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1.
J Neurochem ; 155(5): 538-558, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32374912

RESUMO

Individuals with Fragile X Syndrome (FXS) and autism spectrum disorder (ASD) exhibit cognitive impairments, social deficits, increased anxiety, and sensory hyperexcitability. Previously, we showed that elevated levels of matrix metalloproteinase-9 (MMP-9) may contribute to abnormal development of parvalbumin (PV) interneurons and perineuronal nets (PNNs) in the developing auditory cortex (AC) of Fmr1 knock-out (KO) mice, which likely underlie auditory hypersensitivity. Thus, MMP-9 may serve as a potential target for treatment of auditory hypersensitivity in FXS. Here, we used the MMP-2/9 inhibitor, SB-3CT, to pharmacologically inhibit MMP-9 activity during a specific developmental period and to test whether inhibition of MMP-9 activity reverses neural oscillation deficits and behavioral impairments by enhancing PNN formation around PV cells in Fmr1 KO mice. Electroencephalography (EEG) was used to measure resting state and sound-evoked electrocortical activity in auditory and frontal cortices of postnatal day (P)22-23 male mice before and one-day after treatment with SB-3CT (25 mg/kg) or vehicle. At P27-28, animal behaviors were tested to measure the effects of the treatment on anxiety and hyperactivity. Results show that acute inhibition of MMP-9 activity improved evoked synchronization to auditory stimuli and ameliorated mouse behavioral deficits. MMP-9 inhibition enhanced PNN formation, increased PV levels and TrkB phosphorylation yet reduced Akt phosphorylation in the AC of Fmr1 KO mice. Our results show that MMP-9 inhibition during early postnatal development is beneficial in reducing some auditory processing deficits in the FXS mouse model and may serve as a candidate therapeutic for reversing sensory hypersensitivity in FXS and possibly other ASDs.


Assuntos
Estimulação Acústica/métodos , Percepção Auditiva/fisiologia , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Compostos Heterocíclicos com 1 Anel/farmacologia , Metaloproteinase 9 da Matriz/metabolismo , Rede Nervosa/metabolismo , Sulfonas/farmacologia , Animais , Animais Recém-Nascidos , Córtex Auditivo/efeitos dos fármacos , Córtex Auditivo/metabolismo , Percepção Auditiva/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Inibidores Enzimáticos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Rede Nervosa/efeitos dos fármacos , Nervos Periféricos/crescimento & desenvolvimento , Nervos Periféricos/metabolismo
2.
Neurobiol Dis ; 138: 104794, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32036032

RESUMO

Fragile X Syndrome (FXS) is a leading known genetic cause of intellectual disability with symptoms that include increased anxiety and social and sensory processing deficits. Recent EEG studies in humans with FXS have identified neural oscillation deficits that include increased resting state gamma power, increased amplitude of auditory evoked potentials, and reduced inter-trial phase coherence of sound-evoked gamma oscillations. Identification of comparable EEG biomarkers in mouse models of FXS could facilitate the pre-clinical to clinical therapeutic pipeline. However, while human EEG studies have involved 128-channel scalp EEG acquisition, no mouse studies have been performed with more than three EEG channels. In the current study, we employed a recently developed 30-channel mouse multielectrode array (MEA) system to record and analyze resting and stimulus-evoked EEG signals in WT vs. Fmr1 KO mice. Using this system, we now report robust MEA-derived phenotypes including higher resting EEG power, altered event-related potentials (ERPs) and reduced inter-trial phase coherence to auditory chirp stimuli in Fmr1 KO mice that are remarkably similar to those reported in humans with FXS. We propose that the MEA system can be used for: (i) derivation of higher-level EEG parameters; (ii) EEG biomarkers for drug testing; and (ii) mechanistic studies of FXS pathophysiology.


