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1.
Neurobiol Dis ; 200: 106628, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39111703

RESUMO

Autism Spectrum Disorders (ASD) encompass a wide array of debilitating symptoms, including severe sensory deficits and abnormal language development. Sensory deficits early in development may lead to broader symptomatology in adolescents and adults. The mechanistic links between ASD risk genes, sensory processing and language impairment are unclear. There is also a sex bias in ASD diagnosis and symptomatology. The current study aims to identify the developmental trajectory and genotype- and sex-dependent differences in auditory sensitivity and temporal processing in a Pten-deletion (phosphatase and tensin homolog missing on chromosome 10) mouse model of ASD. Auditory temporal processing is crucial for speech recognition and language development and deficits will cause language impairments. However, very little is known about the development of temporal processing in ASD animal models, and if there are sex differences. To address this major gap, we recorded epidural electroencephalography (EEG) signals from the frontal (FC) and auditory (AC) cortex in developing and adult Nse-cre PTEN mice, in which Pten is deleted in specific cortical layers (layers III-V) (PTEN conditional knock-out (cKO). We quantified resting EEG spectral power distribution, auditory event related potentials (ERP) and temporal processing from awake and freely moving male and female mice. Temporal processing is measured using a gap-in-noise-ASSR (auditory steady state response) stimulus paradigm. The experimental manipulation of gap duration and modulation depth allows us to measure cortical entrainment to rapid gaps in sounds. Temporal processing was quantified using inter-trial phase clustering (ITPC) values that account for phase consistency across trials. The results show genotype differences in resting power distribution in PTEN cKO mice throughout development. Male and female cKO mice have significantly increased beta power but decreased high frequency oscillations in the AC and FC. Both male and female PTEN cKO mice show diminished ITPC in their gap-ASSR responses in the AC and FC compared to control mice. Overall, deficits become more prominent in adult (p60) mice, with cKO mice having significantly increased sound evoked power and decreased ITPC compared to controls. While both male and female cKO mice demonstrated severe temporal processing deficits across development, female cKO mice showed increased hypersensitivity compared to males, reflected as increased N1 and P2 amplitudes. These data identify a number of novel sensory processing deficits in a PTEN-ASD mouse model that are present from an early age. Abnormal temporal processing and hypersensitive responses may contribute to abnormal development of language function in ASD.


Assuntos
Percepção Auditiva , Transtorno do Espectro Autista , PTEN Fosfo-Hidrolase , Caracteres Sexuais , Animais , Feminino , Masculino , Camundongos , Estimulação Acústica , Córtex Auditivo/fisiopatologia , Córtex Auditivo/crescimento & desenvolvimento , Percepção Auditiva/fisiologia , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Modelos Animais de Doenças , Eletroencefalografia , Potenciais Evocados Auditivos/fisiologia , Camundongos Knockout , PTEN Fosfo-Hidrolase/genética
2.
J Neurodev Disord ; 16(1): 24, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38720271

RESUMO

BACKGROUND: Autism spectrum disorder (ASD) is currently diagnosed in approximately 1 in 44 children in the United States, based on a wide array of symptoms, including sensory dysfunction and abnormal language development. Boys are diagnosed ~ 3.8 times more frequently than girls. Auditory temporal processing is crucial for speech recognition and language development. Abnormal development of temporal processing may account for ASD language impairments. Sex differences in the development of temporal processing may underlie the differences in language outcomes in male and female children with ASD. To understand mechanisms of potential sex differences in temporal processing requires a preclinical model. However, there are no studies that have addressed sex differences in temporal processing across development in any animal model of ASD. METHODS: To fill this major gap, we compared the development of auditory temporal processing in male and female wildtype (WT) and Fmr1 knock-out (KO) mice, a model of Fragile X Syndrome (FXS), a leading genetic cause of ASD-associated behaviors. Using epidural screw electrodes, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (ASSR) paradigm at young (postnatal (p)21 and p30) and adult (p60) ages from both auditory and frontal cortices of awake, freely moving mice. RESULTS: The results show that ERP amplitudes were enhanced in both sexes of Fmr1 KO mice across development compared to WT counterparts, with greater enhancement in adult female than adult male KO mice. Gap-ASSR deficits were seen in the frontal, but not auditory, cortex in early development (p21) in female KO mice. Unlike male KO mice, female KO mice show WT-like temporal processing at p30. There were no temporal processing deficits in the adult mice of both sexes. CONCLUSIONS: These results show a sex difference in the developmental trajectories of temporal processing and hypersensitive responses in Fmr1 KO mice. Male KO mice show slower maturation of temporal processing than females. Female KO mice show stronger hypersensitive responses than males later in development. The differences in maturation rates of temporal processing and hypersensitive responses during various critical periods of development may lead to sex differences in language function, arousal and anxiety in FXS.


