Presentation Title

A Mouse Model for investigating MMP-9 inhibition on cellular and behavior deficits associated with Fragile X Syndrome.

Presenter Information

Walker WoodardFollow

Faculty Mentor

Iryna Ethell

Start Date

23-11-2019 1:15 PM

End Date

23-11-2019 1:30 PM

Location

Markstein 210

Session

oral 3

Type of Presentation

Oral Talk

Subject Area

biological_agricultural_sciences

Abstract

Fragile X Syndrome (FXS) is a neurodevelopmental disorder that causes cognitive impairments and behavior deficits. FXS is the most common monogenetic form of autism spectrum disorders (ASD). Symptoms of FXS include anxiety, repetitive behaviors, social communication deficits, and abnormal sensory processing. An Fmr1 gene mutation leads to reduced Fragile X Mental Retardation Protein (FMRP) expression. FMRP negatively regulates an influential enzyme called matrix metalloproteinase-9 (MMP-9). MMP-9 is a type of zinc-dependant endopeptidase that is involved in synaptic organization during early postnatal development. MMP-9 levels are elevated in the brains of Fmr1 Knock Out (KO) mice and FXS postmortem brain tissues. This increased MMP-9 activity may delay the maturation of neuronal circuits and extend the normal developmental window. In this study, we tested whether acute treatment with an MMP-9 inhibitor, SB-3CT, rescues symptoms associated with FXS in developing Fmr1 KO mice. I hypothesize that the introduction of SB-3CT during the early postnatal period will normalize MMP-9 activity, cellular impairments, and behavior deficits in developing Fmr1 KO mice. This multidisciplinary approach includes pharmacological, anatomical, and behavioral methods such as DQ-gelatin plate assay, immunohistochemistry (IHC), and observational tests. In particular, Elevated Plus Maze has shown that acute treatment with SB-3CT reduces total entries and speed of Fmr1 KO mice, while increasing the percent time they spend in the open arms of the Elevated Plus Maze. This preliminary data indicates that hyperactivity and anxiety-like behaviors are normalized post-treatment. To understand the cellular effects of MMP-9 inhibition, the expression of Parvalbumin (PV) interneurons and Perineuronal nets (PNNs) will be analyzed through IHC. Ultimately, investigating the role of MMP-9 in FXS will aid the development of therapeutics for disorders associated with intellectual disability and autism.

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Nov 23rd, 1:15 PM Nov 23rd, 1:30 PM

A Mouse Model for investigating MMP-9 inhibition on cellular and behavior deficits associated with Fragile X Syndrome.

Markstein 210

Fragile X Syndrome (FXS) is a neurodevelopmental disorder that causes cognitive impairments and behavior deficits. FXS is the most common monogenetic form of autism spectrum disorders (ASD). Symptoms of FXS include anxiety, repetitive behaviors, social communication deficits, and abnormal sensory processing. An Fmr1 gene mutation leads to reduced Fragile X Mental Retardation Protein (FMRP) expression. FMRP negatively regulates an influential enzyme called matrix metalloproteinase-9 (MMP-9). MMP-9 is a type of zinc-dependant endopeptidase that is involved in synaptic organization during early postnatal development. MMP-9 levels are elevated in the brains of Fmr1 Knock Out (KO) mice and FXS postmortem brain tissues. This increased MMP-9 activity may delay the maturation of neuronal circuits and extend the normal developmental window. In this study, we tested whether acute treatment with an MMP-9 inhibitor, SB-3CT, rescues symptoms associated with FXS in developing Fmr1 KO mice. I hypothesize that the introduction of SB-3CT during the early postnatal period will normalize MMP-9 activity, cellular impairments, and behavior deficits in developing Fmr1 KO mice. This multidisciplinary approach includes pharmacological, anatomical, and behavioral methods such as DQ-gelatin plate assay, immunohistochemistry (IHC), and observational tests. In particular, Elevated Plus Maze has shown that acute treatment with SB-3CT reduces total entries and speed of Fmr1 KO mice, while increasing the percent time they spend in the open arms of the Elevated Plus Maze. This preliminary data indicates that hyperactivity and anxiety-like behaviors are normalized post-treatment. To understand the cellular effects of MMP-9 inhibition, the expression of Parvalbumin (PV) interneurons and Perineuronal nets (PNNs) will be analyzed through IHC. Ultimately, investigating the role of MMP-9 in FXS will aid the development of therapeutics for disorders associated with intellectual disability and autism.