approfondimento - Neuroscience - # Striatal circuit dysfunction and repetitive behaviors in a mouse model of autism spectrum disorder

Loss of Cntnap2 Leads to Striatal Neuron Hyperexcitability and Behavioral Inflexibility in Mice

Q: How do the cellular and circuit-level changes in the striatum of Cntnap2-/- mice relate to the broader neural circuit alterations observed in other brain regions in this mouse model

The cellular and circuit-level changes in the striatum of Cntnap2-/- mice are interconnected with broader neural circuit alterations observed in other brain regions in this mouse model. The striatum, particularly the dorsolateral striatum (DLS), plays a crucial role in motor learning, habit formation, and action selection. In Cntnap2-/- mice, there is an increase in the intrinsic excitability of striatal projection neurons (SPNs), particularly in the direct pathway SPNs. This heightened excitability leads to enhanced corticostriatal drive, impacting the function of SPNs in the DLS. These changes in SPN activity contribute to the manifestation of repetitive behaviors and cognitive inflexibility observed in Cntnap2-/- mice. The alterations in the striatum are part of a larger network of neural circuitry affected by the loss of Cntnap2. Other brain regions, such as the cortex and hippocampus, also show changes in excitability and synaptic function in Cntnap2-/- mice. The interconnected nature of these alterations suggests a widespread impact on neural circuits involved in motor control, cognitive flexibility, and repetitive behaviors. The striatal dysfunction in Cntnap2-/- mice is likely intertwined with alterations in other brain regions, creating a complex network-level phenotype characteristic of autism spectrum disorder (ASD) models.

Q: What are the developmental trajectories of the striatal dysfunction and the emergence of repetitive behaviors and cognitive inflexibility in Cntnap2-/- mice

The developmental trajectories of striatal dysfunction and the emergence of repetitive behaviors and cognitive inflexibility in Cntnap2-/- mice involve a dynamic interplay between genetic predisposition and environmental influences. During early development, the loss of Cntnap2 leads to disruptions in the maturation and function of striatal circuits, affecting the balance of excitation and inhibition in SPNs. These early cellular changes set the stage for altered corticostriatal connectivity and increased intrinsic excitability in the striatum. As Cntnap2-/- mice mature, the impact of these cellular changes becomes more pronounced, leading to the emergence of repetitive behaviors and cognitive inflexibility. Repetitive behaviors, such as increased grooming, nose poking, and marble burying, reflect the aberrant functioning of striatal circuits involved in motor control and habit formation. Cognitive inflexibility, as seen in the reversal learning task, highlights the challenges in adapting to changing environmental cues and updating behavioral responses. The developmental trajectory of striatal dysfunction in Cntnap2-/- mice likely involves a cascade of events starting from altered cellular function in early stages to the manifestation of behavioral phenotypes in later stages. Understanding these developmental trajectories is essential for elucidating the underlying mechanisms of ASD-related behaviors and identifying potential targets for intervention.

Q: Could targeted modulation of striatal direct pathway activity rescue the behavioral phenotypes observed in Cntnap2-/- mice, and could this approach have therapeutic implications for autism spectrum disorder

Targeted modulation of striatal direct pathway activity could potentially rescue the behavioral phenotypes observed in Cntnap2-/- mice and have therapeutic implications for autism spectrum disorder (ASD). The direct pathway SPNs in the striatum play a critical role in initiating and facilitating motor actions. In Cntnap2-/- mice, the increased excitability of direct pathway SPNs contributes to the development of repetitive behaviors and cognitive inflexibility. By selectively modulating the activity of direct pathway SPNs, either through pharmacological interventions or optogenetic techniques, it may be possible to restore the balance of corticostriatal signaling and normalize striatal function in Cntnap2-/- mice. This targeted approach could potentially alleviate the repetitive behaviors, enhance cognitive flexibility, and improve motor learning abilities in these mice. Furthermore, the findings from studies on Cntnap2-/- mice could inform therapeutic strategies for individuals with ASD. Understanding the role of striatal dysfunction in ASD-related behaviors and exploring interventions that target specific neural circuits may lead to novel treatment approaches for individuals with ASD who exhibit similar behavioral phenotypes. By elucidating the link between striatal circuitry and behavioral outcomes, targeted modulation of the striatum could offer promising avenues for therapeutic interventions in ASD.

Concetti Chiave

Loss of the autism spectrum disorder risk gene Cntnap2 leads to increased intrinsic excitability of striatal projection neurons, particularly in the direct pathway, which contributes to the manifestation of repetitive behaviors and cognitive inflexibility in mice.

Sintesi

The study investigates how loss of the autism spectrum disorder (ASD) risk gene Cntnap2 impacts striatal neuron function and behavior in mice. The key findings are:

Striatal projection neurons (SPNs) in the direct and indirect pathways exhibit increased cortical drive in Cntnap2-/- mice, despite no changes in excitatory or inhibitory synaptic inputs.
The increased cortical drive onto SPNs is likely due to enhanced intrinsic excitability of these neurons, particularly in direct pathway SPNs.
Cntnap2-/- mice exhibit increased repetitive behaviors, including spontaneous grooming, marble burying, and nose poking in the holeboard assay.
Cntnap2-/- mice show enhanced motor learning on the accelerating rotarod task, which is associated with increased activity in the dorsolateral striatum.
Cntnap2-/- mice exhibit cognitive inflexibility, as demonstrated by impaired performance in an odor-based reversal learning task. This is characterized by perseverative errors, where the mice continue to choose the previously rewarded odor.