Assuntos
Modelos Animais de Doenças , Potenciais Evocados Auditivos , Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil , Camundongos Knockout , Caracteres Sexuais , Animais , Síndrome do Cromossomo X Frágil/fisiopatologia , Feminino , Masculino , Camundongos , Potenciais Evocados Auditivos/fisiologia , Proteína do X Frágil da Deficiência Intelectual/genética , Percepção Auditiva/fisiologia , Transtorno do Espectro Autista/fisiopatologia , Córtex Auditivo/fisiopatologia , Camundongos Endogâmicos C57BL
3.
Cell Rep ; 43(4): 114056, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38581678

RESUMO

Little is known of the brain mechanisms that mediate sex-specific autism symptoms. Here, we demonstrate that deletion of the autism spectrum disorder (ASD)-risk gene, Pten, in neocortical pyramidal neurons (NSEPten knockout [KO]) results in robust cortical circuit hyperexcitability selectively in female mice observed as prolonged spontaneous persistent activity states. Circuit hyperexcitability in females is mediated by metabotropic glutamate receptor 5 (mGluR5) and estrogen receptor α (ERα) signaling to mitogen-activated protein kinases (Erk1/2) and de novo protein synthesis. Pten KO layer 5 neurons have a female-specific increase in mGluR5 and mGluR5-dependent protein synthesis. Furthermore, mGluR5-ERα complexes are generally elevated in female cortices, and genetic reduction of ERα rescues enhanced circuit excitability, protein synthesis, and neuron size selectively in NSEPten KO females. Female NSEPten KO mice display deficits in sensory processing and social behaviors as well as mGluR5-dependent seizures. These results reveal mechanisms by which sex and a high-confidence ASD-risk gene interact to affect brain function and behavior.


Assuntos
Transtorno Autístico , Modelos Animais de Doenças , Receptor alfa de Estrogênio , Camundongos Knockout , Neocórtex , PTEN Fosfo-Hidrolase , Receptor de Glutamato Metabotrópico 5 , Animais , Feminino , Masculino , Camundongos , Transtorno Autístico/metabolismo , Transtorno Autístico/fisiopatologia , Transtorno Autístico/genética , Transtorno Autístico/patologia , Receptor alfa de Estrogênio/metabolismo , Camundongos Endogâmicos C57BL , Neocórtex/metabolismo , Neocórtex/patologia , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/genética , Células Piramidais/metabolismo , Receptor de Glutamato Metabotrópico 5/metabolismo , Comportamento Social
4.
Neurobiol Dis ; 195: 106496, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38582333

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 electroencephalographic (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 phase locking of sound-evoked gamma oscillations. Similar EEG phenotypes are present in mouse models of FXS, but very little is known about the development of such abnormal responses. In the current study, we employed a 30-channel mouse multielectrode array (MEA) system to record and analyze resting and stimulus-evoked EEG signals in male P21 and P91 WT and Fmr1 KO mice. This led to several novel findings. First, P91, but not P21, Fmr1 KO mice have significantly increased resting EEG power in the low- and high-gamma frequency bands. Second, both P21 and P91 Fmr1 KO mice have markedly attenuated inter-trial phase coherence (ITPC) to spectrotemporally dynamic auditory stimuli as well as to 40 Hz and 80 Hz auditory steady-state response (ASSR) stimuli. This suggests abnormal temporal processing from early development that may lead to abnormal speech and language function in FXS. Third, we found hemispheric asymmetry of fast temporal processing in the mouse auditory cortex in WT but not Fmr1 KO mice. Together, these findings define a set of EEG phenotypes in young and adult mice that can serve as translational targets for genetic and pharmacological manipulation in phenotypic rescue studies.