Assuntos
Eletroencefalografia , Síndrome do Cromossomo X Frágil/fisiopatologia , Estimulação Acústica , Animais , Córtex Auditivo/fisiopatologia , Biomarcadores , Modelos Animais de Doenças , Potenciais Evocados , Potenciais Evocados Auditivos , Proteína do X Frágil da Deficiência Intelectual , Camundongos , Camundongos Knockout , Microeletrodos , Fenótipo
3.
Cereb Cortex ; 30(3): 969-988, 2020 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-31364704

RESUMO

Fragile X syndrome (FXS) is a leading genetic cause of autism with symptoms that include sensory processing deficits. In both humans with FXS and a mouse model [Fmr1 knockout (KO) mouse], electroencephalographic (EEG) recordings show enhanced resting state gamma power and reduced sound-evoked gamma synchrony. We previously showed that elevated levels of matrix metalloproteinase-9 (MMP-9) may contribute to these phenotypes by affecting perineuronal nets (PNNs) around parvalbumin (PV) interneurons in the auditory cortex of Fmr1 KO mice. However, how different cell types within local cortical circuits contribute to these deficits is not known. Here, we examined whether Fmr1 deletion in forebrain excitatory neurons affects neural oscillations, MMP-9 activity, and PV/PNN expression in the auditory cortex. We found that cortical MMP-9 gelatinase activity, mTOR/Akt phosphorylation, and resting EEG gamma power were enhanced in CreNex1/Fmr1Flox/y conditional KO (cKO) mice, whereas the density of PV/PNN cells was reduced. The CreNex1/Fmr1Flox/y cKO mice also show increased locomotor activity, but not the anxiety-like behaviors. These results indicate that fragile X mental retardation protein changes in excitatory neurons in the cortex are sufficient to elicit cellular, electrophysiological, and behavioral phenotypes in Fmr1 KO mice. More broadly, these results indicate that local cortical circuit abnormalities contribute to sensory processing deficits in autism spectrum disorders.


Assuntos
Córtex Auditivo/fisiopatologia , Comportamento Animal , Proteína do X Frágil da Deficiência Intelectual/fisiologia , Síndrome do Cromossomo X Frágil/fisiopatologia , Neurônios/fisiologia , Prosencéfalo/fisiopatologia , Estimulação Acústica , Animais , Modelos Animais de Doenças , Eletroencefalografia , Feminino , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Ritmo Gama , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Transdução de Sinais
4.
Neurobiol Dis ; 115: 39-48, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29605426

RESUMO

Identification of comparable biomarkers in humans and validated animal models will facilitate pre-clinical to clinical therapeutic pipelines to treat neurodevelopmental disorders. Fragile X Syndrome (FXS) is a leading known genetic cause of intellectual disability with symptoms that include increased anxiety, social and sensory processing deficits. Recent EEG studies in humans with FXS have identified neural oscillation deficits that include enhanced resting state gamma power and reduced inter-trial coherence of sound evoked gamma oscillations. To determine if analogous phenotypes are present in an animal model of FXS, we recorded EEGs in awake, freely moving Fmr1 knock out (KO) mice using similar stimuli as in the human studies. We report remarkably similar neural oscillation phenotypes in the Fmr1 KO mouse including enhanced resting state gamma power and reduced evoked gamma synchronization. The gamma band inter-trial coherence of neural response was reduced in both auditory and frontal cortex of Fmr1 KO mice stimulated with a sound whose envelope was modulated from 1 to 100 Hz, similar to that seen in humans with FXS. These deficits suggest a form of enhanced 'resting state noise' that interferes with the ability of the circuit to mount a synchronized response to sensory input, predicting specific sensory and cognitive deficits in FXS. The abnormal gamma oscillations are consistent with parvalbumin neuron and perineuronal net deficits seen in the Fmr1 KO mouse auditory cortex indicating that the EEG biomarkers are not only clinically relevant, but could also be used to probe cellular and circuit mechanisms of sensory hypersensitivity in FXS.


Assuntos
Modelos Animais de Doenças , Eletroencefalografia/métodos , Síndrome do Cromossomo X Frágil/fisiopatologia , Fenótipo , Pesquisa Translacional Biomédica/métodos , Estimulação Acústica/métodos , Animais , Córtex Auditivo/fisiopatologia , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Lobo Frontal/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
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