The emergence ofcorrelated, low-frequency (<30 Hz), rhythmicactivity ofneurons in the subthalamicnucle- us (STN) is critical for the symptomatic expression of Parkinson's disease (PD). GABAergic synaptic inputs from the external globus pallidusand glutamatergicsynaptic inputs from the cortex and thalamus are critical for the normal and pathological patterning ofSTNactivity. The principal hypothesis that will be tested bythis research is that the loss of dopamine in PD leads to abnormal synaptic transmission within the STN, which (in part) underlies the pathological firing pattern. This hypothesis will be tested using electrophysiological recording of STN neurons in brain slices, correlated light and electron microscopy and 2-photon imaging. The influence of dopamine will be assessed by comparison of synaptic transmission and integration in i) the presence and absence of dopamine receptor agonists/antagonists and 2) in normal and dopamine-depleted animals. There are three specific aims of the project.
Specific Aim i : Measure the short-term plasticity and impactof GABAergic and glutamatergic synaptictansmission and their modulationby dopamine receptor agonists and antagonists.
Specific Aim2 : Determine the pre- and/or postynaptic activity patterns that underlielong-term plasticity of GABAergicand glutamatergic synaptic transmission in the STN.
Specific Aim 3 : Compare the operation and influence of GABAergic and glutamatergic synapses in the STNin control animalsand experi- mental models of PD. The knowledgegenerated bythis project will further our understandingofthe factors underlying pathological activity in the STNand assist the rational development oftherapies that ameliorate the symptoms and inter- rupt the progression of PD by modification of STN activity. Lay Description: Abolition of pathological activity of nerve cells in the subthalamic nucleus (STN) leads to a profound improvement in the symptoms of Parkinson's disease (PD). This project will test the hypothesis that pathological STNactivity is driven (in part) by abnormal inputs to STNnerve cells in PD. By elucidating the mechanisms underlyingabnormal activity, this research will guidethe rational development of therapies that ameliorate the symptoms and interrupt the progression ofPDthroughthe normalizationof STNactivity.
|Atherton, Jeremy F; Menard, Ariane; Urbain, Nadia et al. (2013) Short-term depression of external globus pallidus-subthalamic nucleus synaptic transmission and implications for patterning subthalamic activity. J Neurosci 33:7130-44|
|Fan, Kai Y; Baufreton, Jérôme; Surmeier, D James et al. (2012) Proliferation of external globus pallidus-subthalamic nucleus synapses following degeneration of midbrain dopamine neurons. J Neurosci 32:13718-28|
|Wilson, C J; Bevan, M D (2011) Intrinsic dynamics and synaptic inputs control the activity patterns of subthalamic nucleus neurons in health and in Parkinson's disease. Neuroscience 198:54-68|
|Atherton, Jeremy F; Kitano, Katsunori; Baufreton, Jerome et al. (2010) Selective participation of somatodendritic HCN channels in inhibitory but not excitatory synaptic integration in neurons of the subthalamic nucleus. J Neurosci 30:16025-40|
|Baufreton, Jérôme; Kirkham, Erin; Atherton, Jeremy F et al. (2009) Sparse but selective and potent synaptic transmission from the globus pallidus to the subthalamic nucleus. J Neurophysiol 102:532-45|
|Blythe, Sarah N; Wokosin, David; Atherton, Jeremy F et al. (2009) Cellular mechanisms underlying burst firing in substantia nigra dopamine neurons. J Neurosci 29:15531-41|
|Ramanathan, Sankari; Tkatch, Tatiana; Atherton, Jeremy F et al. (2008) D2-like dopamine receptors modulate SKCa channel function in subthalamic nucleus neurons through inhibition of Cav2.2 channels. J Neurophysiol 99:442-59|
|Atherton, Jeremy F; Wokosin, David L; Ramanathan, Sankari et al. (2008) Autonomous initiation and propagation of action potentials in neurons of the subthalamic nucleus. J Physiol 586:5679-700|
|Baufreton, Jerome; Bevan, Mark D (2008) D2-like dopamine receptor-mediated modulation of activity-dependent plasticity at GABAergic synapses in the subthalamic nucleus. J Physiol 586:2121-42|
|Blythe, Sarah N; Atherton, Jeremy F; Bevan, Mark D (2007) Synaptic activation of dendritic AMPA and NMDA receptors generates transient high-frequency firing in substantia nigra dopamine neurons in vitro. J Neurophysiol 97:2837-50|
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