Assuntos
Eletroencefalografia , Potenciais Evocados Auditivos , Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil , Animais , Masculino , Camundongos , Estimulação Acústica , Biomarcadores , Modelos Animais de Doenças , Eletroencefalografia/métodos , Potenciais Evocados Auditivos/fisiologia , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo
5.
bioRxiv ; 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-37609208

RESUMO

Autism manifests differently in males and females and the brain mechanisms that mediate these sex-dependent differences are unknown. Here, we demonstrate that deletion of the ASD-risk gene, Pten, in neocortical pyramidal neurons (NSE Pten KO) results in robust hyperexcitability of local neocortical circuits in female, but not male, mice, observed as prolonged, spontaneous persistent activity states (UP states). Circuit hyperexcitability in NSE Pten KO mice is mediated by enhanced and/or altered signaling of metabotropic glutamate receptor 5 (mGluR5) and estrogen receptor α (ERα) to ERK and protein synthesis selectively in Pten deleted female neurons. In support of this idea, Pten deleted Layer 5 cortical neurons have female-specific increases in mGluR5 and mGluR5-driven protein synthesis. In addition, mGluR5-ERα complexes are elevated in female cortex and genetic reduction of ERα in Pten KO cortical neurons rescues circuit excitability, protein synthesis and enlarged neurons selectively in females. Abnormal timing and hyperexcitability of neocortical circuits in female NSE Pten KO mice are associated with deficits in temporal processing of sensory stimuli and social behaviors as well as mGluR5-dependent seizures. Female-specific cortical hyperexcitability and mGluR5-dependent seizures are also observed in a human disease relevant mouse model, germline Pten +/- mice. Our results reveal molecular mechanisms by which sex and a high impact ASD-risk gene interact to affect brain function and behavior.

6.
J Neurodev Disord ; 15(1): 23, 2023 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-37516865

RESUMO

BACKGROUND: Autism spectrum disorders (ASD) encompass a wide array of debilitating symptoms, including sensory dysfunction and delayed language development. Auditory temporal processing is crucial for speech perception and language development. Abnormal development of temporal processing may account for the language impairments associated with ASD. Very little is known about the development of temporal processing in any animal model of ASD. METHODS: In the current study, we quantify auditory temporal processing throughout development in the Fmr1 knock-out (KO) mouse model of Fragile X Syndrome (FXS), a leading genetic cause of intellectual disability and ASD-associated behaviors. Using epidural electrodes in awake and freely moving wildtype (WT) and KO mice, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (gap-ASSR) paradigm. Mice were recorded at three different ages in a cross sectional design: postnatal (p)21, p30 and p60. Recordings were obtained from both auditory and frontal cortices. The gap-ASSR requires underlying neural generators to synchronize responses to gaps of different widths embedded in noise, providing an objective measure of temporal processing across genotypes and age groups. RESULTS: We present evidence that the frontal, but not auditory, cortex shows significant temporal processing deficits at p21 and p30, with poor ability to phase lock to rapid gaps in noise. Temporal processing was similar in both genotypes in adult mice. ERP amplitudes were larger in Fmr1 KO mice in both auditory and frontal cortex, consistent with ERP data in humans with FXS. CONCLUSIONS: These data indicate cortical region-specific delays in temporal processing development in Fmr1 KO mice. Developmental delays in the ability of frontal cortex to follow rapid changes in sounds may shape language delays in FXS, and more broadly in ASD.


Assuntos
Síndrome do Cromossomo X Frágil , Percepção do Tempo , Humanos , Adulto , Animais , Camundongos , Síndrome do Cromossomo X Frágil/complicações , Estudos Transversais , Modelos Animais de Doenças , Camundongos Knockout , Proteína do X Frágil da Deficiência Intelectual/genética
7.
Neurobiol Aging ; 120: 10-26, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36084545

RESUMO

Neural oscillations at specific frequency bands are associated with cognitive functions and can identify abnormalities in cortical dynamics. In this study, we analyzed EEG signals recorded from auditory and frontal cortex of awake mice across young, middle and old ages, and found multiple robust and novel age-related changes in cortical oscillations. Notably, resting, evoked, and induced gamma power diminished with age, with some changes observed even in the middle age groups. Inter-trial phase coherence of responses to time-varying stimuli is reduced in old mice. Movement-related modulation of gamma power is reduced in old mice. An acute injection of nicotine (0.5 mg/kg), but not saline, in old mice partially or fully reversed the age-related changes in EEG responses. Nicotine had no effect on auditory brainstem responses , suggesting the effects occur more centrally. The age-related changes are consistent with reduced activation of specific inhibitory interneuron subtypes. Importantly, our data suggest that the auditory circuits that generate 'young' responses to sounds are present in old mice, and can be activated by nicotine.


