Behavioral assay of the lack of the SLITRK1 gene in C57BL/6 mice
Tourette syndrome (TS) is a neurodevelopmental disorder that affects approximately 0.5% of the population, with a peak onset in preadolescence with symptoms ranging from mild to disabling. We are currently working on a project which is working to gain a better appreciation for the neurochemical substrates underlying TS in order to set a path for developing new pharmacological treatment. Data from a recent genetic study found a connection between mutations in the slit and trk-like family member 1 (SLITRK1) gene and TS. Mice with a global knockout of this gene have been produced and we have been assessing the phenotype of knockout, heterozygous, and control littermates in several behavioral experiments.
Behavioral assay of the lack of central serotonin neurons in mice
Excessive or compulsive grooming in animal models has been proposed as a behavioral model of the repetitive behaviors seen in OCD and related disorders. Selective serotonin reuptake inhibitors (SSRIs) have been shown to reduce excessive grooming in two proposed animal models; however, how these compounds help is poorly understood. Recently, a transgenic mouse was developed that lacks serotonin neurons in the central nervous system and a high incidence of grooming-related skin lesions in adult male Lmx1b-KO animals was observed under normal vivarium conditions, suggesting that developmental absence of CNS serotonin may lead to grooming abnormalities. We have been assessing grooming in these mice at baseline and are conducting a battery of behavioral tasks to assay phenotypes of potential relevance to OCD and related disorders.
Investigating the neurobiological processes that may underlie the pathophysiology of Tourette syndrome using a mouse model of interneuronal deficit.
Recent post-mortem findings indicate pathology of cholinergic (ChAT) and parvalbumin (PV) interneuronal populations in the basal ganglia in severe TS. We have achieved the highly specific and effective ablation of both striatal ChAT and PV interneurons using a combination of the local infusion of a recombinant inducible DTR (iDTR) adeno-associated virus (AAV) and CRE transgenic mice and shown behavioral consequences that recapitulate key aspects of TS. With this conceptual background and versatile tool, we are continuing to study the molecular, neurochemical, and behavioral consequences of recapitulating these cellular abnormalities in mouse models.