Reviewer #3 (Public Review): Cntnap2 loss drives striatal neuron hyperexcitability and behavioral inflexibility DOI Open Access

Published: July 29, 2024

Autism spectrum disorder (ASD) is a neurodevelopmental characterized by two major diagnostic criteria - persistent deficits in social communication and interaction, the presence of restricted, repetitive patterns behavior (RRBs). Evidence from both human animal model studies ASD suggest that alteration striatal circuits, which mediate motor learning, action selection, habit formation, may contribute to manifestation RRBs. CNTNAP2 syndromic risk gene, loss function Cntnap2 mice associated with How impacts neuron largely unknown. In this study, we utilized Cntnap2-/- test whether altered activity contributes aberrant behaviors relevant ASD. We find exhibit increased cortical drive projection neurons (SPNs), most pronounced effects direct pathway SPNs. This enhanced likely due intrinsic excitability SPNs, make them more responsive inputs. also spontaneous behaviors, routine cognitive inflexibility. Increased corticostriatal drive, particular pathway, acquisition repetitive, inflexible mice.

Language: Английский

Altered motor learning and coordination in mouse models of autism spectrum disorder DOI Creative Commons
Katherine R. Cording, Helen S. Bateup

Frontiers in Cellular Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: Nov. 8, 2023

Autism spectrum disorder (ASD) is a complex neurodevelopmental with increasing prevalence. Over 1,000 risk genes have now been implicated in ASD, suggesting diverse etiology. However, the diagnostic criteria for still comprise two major behavioral domains - deficits social communication and interaction, presence of restricted repetitive patterns behavior (RRBs). The RRBs associated ASD include both stereotyped movements other motor manifestations including changes gait, balance, coordination, skill learning. In recent years, striatum, primary input center basal ganglia, has these ASD-associated behaviors, due to striatum’s role action selection, learning, habit formation. Numerous mouse models mutations developed shown alterations ASD-relevant behaviors. One commonly used assay, accelerating rotarod, allows assessment basic coordination this corticostriatal-dependent task, mice walk on rotating rod that gradually increases speed. extended version engage striatal-dependent learning mechanisms optimize their routine stay longer periods. This review summarizes findings studies examining rotarod performance across range models, resulting implications involvement striatal circuits ASD-related While task not uniform there cohort show increased performance. A growing number suggest propensity learn fixed may reflect common enhancement corticostriatal drive subset ASD-risk genes.

Language: Английский

Citations

30
Dim Light at Night Disrupts the Sleep-Wake Cycle and Exacerbates Seizure Activity in Cntnap2 Knockout Mice: Implications for Autism Spectrum Disorders DOI Creative Commons
Yumeng Wang, Ketema N. Paul,

Gene D. Block

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 24, 2025

Abstract Epilepsy is one of the most common comorbidities in individuals with autism spectrum disorders (ASDs). Many patients epilepsy as well ASD experience disruptions their sleep-wake cycle and exhibit daily rhythms expression symptoms. Chronic exposure to light at nighttime can disrupt sleep circadian rhythms. Contactin associated protein-like 2 knockout ( Cntnap2 KO) mice, a model for disorder (ASD) epilepsy, disturbances seizure-like events. This study examines how chronic dim night (DLaN) affects architecture, EEG power spectra, seizure activity KO wildtype (WT) mice. Using electroencephalography (EEG) recordings, male female WT mice were exposed DLaN (5 lux) or 6 weeks. recordings analyzed assess spectrum, delays wake onset disrupts patterns sex-dependent manner, females being more affected. significantly increased slow-wave (SWA, 0.5–4 Hz) both indicating pressure. Finally, we found that dramatically frequency events even occurrence rate Spectral analysis revealed theta power, suggesting involvement hippocampus. increases sex-specific differences. These findings emphasize potential risks reinforcing need manage improve quality reduce risk.