Assuntos
Córtex Auditivo , Potenciais Evocados Auditivos do Tronco Encefálico , Animais , Camundongos , Potenciais Evocados Auditivos/fisiologia , Córtex Auditivo/fisiologia , Nicotina/farmacologia , Lobo Frontal , Estimulação Acústica
8.
J Neurodev Disord ; 14(1): 52, 2022 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-36167501

RESUMO

BACKGROUND: Fragile X syndrome (FXS) is the most common inherited form of neurodevelopmental disability. It is often characterized, especially in males, by intellectual disability, anxiety, repetitive behavior, social communication deficits, delayed language development, and abnormal sensory processing. Recently, we identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS. METHODS: In this report, we evaluate small molecule target engagement utilizing multielectrode array electrophysiology in the Fmr1 KO mouse and in humans with FXS. Neurophysiologic target engagement was evaluated using single doses of the GABAB selective agonist racemic baclofen (RBAC). RESULTS: In Fmr1 KO mice and in humans with FXS, baclofen use was associated with suppression of elevated gamma power and increase in low-frequency power at rest. In the Fmr1 KO mice, a baclofen-associated improvement in auditory chirp synchronization was also noted. CONCLUSIONS: Overall, we noted synchronized target engagement of RBAC on resting state electrophysiology, in particular the reduction of aberrant high frequency gamma activity, across species in FXS. This finding holds promise for translational medicine approaches to drug development for FXS, synchronizing treatment study across species using well-established EEG biological markers in this field. TRIAL REGISTRATION: The human experiments are registered under NCT02998151.


Assuntos
Síndrome do Cromossomo X Frágil , Animais , Baclofeno/farmacologia , Modelos Animais de Doenças , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/complicações , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Humanos , Masculino , Camundongos , Camundongos Knockout
9.
Behav Brain Res ; 434: 114024, 2022 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-35882277

RESUMO

The onset of mammalian maternal care is associated with plasticity in neural processing of infant-related sensory stimuli; however, little is known about sensory plasticity associated with fatherhood. We quantified behavioral and neural responses of virgin males and new fathers to olfactory and auditory stimuli from young, unfamiliar pups in the biparental California mouse (Peromyscus californicus). Each male was exposed for 10 min to one of four combinations of a chemosensory stimulus (pup-scented or unscented cotton [control]) and an auditory stimulus (pup vocalizations or white noise [control]). Behavior did not differ between fathers and virgins during exposure to sensory stimuli or during the following hour; however, males in both groups were more active both during and after exposure to pup-related stimuli compared to control stimuli. Fathers had lower expression of Fos in the main olfactory bulbs (MOB) but higher expression in the medial preoptic area (MPOA) and bed nucleus of the stria terminalis medial division, ventral part (STMV) compared to virgins. Lastly, males had higher Fos expression in MPOA when exposed to pup odor compared to control stimuli, and when exposed to pup odor and pup calls compared to pup calls only or control stimuli. These findings suggest that the onset of fatherhood alters activity of MOB, MPOA and STMV and that pup odors and vocalizations have additive or synergistic effects on males' behavior and MPOA activation.


Assuntos
Comportamento Paterno , Peromyscus , Animais , Comportamento Animal , Pai , Humanos , Masculino , Odorantes , Área Pré-Óptica
10.
Neurobiol Dis ; 162: 105577, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34871737

