The impact of autism spectrum disorder risk gene mutations on striatal circuit function

Introduction

 

Autism spectrum disorder (ASD) is a highly complex neurodevelopmental condition marked by persistent deficits in social communication, interaction, and the presence of restricted and repetitive behaviors. Despite advances in understanding its genetic roots, ASD remains a heterogeneous disorder with diverse genetic causes that converge upon a relatively consistent set of behavioral symptoms. Katherine Rose Cording’s research, “The Impact of Autism Spectrum Disorder Risk Gene Mutations on Striatal Circuit Function,” focuses on how mutations in ASD-associated risk genes affect brain circuitry, particularly the striatum, a critical region for motor learning and behavior.

 

The Growing Genetic Understanding of ASD

 

ASD is one of the most heritable neurodevelopmental disorders, with studies showing that the disorder is influenced by a variety of genetic factors. Recent large-scale genetic sequencing efforts have uncovered over 100 high-confidence ASD risk genes, each of which encodes proteins essential to neuronal function. These proteins range from ion channels and neurotransmitter receptors to cell adhesion molecules and regulators of gene transcription and protein synthesis. Despite the genetic diversity, individuals diagnosed with ASD generally display common core symptoms, including difficulties with social communication and repetitive behaviors.

 

This study by Cording focuses on two of these critical risk genes: Tsc1 and Cntnap2, which belong to distinct families of ASD-related genes. Tsc1 regulates the mTOR pathway, which controls protein synthesis and cellular growth, while Cntnap2 is involved in cell adhesion and synaptic function. These genes play key roles in brain circuits that influence motor control and learning, particularly in the basal ganglia, where the striatum is located. By investigating the functional consequences of mutations in these genes, Cording sheds light on how alterations in striatal circuits may underlie the repetitive behaviors seen in ASD.

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The Striatum and Its Role in Autism

 

The basal ganglia, and specifically the striatum, is a brain region long associated with motor learning, habit formation, and the execution of intentional behaviors. The striatum serves as the primary input center for the basal ganglia and receives excitatory input from the cortex. This cortical-striatal circuit is essential for selecting and initiating appropriate actions based on sensory and motor input.

 

The striatum’s involvement in repetitive behaviors in ASD is particularly compelling. Many ASD mouse models exhibit abnormalities in the striatum, including changes in synaptic connectivity, neuronal excitability, and altered behavior. Importantly, the striatum is highly enriched in ASD risk genes, making it a prime candidate for studying the functional consequences of genetic mutations in ASD.

 

Investigating Tsc1: A Key Regulator of Motor Learning

 

The Tsc1 gene encodes a protein that negatively regulates the mTORC1 signaling pathway, which plays a crucial role in cell growth and protein synthesis. Dysregulation of this pathway has been implicated in ASD, particularly in disorders like tuberous sclerosis complex (TSC), which is characterized by mutations in Tsc1 and Tsc2. In this study, Cording specifically examines the effects of deleting Tsc1 from striatal direct pathway neurons (dSPNs), which are responsible for initiating movement and facilitating motor learning.

 

Her findings reveal that the loss of Tsc1 in dSPNs leads to increased cortical drive, meaning these neurons receive enhanced excitatory input from the cortex. This heightened cortical input results in enhanced motor learning, as evidenced by improved performance in the accelerating rotarod task, a behavioral assay used to measure motor coordination and learning. Mice with Tsc1 deletions in dSPNs exhibited superior motor performance, suggesting that the mutation promotes an overactive motor learning system.

 

Interestingly, this effect was not observed in the indirect pathway neurons (iSPNs), which are typically involved in inhibiting competing actions. The selective impact of Tsc1 deletion on dSPNs highlights the specificity of how different striatal circuits contribute to ASD-related behaviors. This increased cortical input to dSPNs suggests a potential mechanism by which individuals with ASD may develop stereotyped, repetitive motor behaviors—one of the hallmark symptoms of the disorder.

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Cntnap2: Increased Excitability and Repetitive Behaviors

 

In addition to Tsc1, Cording’s research also examines the Cntnap2 gene, which encodes a cell adhesion molecule important for the stabilization of potassium channels at synapses. Cntnap2 mutations have been strongly linked to both ASD and specific language impairments, and individuals with these mutations often exhibit severe speech and language delays, along with repetitive behaviors.

 

The study found that mice lacking Cntnap2 exhibited increased excitability in both direct and indirect pathway neurons of the striatum. This increased intrinsic excitability made the neurons more responsive to cortical input, but, unlike in the Tsc1 model, the primary difference was in the inherent properties of the striatal projection neurons (SPNs), rather than changes in cortical input. This suggests that the neurons themselves are more likely to fire in response to stimuli, possibly leading to the repetitive and inflexible behaviors observed in these mice.

 

The behavioral impact of Cntnap2 loss was evident in several assays. In the accelerating rotarod task, Cntnap2 knockout mice exhibited enhanced motor learning similar to the Tsc1 model. However, these mice also showed increased spontaneous repetitive behaviors, such as repetitive grooming, and impaired cognitive flexibility, as demonstrated in reversal learning tasks. These findings align with the core behavioral symptoms of ASD and suggest that Cntnap2 mutations directly impact striatal circuits involved in both motor learning and cognitive flexibility.

 

Corticostriatal Circuit Alterations: A Common Theme in ASD

 

One of the most important conclusions from Cording’s research is that despite the genetic heterogeneity of ASD, there may be a common theme of altered corticostriatal function across different genetic models. Both Tsc1 and Cntnap2 mutations lead to increased cortical drive and altered excitability in striatal neurons, ultimately affecting behaviors related to motor learning and repetitive actions.

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This finding supports the theory that corticostriatal dysfunction may be a shared pathophysiology in ASD, particularly in relation to the restricted and repetitive behavior domain. Alterations in the balance of excitatory and inhibitory inputs within the striatum could disrupt normal motor and cognitive processes, leading to the behaviors observed in ASD.

 

Broader Implications for ASD Research

 

Cording’s work provides important insights into how mutations in two distinct ASD risk genes can lead to similar disruptions in striatal function. While Tsc1 and Cntnap2 mutations affect different cellular processes—Tsc1 impacting protein synthesis and growth through mTOR regulation and Cntnap2 affecting synaptic stability and excitability—both ultimately result in increased excitatory drive in the striatum. This suggests that ASD may not be driven by a single molecular mechanism, but rather by disruptions in common neural circuits that regulate behavior.

 

The striatum’s role in both motor and social behavior makes it an ideal region to focus future ASD research. Imaging studies in humans have already shown that individuals with ASD often have altered striatal morphology and connectivity, and rodent models like those used in this study further support the idea that striatal dysfunction may be a key contributor to the behavioral symptoms of ASD.

 

Future Directions for Treatment and Intervention

 

Understanding how different ASD risk genes converge on the same brain circuits opens the door for potential therapeutic interventions. By targeting specific components of the corticostriatal circuit—whether through pharmacological means, gene therapy, or neuromodulation—researchers may be able to develop treatments that address the core symptoms of ASD, regardless of the underlying genetic cause.

 

Cording’s research lays the groundwork for future studies aimed at dissecting the precise mechanisms by which these genetic mutations alter brain function. It also highlights the need for further exploration of how these changes manifest in social behaviors, another key domain of ASD. The possibility of identifying common circuit-level dysfunctions across diverse genetic causes of ASD offers hope for developing more targeted and effective treatments.

 

Source:

https://escholarship.org/uc/item/63d963h9

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