Dopamine system in a neurodevelopmental disorder mouse model

Cav1.3 L-type Ca2+ channels (LTCCs) are required for proper brain function and gain-of-function mutations in the gene encoding the Cav1.3 pore-forming subunit (CACNA1D gene) have been found in patients with neurodevelopmental disease. We have established a respective disease mouse model by introducing the A749G CACNA1D mutation, found in a patient with autism and intellectual disability. This novel disease model shows altered in vivo Cav1.3 Ca2+-currents and behavioral changes reconstituting several aspects of the human disease spectrum, including hyperlocomotion and autism- like behaviors. As dopamine controls emotional, motor and cognitive functions, and Cav1.3 plays key roles in the dopamine midbrain system, we hypothesize that enhanced Cav1.3 activity results in changes within this brain system that underlie the observed symptoms. To prove this hypothesis, we will first study if the altered Cav1.3 Ca 2+ influx in our disease model indeed induces functional changes within the dopamine midbrain system using brain slice electrophysiology that allows to investigate the cellular firing of specific subsets of dopamine neurons. The primary role of these neurons is the release of the neurotransmitter dopamine within their target brain regions such as the striatum, important for motor and emotional behavior. Thus, we will optically monitor the striatal dopamine release in awake mice during behaviors that are affected in our disease model using the state- of-the-art technique in vivo fiber photometry. These experiments will help to identify processes that contribute to the disease spectrum as well as affected brain circuits. Next, we will focus on possibilities to attenuate the observed phenotype in our disease model, using a genetic as well as a pharmacological approach to directly target Cav1.3 Ca2+ channels. First, we will genetically reduce the amount of Cav1.3 within a subregion of the dopamine midbrain system that is important for locomotion and evaluate the effects on the hyperlocomotive phenotype of our mouse model. Moreover, the pharmacological agent isradipine, a LTCC inhibitor, will be evaluated for its disease-modifying potential. Although isradipine is not selective for Cav1.3 but also acts on the other brain LTCC isoform Cav1.2, the big advantage of this approach is the direct translational potential of this type of drugs. They are clinically approved and safe antihypertensives that could be readily repurposed for off-label treatment of affected patients to alleviate symptoms associated with this disease spectrum. Altogether, this project aims to characterize the first disease model of CACNA1D-related neurodevelopmental disorders and to identify disease-underlying mechanisms. The proposed pharmacological experiments may have direct clinical implications for the treatment of patients with CACNA1D mutations and the identified affected brain circuits may represent additional therapeutic targets in neurodevelopmental disease such as autism.