RESUMO

BACKGROUND: Fragile X syndrome (FXS) is a leading genetic cause of autism and intellectual disability with cortical hyperexcitability and sensory hypersensitivity attributed to loss and hypofunction of inhibitory parvalbumin-expressing (PV) cells. Our studies provide novel insights into the role of excitatory neurons in abnormal development of PV cells during a postnatal period of inhibitory circuit refinement. METHODS: To achieve Fragile X mental retardation gene (Fmr1) deletion and re-expression in excitatory neurons during the postnatal day (P)14-P21 period, we generated CreCaMKIIa/Fmr1Flox/y (cOFF) and CreCaMKIIa/Fmr1FloxNeo/y (cON) mice, respectively. Cortical phenotypes were evaluated in adult mice using biochemical, cellular, clinically relevant electroencephalogram (EEG) and behavioral tests. RESULTS: We found that similar to global Fmr1 KO mice, the density of PV-expressing cells, their activation, and sound-evoked gamma synchronization were impaired in cOFF mice, but the phenotypes were improved in cON mice. cOFF mice also showed enhanced cortical gelatinase activity and baseline EEG gamma power, which were reduced in cON mice. In addition, TrkB phosphorylation and PV levels were lower in cOFF mice, which also showed increased locomotor activity and anxiety-like behaviors. Remarkably, when FMRP levels were restored in only excitatory neurons during the P14-P21 period, TrkB phosphorylation and mouse behaviors were also improved. CONCLUSIONS: These results indicate that postnatal deletion or re-expression of FMRP in excitatory neurons is sufficient to elicit or ameliorate structural and functional cortical deficits, and abnormal behaviors in mice, informing future studies about appropriate treatment windows and providing fundamental insights into the cellular mechanisms of cortical circuit dysfunction in FXS.


Assuntos
Síndrome do Cromossomo X Frágil , Animais , Modelos Animais de Doenças , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Camundongos , Camundongos Knockout , Neurônios/fisiologia
11.
Hear Res ; 412: 108380, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34758398

RESUMO

Age-related changes in auditory processing affect the quality of life of older adults with and without hearing loss. To distinguish between the effects of sensorineural hearing loss and aging on cortical processing, the main goal of the present study was to compare cortical responses using the same stimulus paradigms and recording conditions in two strains of mice (C57BL/6J and FVB) that differ in the degree of age-related hearing loss. Electroencephalogram (EEG) recordings were obtained from freely moving young and old mice using epidural screw electrodes. We measured event related potentials (ERP) and 40 Hz auditory steady-state responses (ASSR). We used a novel stimulus, termed the gap-ASSR stimulus, which elicits an ASSR by rapidly presenting short gaps in continuous noise. By varying the gap widths and modulation depths, we probed the limits of temporal processing in young and old mice. Temporal fidelity of ASSR and gap-ASSR responses were measured as phase consistency across trials (inter-trial phase clustering; ITPC). The old C57 mice, which show severe hearing loss, produced larger ERP amplitudes compared to young mice. Despite robust ERPs, the old C57 mice showed significantly diminished ITPC in the ASSR and gap-ASSR responses, even with 100% modulation depth. The FVB mice, which show mild hearing loss with age, generated similar ERP amplitudes and ASSR ITPC across the age groups tested. However, the old FVB mice showed decreased gap-ASSR responses compared to young mice, particularly for modulation depths <100%. The C57 mice data suggest that severe presbycusis leads to increased gain in the auditory cortex, but with reduced temporal fidelity. The FVB mice data suggest that with mild hearing loss, age-related changes in temporal processing become apparent only when tested with more challenging sounds (shorter gaps and shallower modulation).


Assuntos
Córtex Auditivo , Percepção do Tempo , Estimulação Acústica , Animais , Córtex Auditivo/fisiologia , Limiar Auditivo/fisiologia , Potenciais Evocados , Potenciais Evocados Auditivos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Qualidade de Vida
12.
J Neurodev Disord ; 13(1): 47, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645383

RESUMO

BACKGROUND: Individuals with Fragile X syndrome (FXS) and autism spectrum disorder (ASD) exhibit an array of symptoms, including sociability deficits, increased anxiety, hyperactivity, and sensory hyperexcitability. It is unclear how endocannabinoid (eCB) modulation can be targeted to alleviate neurophysiological abnormalities in FXS as behavioral research reveals benefits to inhibiting cannabinoid (CB) receptor activation and increasing endocannabinoid ligand levels. Here, we hypothesize that enhancement of 2-arachidonoyl-sn-glycerol (2-AG) in Fragile X mental retardation 1 gene knock-out (Fmr1 KO) mice may reduce cortical hyperexcitability and behavioral abnormalities observed in FXS. METHODS: To test whether an increase in 2-AG levels normalized cortical responses in a mouse model of FXS, animals were subjected to electroencephalography (EEG) recording and behavioral assessment following treatment with JZL-184, an irreversible inhibitor of monoacylglycerol lipase (MAGL). Assessment of 2-AG was performed using lipidomic analysis in conjunction with various doses and time points post-administration of JZL-184. Baseline electrocortical activity and evoked responses to sound stimuli were measured using a 30-channel multielectrode array (MEA) in adult male mice before, 4 h, and 1 day post-intraperitoneal injection of JZL-184 or vehicle. Behavior assessment was done using the open field and elevated plus maze 4 h post-treatment. RESULTS: Lipidomic analysis showed that 8 mg/kg JZL-184 significantly increased the levels of 2-AG in the auditory cortex of both Fmr1 KO and WT mice 4 h post-treatment compared to vehicle controls. EEG recordings revealed a reduction in the abnormally enhanced baseline gamma-band power in Fmr1 KO mice and significantly improved evoked synchronization to auditory stimuli in the gamma-band range post-JZL-184 treatment. JZL-184 treatment also ameliorated anxiety-like and hyperactivity phenotypes in Fmr1 KO mice. CONCLUSIONS: Overall, these results indicate that increasing 2-AG levels may serve as a potential therapeutic approach to normalize cortical responses and improve behavioral outcomes in FXS and possibly other ASDs.


