Genetic Reduction of Matrix Metalloproteinase-9 Promotes Formation of Perineuronal Nets Around Parvalbumin-Expressing Interneurons and Normalizes Auditory Cortex Responses in Developing Fmr1 Knock-Out Mice. 2018

Teresa H Wen, and Sonia Afroz, and Sarah M Reinhard, and Arnold R Palacios, and Kendal Tapia, and Devin K Binder, and Khaleel A Razak, and Iryna M Ethell
Division of Biomedical Sciences, University of California Riverside School of Medicine, Riverside, CA, USA.

Abnormal sensory responses associated with Fragile X Syndrome (FXS) and autism spectrum disorders include hypersensitivity and impaired habituation to repeated stimuli. Similar sensory deficits are also observed in adult Fmr1 knock-out (KO) mice and are reversed by genetic deletion of Matrix Metalloproteinase-9 (MMP-9) through yet unknown mechanisms. Here we present new evidence that impaired development of parvalbumin (PV)-expressing inhibitory interneurons may underlie hyper-responsiveness in auditory cortex of Fmr1 KO mice via MMP-9-dependent regulation of perineuronal nets (PNNs). First, we found that PV cell development and PNN formation around GABAergic interneurons were impaired in developing auditory cortex of Fmr1 KO mice. Second, MMP-9 levels were elevated in P12-P18 auditory cortex of Fmr1 KO mice and genetic reduction of MMP-9 to WT levels restored the formation of PNNs around PV cells. Third, in vivo single-unit recordings from auditory cortex neurons showed enhanced spontaneous and sound-driven responses in developing Fmr1 KO mice, which were normalized following genetic reduction of MMP-9. These findings indicate that elevated MMP-9 levels contribute to the development of sensory hypersensitivity by influencing formation of PNNs around PV interneurons suggesting MMP-9 as a new therapeutic target to reduce sensory deficits in FXS and potentially other autism spectrum disorders.

UI MeSH Term Description Entries
D007395 Interneurons Most generally any NEURONS which are not motor or sensory. Interneurons may also refer to neurons whose AXONS remain within a particular brain region in contrast to projection neurons, which have axons projecting to other brain regions. Intercalated Neurons,Intercalated Neuron,Interneuron,Neuron, Intercalated,Neurons, Intercalated
D008297 Male Males
D009415 Nerve Net A meshlike structure composed of interconnecting nerve cells that are separated at the synaptic junction or joined to one another by cytoplasmic processes. In invertebrates, for example, the nerve net allows nerve impulses to spread over a wide area of the net because synapses can pass information in any direction. Neural Networks (Anatomic),Nerve Nets,Net, Nerve,Nets, Nerve,Network, Neural (Anatomic),Networks, Neural (Anatomic),Neural Network (Anatomic)
D010320 Parvalbumins Low molecular weight, calcium binding muscle proteins. Their physiological function is possibly related to the contractile process. Parvalbumin,Parvalbumin B
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
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
D001303 Auditory Cortex The region of the cerebral cortex that receives the auditory radiation from the MEDIAL GENICULATE BODY. Brodmann Area 41,Brodmann Area 42,Brodmann's Area 41,Heschl Gyrus,Heschl's Gyrus,Auditory Area,Heschl's Convolutions,Heschl's Gyri,Primary Auditory Cortex,Temporal Auditory Area,Transverse Temporal Gyri,Area 41, Brodmann,Area 41, Brodmann's,Area 42, Brodmann,Area, Auditory,Area, Temporal Auditory,Auditory Areas,Auditory Cortex, Primary,Brodmanns Area 41,Cortex, Auditory,Cortex, Primary Auditory,Gyrus, Heschl,Gyrus, Heschl's,Gyrus, Transverse Temporal,Heschl Convolutions,Heschl Gyri,Heschls Convolutions,Heschls Gyri,Heschls Gyrus,Primary Auditory Cortices,Temporal Auditory Areas,Temporal Gyrus, Transverse,Transverse Temporal Gyrus
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
D059330 GABAergic Neurons Neurons whose primary neurotransmitter is GAMMA-AMINOBUTYRIC ACID. GABA Cells,GABA Neurons,Cell, GABA,Cells, GABA,GABA Cell,GABA Neuron,GABAergic Neuron,Neuron, GABA,Neuron, GABAergic,Neurons, GABA,Neurons, GABAergic

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