Genetic reduction of MMP-9 in the Fmr1 KO mouse partially rescues prepulse inhibition of acoustic startle response
| Autor: | Erin M. Alderson, Sarah M. Reinhard, Jamiela Kokash, Cynthia A. Crawford, Devin K. Binder, Khaleel A. Razak, Iryna M. Ethell |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Inferior colliculus Male Startle response Reflex Startle medicine.medical_treatment Autism Sensorimotor gating Mice Fragile X Mental Retardation Protein 0302 clinical medicine 2.1 Biological and endogenous factors Psychology Aetiology Prepulse inhibition Mice Knockout Pediatric medicine.diagnostic_test Prepulse Inhibition General Neuroscience Startle Matrix metalloproteinase-9 Sensory Gating Fragile X syndrome Phenotype Mental Health Matrix Metalloproteinase 9 Cognitive Sciences Acoustic startle response medicine.medical_specialty congenital hereditary and neonatal diseases and abnormalities Sensory processing Genotype Knockout Intellectual and Developmental Disabilities (IDD) Sensory system Article 03 medical and health sciences Rare Diseases Internal medicine Reflex medicine Genetics Animals Molecular Biology Neurology & Neurosurgery business.industry Animal Wild type Neurosciences medicine.disease FMR1 Brain Disorders Disease Models Animal 030104 developmental biology Endocrinology Acoustic Stimulation Fragile X Syndrome Disease Models Neurology (clinical) business 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | Brain Res |
| Popis: | Sensory processing abnormalities are consistently associated with autism, but the underlying mechanisms and treatment options are unclear. Fragile X Syndrome (FXS) is the leading known genetic cause of intellectual disabilities and autism. One debilitating symptom of FXS is hypersensitivity to sensory stimuli. Sensory hypersensitivity is seen in both humans with FXS and FXS mouse model, the Fmr1 knock out (Fmr1 KO) mouse. Abnormal sensorimotor gating may play a role in the hypersensitivity to sensory stimuli. Humans with FXS and Fmr1 KO mice show abnormalities in acoustic startle response (ASR) and prepulse inhibition (PPI) of startle, responses commonly used to quantify sensorimotor gating. Recent studies have suggested abnormally high levels of matrix metalloproteinase-9 (MMP-9) as a potential mechanism of sensory abnormalities in FXS. Here we tested the hypothesis that genetic reduction of MMP-9 in Fmr1 KO mice rescues ASR and PPI phenotypes in adult Fmr1 KO mice. We measured MMP-9 levels in the inferior colliculus (IC), an integral region of the PPI circuit, of WT and Fmr1 KO mice at P7, P12, P18, and P40. MMP-9 levels were higher in the IC of Fmr1 KO mice during early development (P7, P12), but not in adults. We compared ASR and PPI responses in young (P23–25) and adult (P50–80) Fmr1 KO mice to their age-matched wildtype (WT) controls. We found that both ASR and PPI were reduced in the young Fmr1 KO mice compared to age-matched WT mice. There was no genotype difference for ASR in the adult mice, but PPI was significantly reduced in the adult Fmr1 KO mice. The adult mouse data are similar to those observed in humans with FXS. Genetic reduction of MMP-9 in the Fmr1 KO mice resulted in a rescue of adult PPI responses to WT levels. Taken together, these results show sensorimotor gating abnormalities in Fmr1 KO mice, and suggest the potential for MMP-9 regulation as a therapeutic target to reduce sensory hypersensitivity. |
| Databáze: | OpenAIRE |
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