Posted September 20, 2022

Anis Contractor, Ph.D., and Dalton Surmeier, Ph.D., Northwestern University

Autism Spectrum Disorders (ASDs) are characterized by problems with social engagement and communication, as well as inappropriate, restrictive, and repetitive behaviors. While the etiology of ASDs in many cases is idiopathic, a growing list of de novo genetic variants has been identified as causal to the disorder. Recently, several de novo mutations were found in individuals with ASDs in genes that code for important neuronal Ca2+ channels. These ion channels are known to affect neuronal and synaptic development and are likely related to autism diagnosed in these patients. More specifically, because these mutations are known to cause a gain-of-function phenotype, increasing Ca2+ flow through the channel, they provide a unique opportunity to model the disorder in a mouse and establish a molecular basis for understanding how brain circuits are functionally altered in ASDs.

With support from a Fiscal Year 2017 Autism Research Program Idea Development Award from the Congressionally Directed Medical Research Programs (CDMRP), Dr. Anis Contractor and Dr. Dalton Surmeier of Northwestern University utilized a mouse model with a disease-associated mutation in the Ca2+ ion channel (G407R mutation). The researchers studied how this mutation affects Ca2+ channel activity and the impact on synaptic plasticity, neural circuits, and behavior. Specifically, they focused on how this mutation disrupts synaptic plasticity in a region of the brain called the striatum, which is important for habitual and perseverative behaviors that can be disrupted in ASDs.

Using both single-cell electrophysiology and imaging of activity-induced changes in Ca2+ activity, the team found the Ca2+ response was elevated in the dendrites of striatal neurons in the G407R mutant mice. Moreover, a form of synaptic depression that requires nitric oxide (NO) signaling and is directly inhibited by Ca2+ activity was impaired in the mutant mice. They hypothesized that this plasticity is required for behavioral flexibility, which is importantly affected in people with ASDs. To test this in mice, they trained the mice in a two-choice task to touch one of two screens, and then tested how quickly they could relearn this task when the correct choice was reversed. As hypothesized, the mutant mice did not perform as well in the reversal task, suggesting that their behavioral flexibility was impaired. Importantly, blocking the NO dependent striatal depression in wildtype mice also impaired reverse-learning behavior, linking the behavior to synaptic plasticity in the striatum.

These findings demonstrate disease-associated mutations in the Cav1.3 Ca2+ channel that disrupt the activity of the channels can impair synaptic plasticity in the striatum, thus disrupting how mice relearn a new task, which is a correlation of altered behavioral flexibility in ASDs. This research can provide more information about the synaptic and circuit mechanisms that contribute to altered behaviors observed in ASD. Ultimately, this work will inform potential therapies that can correct neuronal plasticity dysfunction and influence the awareness of symptoms of ASD.

Links:
Public and Technical Abstracts: Autism-Associated Mutations in L-Type Ca2+ Channels

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