Assuntos
Transtorno do Espectro Autista , Proteína do X Frágil da Deficiência Intelectual , Animais , Endocanabinoides , Proteína do X Frágil da Deficiência Intelectual/genética , Glicerol , Masculino , Camundongos , Camundongos Knockout
13.
Front Psychiatry ; 12: 720752, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34690832

RESUMO

The mechanisms underlying the common association between autism spectrum disorders (ASD) and sensory processing disorders (SPD) are unclear, and treatment options to reduce atypical sensory processing are limited. Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and ASD behaviors. As in most children with ASD, atypical sensory processing is a common symptom in FXS, frequently manifesting as sensory hypersensitivity. Auditory hypersensitivity is a highly debilitating condition in FXS that may lead to language delays, social anxiety and ritualized repetitive behaviors. Animal models of FXS, including Fmr1 knock out (KO) mouse, also show auditory hypersensitivity, providing a translation relevant platform to study underlying pathophysiological mechanisms. The focus of this review is to summarize recent studies in the Fmr1 KO mouse that identified neural correlates of auditory hypersensitivity. We review results of electroencephalography (EEG) recordings in the Fmr1 KO mice and highlight EEG phenotypes that are remarkably similar to EEG findings in humans with FXS. The EEG phenotypes associated with the loss of FMRP include enhanced resting EEG gamma band power, reduced cross frequency coupling, reduced sound-evoked synchrony of neural responses at gamma band frequencies, increased event-related potential amplitudes, reduced habituation of neural responses and increased non-phase locked power. In addition, we highlight the postnatal period when the EEG phenotypes develop and show a strong association of the phenotypes with enhanced matrix-metalloproteinase-9 (MMP-9) activity, abnormal development of parvalbumin (PV)-expressing inhibitory interneurons and reduced formation of specialized extracellular matrix structures called perineuronal nets (PNNs). Finally, we discuss how dysfunctions of inhibitory PV interneurons may contribute to cortical hyperexcitability and EEG abnormalities observed in FXS. Taken together, the studies reviewed here indicate that EEG recordings can be utilized in both pre-clinical studies and clinical trials, while at the same time, used to identify cellular and circuit mechanisms of dysfunction in FXS. New therapeutic approaches that reduce MMP-9 activity and restore functions of PV interneurons may succeed in reducing FXS sensory symptoms. Future studies should examine long-lasting benefits of developmental vs. adult interventions on sensory phenotypes.