The authors propose that the increased intrinsic excitability and cortical drive of striatal projection neurons, particularly in the direct pathway, may contribute to the manifestation of repetitive behaviors and cognitive inflexibility in this mouse model of ASD.

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Statistiche

Cntnap2-/- mice exhibit increased number of action potentials evoked in direct pathway SPNs compared to wild-type controls.
Cntnap2-/- mice exhibit increased number of action potentials evoked in indirect pathway SPNs compared to wild-type controls.
Cntnap2-/- direct pathway SPNs have reduced rheobase current compared to wild-type.
Cntnap2-/- mice bury more marbles in the marble burying assay compared to wild-type.
Cntnap2-/- mice make more nose pokes in the holeboard assay compared to wild-type.
Cntnap2-/- mice take more trials to reach criterion in the reversal phase of the odor-based reversal learning task compared to wild-type.
Cntnap2-/- mice make more perseverative and regressive errors in the reversal learning task compared to wild-type.

Citazioni

"Cntnap2-/- SPNs exhibit increased cortical drive"
"Increased corticostriatal drive, in particular of the direct pathway, may contribute to the acquisition of repetitive, inflexible behaviors in Cntnap2 mice."
"Cntnap2-/- mice exhibit increased repetitive behaviors including increased grooming, nose poking, and marble burying."
"Cntnap2-/- mice exhibit cognitive inflexibility in the four-choice reversal learning task."

Approfondimenti chiave tratti da

Cntnap2 loss drives striatal neuron hyperexcitability and behavioral inflexibility

by Cording,K. R... alle www.biorxiv.org 05-09-2024

https://www.biorxiv.org/content/10.1101/2024.05.09.593387v1

Domande più approfondite

How do the cellular and circuit-level changes in the striatum of Cntnap2-/- mice relate to the broader neural circuit alterations observed in other brain regions in this mouse model

The cellular and circuit-level changes in the striatum of Cntnap2-/- mice are interconnected with broader neural circuit alterations observed in other brain regions in this mouse model. The striatum, particularly the dorsolateral striatum (DLS), plays a crucial role in motor learning, habit formation, and action selection. In Cntnap2-/- mice, there is an increase in the intrinsic excitability of striatal projection neurons (SPNs), particularly in the direct pathway SPNs. This heightened excitability leads to enhanced corticostriatal drive, impacting the function of SPNs in the DLS. These changes in SPN activity contribute to the manifestation of repetitive behaviors and cognitive inflexibility observed in Cntnap2-/- mice.
The alterations in the striatum are part of a larger network of neural circuitry affected by the loss of Cntnap2. Other brain regions, such as the cortex and hippocampus, also show changes in excitability and synaptic function in Cntnap2-/- mice. The interconnected nature of these alterations suggests a widespread impact on neural circuits involved in motor control, cognitive flexibility, and repetitive behaviors. The striatal dysfunction in Cntnap2-/- mice is likely intertwined with alterations in other brain regions, creating a complex network-level phenotype characteristic of autism spectrum disorder (ASD) models.

What are the developmental trajectories of the striatal dysfunction and the emergence of repetitive behaviors and cognitive inflexibility in Cntnap2-/- mice

The developmental trajectories of striatal dysfunction and the emergence of repetitive behaviors and cognitive inflexibility in Cntnap2-/- mice involve a dynamic interplay between genetic predisposition and environmental influences. During early development, the loss of Cntnap2 leads to disruptions in the maturation and function of striatal circuits, affecting the balance of excitation and inhibition in SPNs. These early cellular changes set the stage for altered corticostriatal connectivity and increased intrinsic excitability in the striatum.
As Cntnap2-/- mice mature, the impact of these cellular changes becomes more pronounced, leading to the emergence of repetitive behaviors and cognitive inflexibility. Repetitive behaviors, such as increased grooming, nose poking, and marble burying, reflect the aberrant functioning of striatal circuits involved in motor control and habit formation. Cognitive inflexibility, as seen in the reversal learning task, highlights the challenges in adapting to changing environmental cues and updating behavioral responses.
The developmental trajectory of striatal dysfunction in Cntnap2-/- mice likely involves a cascade of events starting from altered cellular function in early stages to the manifestation of behavioral phenotypes in later stages. Understanding these developmental trajectories is essential for elucidating the underlying mechanisms of ASD-related behaviors and identifying potential targets for intervention.

Could targeted modulation of striatal direct pathway activity rescue the behavioral phenotypes observed in Cntnap2-/- mice, and could this approach have therapeutic implications for autism spectrum disorder

Targeted modulation of striatal direct pathway activity could potentially rescue the behavioral phenotypes observed in Cntnap2-/- mice and have therapeutic implications for autism spectrum disorder (ASD). The direct pathway SPNs in the striatum play a critical role in initiating and facilitating motor actions. In Cntnap2-/- mice, the increased excitability of direct pathway SPNs contributes to the development of repetitive behaviors and cognitive inflexibility.
By selectively modulating the activity of direct pathway SPNs, either through pharmacological interventions or optogenetic techniques, it may be possible to restore the balance of corticostriatal signaling and normalize striatal function in Cntnap2-/- mice. This targeted approach could potentially alleviate the repetitive behaviors, enhance cognitive flexibility, and improve motor learning abilities in these mice.
Furthermore, the findings from studies on Cntnap2-/- mice could inform therapeutic strategies for individuals with ASD. Understanding the role of striatal dysfunction in ASD-related behaviors and exploring interventions that target specific neural circuits may lead to novel treatment approaches for individuals with ASD who exhibit similar behavioral phenotypes. By elucidating the link between striatal circuitry and behavioral outcomes, targeted modulation of the striatum could offer promising avenues for therapeutic interventions in ASD.