TS-EUROTRAIN - Projects

Finding developmental aspects and possible drug targets of TS and OCD: metabotropic glutamatergic mechanisms in a neurodevelopmental rat model of repetitive behaviors (WP3)

Objectives: 1. Establish a developmental model of unilateral 6-OHDA lesion in rats in early developmental stages 2. Comparison of the repetitive behaviour induced by l-dopa application in the developmental and the adult model 3. Molecular analysis of lesion-induced changes  4. Test of tool compounds which modulate glutamatergic neurotransmission.

Fellow ESR9
Host institution: BI PHARMA/UULM
Duration: 36 months    
Supervisor: B. Hengerer, BI PHARMA; Co-supervisor: A. Ludolph, T. Böckers, UULM; Host Company: BI PHARMA.

Tasks and methodology: After unilateral, 6-OHDA induced degeneration of nigra-striatal neurons and subsequent chronic application of l-dopa, rats develop repetitive, involuntary movements. The abnormal involuntary movements involve the forepaw and oro-facial movements with tongue protrusion. Several pharmacological approaches have been shown to reduce the repetitive, dyskinetic movements. Similar, repetitive involuntary movements are evoked in mouse and monkey models after degeneration of nigral dopaminergic neurons and chronic l-dopa treatment. All published studies have been performed in adult animals. The DA neurodegeneration will be induced in post-natal rats to study the neurodevelopmental consequences of the lesion. Different dopamine agonists will be used to induce the repetitive movements, investigating the relative involvement of the direct and indirect pathways. The influence of non-dopaminergic mechanisms on the repetitive behavior will be studied with available, brain-penetrant tool compounds with a special emphasis on modulators of metabotropic glutamate receptors. The influence of pre- and postsynaptic modulation of glutamatergic synapses will be addressed by mGlu2 PAMs and mGlu5 NAMs, respectively.

  • Task 1: Repetitive behaviour induced by l-dopa application in 6-OHDA lesioned animals is a well established model of dysregulated activity of the cortico-striato-thalamo-cortical pathway. The lesions are usually induced in adult animals and the first task will be to establish suitable experimental conditions for induction of dopaminergic lesions to various extents in young animals. The lesions will be quantified by Tyrosine hydroxylase IHC and dopamine measurement.
  • Task 2: After establishing the model in young animals, the behavioural consequences of the dopaminergic lesion will be investigated and compared to the adult lesioned animals.
  • Task 3: The underlying pathological changes will be studied with a variety of readouts such as IHC, Golgie stain of synaptic spines, neurotransmitter quantification in tissue extracts etc.
  • Task 4: Various tool compounds (mGlu2 PAMs and mGlu5 NAMs) which are well characterized and penetrate the BBB and modulate glutamatergic pre- and postsynapses will be applied to the animals and their effects after acute and chronic application will be evaluated.

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