14.
Front Neurosci ; 14: 771, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32848552

RESUMO

Fragile X Syndrome (FXS) is a leading known genetic cause of intellectual disability. Many symptoms of FXS overlap with those in autism including repetitive behaviors, language delays, anxiety, social impairments and sensory processing deficits. Electroencephalogram (EEG) recordings from humans with FXS and an animal model, the Fmr1 knockout (KO) mouse, show remarkably similar phenotypes suggesting that EEG phenotypes can serve as biomarkers for developing treatments. This includes enhanced resting gamma band power and sound evoked total power, and reduced fidelity of temporal processing and habituation of responses to repeated sounds. Given the therapeutic potential of the antibiotic minocycline in humans with FXS and animal models, it is important to determine sensitivity and selectivity of EEG responses to minocycline. Therefore, in this study, we examined if a 10-day treatment of adult Fmr1 KO mice with minocycline (oral gavage, 30 mg/kg per day) would reduce EEG abnormalities. We tested if minocycline treatment has specific effects based on the EEG measurement type (e.g., resting versus sound-evoked) from the frontal and auditory cortex of the Fmr1 KO mice. We show increased resting EEG gamma power and reduced phase locking to time varying stimuli as well as the 40 Hz auditory steady state response in the Fmr1 KO mice in the pre-drug condition. Minocycline treatment increased gamma band phase locking in response to auditory stimuli, and reduced sound-evoked power of auditory event related potentials (ERP) in Fmr1 KO mice compared to vehicle treatment. Minocycline reduced resting EEG gamma power in Fmr1 KO mice, but this effect was similar to vehicle treatment. We also report frequency band-specific effects on EEG responses. Taken together, these data indicate that sound-evoked EEG responses may serve as more sensitive measures, compared to resting EEG measures, to isolate minocycline effects from placebo in humans with FXS. Given the use of minocycline and EEG recordings in a number of neurodegenerative and neurodevelopmental conditions, these findings may be more broadly applicable in translational neuroscience.

15.
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
16.
J Neurodev Disord ; 12(1): 13, 2020 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-32359368

RESUMO

Fragile X syndrome (FXS) is the most common single gene cause of autism and intellectual disabilities. Humans with FXS exhibit increased anxiety, sensory hypersensitivity, seizures, repetitive behaviors, cognitive inflexibility, and social behavioral impairments. The main purpose of this review is to summarize developmental studies of FXS in humans and in the mouse model, the Fmr1 knockout mouse. The literature presents considerable evidence that a number of early developmental deficits can be identified and that these early deficits chart a course of altered developmental experience leading to symptoms well characterized in adolescents and adults. Nevertheless, a number of critical issues remain unclear or untested regarding the development of symptomology and underlying mechanisms. First, what is the role of FMRP, the protein product of Fmr1 gene, during different developmental ages? Does the absence of FMRP during early development lead to irreversible changes, or could reintroduction of FMRP or therapeutics aimed at FMRP-interacting proteins/pathways hold promise when provided in adults? These questions have implications for clinical trial designs in terms of optimal treatment windows, but few studies have systematically addressed these issues in preclinical and clinical work. Published studies also point to complex trajectories of symptom development, leading to the conclusion that single developmental time point studies are unlikely to disambiguate effects of genetic mutation from effects of altered developmental experience and compensatory plasticity. We conclude by suggesting a number of experiments needed to address these major gaps in the field.


Assuntos
Síndrome do Cromossomo X Frágil/genética , Adolescente , Animais , Criança , Pré-Escolar , Modelos Animais de Doenças , Feminino , Proteína do X Frágil da Deficiência Intelectual/genética , Humanos , Lactente , Masculino , Camundongos , Camundongos Knockout , Adulto Jovem
17.
J Neurophysiol ; 123(6): 2101-2121, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32319849

RESUMO

Sensory processing abnormalities are frequently associated with autism spectrum disorders, but the underlying mechanisms are unclear. Here we studied auditory processing in a mouse model of Fragile X Syndrome (FXS), a leading known genetic cause of autism and intellectual disability. Both humans with FXS and the Fragile X mental retardation gene (Fmr1) knockout (KO) mouse model show auditory hypersensitivity, with the latter showing a strong propensity for audiogenic seizures (AGS) early in development. Because midbrain abnormalities cause AGS, we investigated whether the inferior colliculus (IC) of the Fmr1 KO mice shows abnormal auditory processing compared with wild-type (WT) controls at specific developmental time points. Using antibodies against neural activity marker c-Fos, we found increased density of c-Fos+ neurons in the IC, but not auditory cortex, of Fmr1 KO mice at P21 and P34 following sound presentation. In vivo single-unit recordings showed that IC neurons of Fmr1 KO mice are hyperresponsive to tone bursts and amplitude-modulated tones during development and show broader frequency tuning curves. There were no differences in rate-level responses or phase locking to amplitude-modulated tones in IC neurons between genotypes. Taken together, these data provide evidence for the development of auditory hyperresponsiveness in the IC of Fmr1 KO mice. Although most human and mouse work in autism and sensory processing has centered on the forebrain, our new findings, along with recent work on the lower brainstem, suggest that abnormal subcortical responses may underlie auditory hypersensitivity in autism spectrum disorders.NEW & NOTEWORTHY Autism spectrum disorders (ASD) are commonly associated with sensory sensitivity issues, but the underlying mechanisms are unclear. This study presents novel evidence for neural correlates of auditory hypersensitivity in the developing inferior colliculus (IC) in Fmr1 knockout (KO) mouse, a mouse model of Fragile X Syndrome (FXS), a leading genetic cause of ASD. Responses begin to show genotype differences between postnatal days 14 and 21, suggesting an early developmental treatment window.


