Currently the most effective treatment for Parkinson's disease (PD) is levodopa. However, for many patients the benefit of levodopa treatment is limited by the development of levodopa-induced dyskinesias over time. The proposed experiments test the principal hypothesis that BDNF induces levodopa sensitization in the 6-OHDA lesioned rat model of PD through modulation of striatal LTP. The experiments address two specific aims: 1) to demonstrate the existence of synaptic plasticity in the denervated striatum after levodopa sensitization and 2) to establish the role of BDNF as a modulator of this plasticity.
For Specific Aim 1, synaptic efficacy will be measured in medium spiny neurons of the denervated striatum using evoked field potential recordings. The NMDA receptor antagonist APV will then be applied to test of this synaptic efficacy is NMDA receptor-dependent.
For Specific Aim 2, in situ hybridization will be used to examine the expression of BDNF and its receptor TrkB in the striatum and the cerebral cortex of levodopa-sensitized rats. Evoked field potentials will then be measured both when exogenous BDNF is applied to unsensitized denervated striata and when TrkB-IgG fusion protein, a scavenger of endogenous BDFN, is applied to sensitized denervated striata.
| Swanwick, Catherine Croft; Murthy, Namita R; Mtchedlishvili, Zakaria et al. (2006) Development of gamma-aminobutyric acidergic synapses in cultured hippocampal neurons. J Comp Neurol 495:497-510 |
| Swanwick, Catherine Croft; Murthy, Namita R; Kapur, Jaideep (2006) Activity-dependent scaling of GABAergic synapse strength is regulated by brain-derived neurotrophic factor. Mol Cell Neurosci 31:481-92 |