Language: Английский

Citations

1
Prenatal 1‐Nitropyrene Exposure Causes Autism‐Like Behavior Partially by Altering DNA Hydroxymethylation in Developing Brain DOI Creative Commons
Ting Zhao,

Cheng‐Qing Huang,

Yi‐Hao Zhang

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(28)

Published: May 16, 2024

Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by social communication disability and stereotypic behavior. This study aims to investigate the impact of prenatal exposure 1‐nitropyrene (1‐NP), key component motor vehicle exhaust, on autism‐like behaviors in mouse model. Three‐chamber test finds that 1‐NP causes during weaning period. Patch clamp shows inhibitory synaptic transmission reduced medial prefrontal cortex 1‐NP‐exposed pups. Immunofluorescence reduces number glutamate decarboxylase 67 (GAD67) positive interneurons fetuses Moreover, retards tangential migration GAD67‐positive downregulates interneuron migration‐related genes, such as Nrg1 , Erbb4 Sema3F fetal forebrain. Mechanistically, hydroxymethylation genes through inhibiting ten‐eleven translocation (TET) activity Supplement with alpha‐ketoglutarate (α‐KG), cofactor TET enzyme, reverses 1‐NP‐induced hypohydroxymethylation at specific sites genes. α‐KG supplement alleviates retardation Finally, maternal improves offspring. In conclusion, behavior partially altering DNA developing brain.

Language: Английский

Citations

6
The Role of Parvalbumin Interneurons in Autism Spectrum Disorder DOI
Yiwei Yao, Qian Li

Journal of Neuroscience Research, Journal Year: 2024, Volume and Issue: 102(10)

Published: Oct. 1, 2024

ABSTRACT As an important subtype of GABAergic interneurons, parvalbumin ( PV ) interneurons play a critical role in regulating cortical circuits and neural networks. Abnormalities the development or function have been linked to autism spectrum disorder (ASD), neurodevelopmental characterized by social language deficits. In this review, we focus on abnormalities ASD , including quantity discuss underlying mechanisms impairments pathology . Finally, propose potential therapeutic approaches targeting such as transplanting MGE progenitor cells utilizing optogenetic stimulation treatment ASD.

Language: Английский

Citations

5
Cntnap2 loss drives striatal neuron hyperexcitability and behavioral inflexibility DOI Open Access
Katherine R. Cording, Emilie M Tu, Hongli Wang

et al.

Published: May 2, 2025

Autism spectrum disorder (ASD) is a neurodevelopmental characterized by two major diagnostic criteria – persistent deficits in social communication and interaction, the presence of restricted, repetitive patterns behavior (RRBs). Evidence from both human animal model studies ASD suggest that alteration striatal circuits, which mediate motor learning, action selection, habit formation, may contribute to manifestation RRBs. CNTNAP2 syndromic risk gene, loss function Cntnap2 mice associated with How impacts neuron largely unknown. In this study, we utilized −/− test whether altered activity contributes aberrant behaviors relevant ASD. We find exhibit increased cortical drive direct pathway projection neurons (dSPNs). This enhanced likely due intrinsic excitability dSPNs, make them more responsive inputs. spontaneous behaviors, routine perseveration, cognitive inflexibility. Increased corticostriatal therefore acquisition repetitive, inflexible mice.

Language: Английский

Citations

0
Developmental alterations of indirect-pathway medium spiny neurons in mouse models of Huntington's disease DOI Creative Commons

Margaux Lebouc,

L. Bonamy, Thibault Dhellemmes

et al.

Neurobiology of Disease, Journal Year: 2025, Volume and Issue: unknown, P. 106874 - 106874

Published: March 1, 2025

Language: Английский

Citations

0
Cntnap2loss drives striatal neuron hyperexcitability and behavioral inflexibility DOI Creative Commons
Katherine R. Cording, Emilie M Tu, Hongli Wang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 9, 2024

Autism spectrum disorder (ASD) is a neurodevelopmental characterized by two major diagnostic criteria - persistent deficits in social communication and interaction, the presence of restricted, repetitive patterns behavior (RRBs). Evidence from both human animal model studies ASD suggest that alteration striatal circuits, which mediate motor learning, action selection, habit formation, may contribute to manifestation RRBs.