Assuntos
Transtornos da Percepção Auditiva/fisiopatologia , Síndrome do Cromossomo X Frágil/fisiopatologia , Colículos Inferiores/crescimento & desenvolvimento , Colículos Inferiores/fisiopatologia , Animais , Transtornos da Percepção Auditiva/etiologia , Modelos Animais de Doenças , Fenômenos Eletrofisiológicos/fisiologia , Epilepsia Reflexa/etiologia , Epilepsia Reflexa/fisiopatologia , Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil/complicações , Masculino , Camundongos , Camundongos Knockout , Neurônios/fisiologia
18.
Mater Sci Eng C Mater Biol Appl ; 110: 110614, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32204062

RESUMO

This article reports fabrication, characterization, degradation and electrical properties of biodegradable magnesium (Mg) microwires coated with two functional polymers, and the first in vivo evidence on the feasibility of Mg-based biodegradable microelectrodes for neural recording. Conductive poly(3,4­ethylenedioxythiophene) (PEDOT) coating was first electrochemically deposited onto Mg microwire surface, and insulating biodegradable poly(glycerol sebacate) (PGS) was then spray-coated onto PEDOT surface to improve the overall properties of microelectrode. The assembled PGS/PEDOT-coated Mg microelectrodes showed high homogeneity in coating thickness, surface morphology and composition before and after in vivo recording. The charge storage capacity (CSC) of PGS/PEDOT-coated Mg microwire (1.72 mC/cm2) was nearly 5 times higher than the standard platinum (Pt) microwire widely used in implantable electrodes. The Mg-based microelectrode demonstrated excellent neural-recording capability and stability during in vivo multi-unit neural recordings in the auditory cortex of a mouse. Specifically, the Mg-based electrode showed clear and stable onset response, and excellent signal-to-noise ratio during spontaneous-activity recordings and three repeats of stimulus-evoked recordings at two different anatomical locations in the auditory cortex. During 10 days of immersion in artificial cerebrospinal fluid (aCSF) in vitro, PGS/PEDOT-coated Mg microelectrodes showed slower degradation and less change in impedance than PEDOT-coated Mg electrodes. The biodegradable PGS coating protected the PEDOT coating from delamination, and prolonged the mechanical integrity and electrical properties of Mg-based microelectrode. Mg-based novel microelectrodes should be further studied toward clinical translation because they can potentially eliminate the risks and costs associated with secondary surgeries for removal of failed or no longer needed electrodes.


Assuntos
Materiais Revestidos Biocompatíveis , Condutividade Elétrica , Eletrodos Implantados , Magnésio , Animais , Compostos Bicíclicos Heterocíclicos com Pontes , Decanoatos , Glicerol/análogos & derivados , Camundongos , Microeletrodos , Polímeros
19.
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
20.
FASEB J ; 34(3): 3501-3518, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32039504

RESUMO

Autism spectrum disorders (ASD) are strongly associated with auditory hypersensitivity or hyperacusis (difficulty tolerating sounds). Fragile X syndrome (FXS), the most common monogenetic cause of ASD, has emerged as a powerful gateway for exploring underlying mechanisms of hyperacusis and auditory dysfunction in ASD. This review discusses examples of disruption of the auditory pathways in FXS at molecular, synaptic, and circuit levels in animal models as well as in FXS individuals. These examples highlight the involvement of multiple mechanisms, from aberrant synaptic development and ion channel deregulation of auditory brainstem circuits, to impaired neuronal plasticity and network hyperexcitability in the auditory cortex. Though a relatively new area of research, recent discoveries have increased interest in auditory dysfunction and mechanisms underlying hyperacusis in this disorder. This rapidly growing body of data has yielded novel research directions addressing critical questions regarding the timing and possible outcomes of human therapies for auditory dysfunction in ASD.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Síndrome do Cromossomo X Frágil/fisiopatologia , Animais , Percepção Auditiva/fisiologia , Transtorno do Espectro Autista/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Humanos , Modelos Biológicos
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