism
D006706 Homeostasis The processes whereby the internal environment of an organism tends to remain balanced and stable. Autoregulation
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013003 Somatosensory Cortex Area of the parietal lobe concerned with receiving sensations such as movement, pain, pressure, position, temperature, touch, and vibration. It lies posterior to the central sulcus. Brodmann Area 1,Brodmann Area 2,Brodmann Area 3,Brodmann Areas 1, 2, 3,Brodmann Areas 1, 2, and 3,Brodmann Areas 3, 1, 2,Brodmann Areas 3, 1, and 2,Brodmann's Area 1,Brodmann's Area 2,Brodmann's Area 3,Brodmann's Areas 1, 2, and 3,Brodmann's Areas 3, 1, and 2,Parietal-Opercular Cortex,Primary Somesthetic Area,S1 Cortex,S2 Cortex,SII Cortex,Anterior Parietal Cortex,Gyrus Postcentralis,Post Central Gyrus,Postcentral Gyrus,Primary Somatic Sensory Area,Primary Somatosensory Area,Primary Somatosensory Areas,Primary Somatosensory Cortex,SI Cortex,Second Somatic Sensory Area,Secondary Sensory Cortex,Secondary Somatosensory Area,Secondary Somatosensory Cortex,Area 1, Brodmann,Area 1, Brodmann's,Area 2, Brodmann,Area 2, Brodmann's,Area 3, Brodmann,Area 3, Brodmann's,Area, Primary Somatosensory,Area, Primary Somesthetic,Area, Secondary Somatosensory,Areas, Primary Somatosensory,Brodmanns Area 1,Brodmanns Area 2,Brodmanns Area 3,Cortex, Anterior Parietal,Cortex, Parietal-Opercular,Cortex, Primary Somatosensory,Cortex, S1,Cortex, S2,Cortex, SI,Cortex, SII,Cortex, Secondary Sensory,Cortex, Secondary Somatosensory,Cortex, Somatosensory,Gyrus, Post Central,Gyrus, Postcentral,Parietal Cortex, Anterior,Parietal Opercular Cortex,Parietal-Opercular Cortices,Primary Somatosensory Cortices,Primary Somesthetic Areas,S1 Cortices,S2 Cortices,SII Cortices,Secondary Somatosensory Areas,Sensory Cortex, Secondary,Somatosensory Area, Primary,Somatosensory Area, Secondary,Somatosensory Areas, Primary,Somatosensory Cortex, Primary,Somatosensory Cortex, Secondary,Somesthetic Area, Primary,Somesthetic Areas, Primary
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D051860 Fragile X Mental Retardation Protein A RNA-binding protein that is found predominately in the CYTOPLASM. It helps regulate GENETIC TRANSLATION in NEURONS and is absent or under-expressed in FRAGILE X SYNDROME. FMRP Protein,Fragile X Mental Retardation-1 Protein,Fragile X Mental Retardation 1 Protein
D053444 Inhibitory Postsynaptic Potentials Hyperpolarization of membrane potentials at the SYNAPTIC MEMBRANES of target neurons during NEUROTRANSMISSION. They are local changes which diminish responsiveness to excitatory signals. IPSP,Inhibitory Postsynaptic Currents,Current, Inhibitory Postsynaptic,Currents, Inhibitory Postsynaptic,IPSPs,Inhibitory Postsynaptic Current,Inhibitory Postsynaptic Potential,Postsynaptic Current, Inhibitory,Postsynaptic Currents, Inhibitory,Postsynaptic Potential, Inhibitory,Postsynaptic Potentials, Inhibitory,Potential, Inhibitory Postsynaptic,Potentials, Inhibitory Postsynaptic

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