Development of a sheep platform and behavioral monitoring methods for assessing deep brain stimulation therapies and devices for movement disorders

Preclinical animal models are essential for successful development of safe and effective commercialized CNS therapies. Objective data from animal models establish proof of concept evidence and provide critical inputs to the design of later phase clinical studies. In medical device development, a large animal with an intact nervous system is preferred because it permits use of human-scaled devices and controlled testing that cannot be replicated with computer modeling or bench-testing. Therefore, we established an in-house sheep platform for early-phase testing of deep brain stimulation (DBS) therapy concepts and devices within the movement disorders space. In twelve animals commercial DBS leads with four active contacts were targeted to the subthalamic nucleus (STN), a common stimulation target in Parkinson disease. Overall, DBS lead implantation was not associated with remarkable neurological or histopathological complications. Assessments of targeting using standard comparisons of pre and post-operative brain images indicated that accuracy was comparable to clinical experience. Methods were developed to quantitatively assess motor behavior of chronically-implanted animals in the awake state. In open and blinded settings, we consistently found that motor behavior responses to STN stimulation significantly depended on the stimulation contact selected and parameters tested, including voltage, pulse width and frequency. Quantitative electromyographic assessments confirmed the motor behavior findings. This work establishes in-house capabilities for controlled testing of emerging DBS therapy concepts and device prototypes. Further work is ongoing to test prototype devices and develop additional objective physiological monitoring methods and biomarkers

Purkinje cell-specific ablation of CaV2.1 Channels is sufficient to cause cerebellar ataxia in mice

The Cacna1a gene encodes the α1A subunit of voltage-gated CaV2.1 Ca2+ channels that are involved in neurotransmission at central synapses. CaV2.1-α1- knockout (α1KO) mice, which lack CaV2.1 channels in all neurons, have a very severe phenotype of cerebellar ataxia and dystonia, and usually die around postnatal day 20. This early lethality, combined with the wide expression of CaV2.1 channels throughout the cerebellar cortex and nuclei, prohibited determination of the contribution of particular cerebellar cell types to the development of the severe neurobiological phenotype in Cacna1a mutant mice. Here, we crossed conditional Cacna1a mice with transgenic mice expressing Cre recombinase, driven by the Purkinje cell-specific Pcp2 promoter, to specifically ablate the CaV2.1- α1A subunit and thereby CaV2.1 channels in Purkinje cells. Purkinje cell CaV2.1-α1A-knockout (PCα1KO) mice aged without difficulties, rescuing the lethal phenotype seen in α1KO mice. PCα1KO mice exhibited cerebellar ataxia starting around P12, much earlier than the first signs of progressive Purkinje cell loss, which appears in these mice between P30 and P45. Secondary cell loss was observed in the granular and molecular layers of the cerebellum and the volume of all individual cerebellar nuclei was reduced. In this mouse model with a cell type-specific ablation of CaV2.1 channels, we show that ablation of CaV2.1 channels restricted to Purkinje cells is sufficient to cause cerebellar ataxia. We demonstrate that spatial ablation of CaV2.1 channels may help in unraveling mechanisms of human disease

Limited regional cerebellar dysfunction induces focal dystonia in mice

Mechanisms of disease, diagnostics and therap

The first knockin mouse model of episodic ataxia type 2

Mechanisms of disease, diagnostics and therap

Stress, caffeine and ethanol trigger neurological dysfunction through shared mechanisms in a mouse calcium channelopathy.

Mechanisms of disease, diagnostics and therap

Purkinje Cell-Specific Ablation of Ca(V)2.1 Channels is Sufficient to Cause Cerebellar Ataxia in Mice

Mechanisms of disease, diagnostics and therap