The glutamatergic subthalamic nucleus (STN) is a major driving force of neuronal activity in the basal ganglia during normal voluntary movement and in movement disorders e.g. in Parkinson's disease (PD). In idiopathic and experimental models of PD, STN neurons display abnormal patterns of activity, which may arise, in part, from an alteration in their intrinsic membrane properties. Cellular plasticity in the STN may result from the loss of dopaminergic neuromodulation within the STN and/or the altered pattern of synaptic input, which results from the depletion of dopamine in other basal ganglia nuclei. The first specific aim is to determine further the ionic, biophysical and molecular principles that underlie the normal firing properties of STN neurons in vitro i.e., spontaneous oscillation, driven high-frequency activity and rebound burst firing. This will be achieved using current- and voltage-clamp recording of STN neurons in vitro using the perforated, whole-cell and nucleated configurations of the patch clamp technique. The roles of specific ion channels in firing behavior will be adressed by examination of firing and ionic currents in the presence of selective channel blockers, the molecular nature of ion channels in STN neurons will be determined using immunocytochemistry of alpha subunits and messenger RNA expression studies. The second specific aim is to determine how dopamine modulates the firing and ion channel properties of STN neurons. This will be addressed using the combined electrophysiological and molecular approach described above, the neuromodulation of ion channels by dopamine will be determined using selective D1-like and D2-like receptor agonists. The membrane properties of STN neurons in normal and dopamine-depleted animals will then be compared to determine whether cellular plasticity contributes to the abnormal activity of STN neurons in PD.
| Guzman, Jaime N; Ilijic, Ema; Yang, Ben et al. (2018) Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress. J Clin Invest 128:2266-2280 |
| Hunt Jr, Albert J; Dasgupta, Rajan; Rajamanickam, Shivakumar et al. (2018) Paraventricular hypothalamic and amygdalar CRF neurons synapse in the external globus pallidus. Brain Struct Funct 223:2685-2698 |
| Higgs, Matthew H; Wilson, Charles J (2017) Measurement of phase resetting curves using optogenetic barrage stimuli. J Neurosci Methods 289:23-30 |
| Surmeier, D James; Obeso, José A; Halliday, Glenda M (2017) Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci 18:101-113 |
| Chu, Hong-Yuan; McIver, Eileen L; Kovaleski, Ryan F et al. (2017) Loss of Hyperdirect Pathway Cortico-Subthalamic Inputs Following Degeneration of Midbrain Dopamine Neurons. Neuron 95:1306-1318.e5 |
| Shi, Han; Deng, Han-Xiang; Gius, David et al. (2017) Sirt3 protects dopaminergic neurons from mitochondrial oxidative stress. Hum Mol Genet 26:1915-1926 |
| Surmeier, D James; Halliday, Glenda M; Simuni, Tanya (2017) Calcium, mitochondrial dysfunction and slowing the progression of Parkinson's disease. Exp Neurol 298:202-209 |
| Galtieri, Daniel J; Estep, Chad M; Wokosin, David L et al. (2017) Pedunculopontine glutamatergic neurons control spike patterning in substantia nigra dopaminergic neurons. Elife 6: |
| Surmeier, D James; Schumacker, Paul T; Guzman, Jaime D et al. (2017) Calcium and Parkinson's disease. Biochem Biophys Res Commun 483:1013-1019 |
| Burbulla, Lena F; Song, Pingping; Mazzulli, Joseph R et al. (2017) Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease. Science 357:1255-1261 |
Showing the most recent 10 out of 119 publications