Language: Английский

Citations

2
Cntnap2 loss drives striatal neuron hyperexcitability and behavioral inflexibility DOI Open Access
Katherine R. Cording, Emilie M Tu, Hongli Wang

et al.

Published: July 29, 2024

Autism spectrum disorder (ASD) is a neurodevelopmental characterized by two major diagnostic criteria - persistent deficits in social communication and interaction, the presence of restricted, repetitive patterns behavior (RRBs). Evidence from both human animal model studies ASD suggest that alteration striatal circuits, which mediate motor learning, action selection, habit formation, may contribute to manifestation RRBs. CNTNAP2 syndromic risk gene, loss function Cntnap2 mice associated with How impacts neuron largely unknown. In this study, we utilized -/- test whether altered activity contributes aberrant behaviors relevant ASD. We find exhibit increased cortical drive projection neurons (SPNs), most pronounced effects direct pathway SPNs. This enhanced likely due intrinsic excitability SPNs, make them more responsive inputs. also spontaneous behaviors, routine cognitive inflexibility. Increased corticostriatal drive, particular pathway, acquisition repetitive, inflexible mice.

Language: Английский

Citations

1
Cntnap2 loss drives striatal neuron hyperexcitability and behavioral inflexibility DOI Open Access
Katherine R. Cording, Emilie M Tu, Hongli Wang

et al.

Published: July 29, 2024

Autism spectrum disorder (ASD) is a neurodevelopmental characterized by two major diagnostic criteria - persistent deficits in social communication and interaction, the presence of restricted, repetitive patterns behavior (RRBs). Evidence from both human animal model studies ASD suggest that alteration striatal circuits, which mediate motor learning, action selection, habit formation, may contribute to manifestation RRBs. CNTNAP2 syndromic risk gene, loss function Cntnap2 mice associated with How impacts neuron largely unknown. In this study, we utilized -/- test whether altered activity contributes aberrant behaviors relevant ASD. We find exhibit increased cortical drive projection neurons (SPNs), most pronounced effects direct pathway SPNs. This enhanced likely due intrinsic excitability SPNs, make them more responsive inputs. also spontaneous behaviors, routine cognitive inflexibility. Increased corticostriatal drive, particular pathway, acquisition repetitive, inflexible mice.

Language: Английский

Citations

1
Developmental alterations of indirect-pathway medium spiny neurons in mouse models of Huntington’s disease DOI Open Access

Margaux Lebouc,

L. Bonamy,

Jakob Scharnholz

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 10, 2024

Abstract Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a mutation in the gene encoding Huntingtin protein (Htt). While symptoms, primarily characterized progressive deterioration of striatum and motor cognitive functions, typically manifest adulthood, recent studies have also highlighted developmental defects HD. Indeed, alterations cortical striatal development been observed individuals carrying as early embryonic stages. However, despite being one most affected regions HD, few investigated potential this structure, especially weeks after birth. To address question, we compared between wild-type (WT) mice two murine models R6/1 CAG140 crossed with reporter to identify D1- D2-expressing medium spiny neurons (D1- D2-MSNs). Using ex vivo electrophysiology neuronal reconstruction, that maturation electrical properties was selectively disrupted D2-MSNs matrix compartment HD during first post-natal days. arbor increased dendritic complexity. When studying establishment afferents, cortico-striatal glutamatergic transmission specifically reduced second postnatal week. All these were transient before circuit normalized on its own These anatomical electrophysiological data highlight significant impact Htt numerous processes period. Interestingly, affect MSNs indirect pathway. This preferential vulnerability aligns death suggesting treatment could potentially modify disease’s progression.

Language: Английский

Citations

1