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Title: GABAergic synaptic transmission, plasticity and integration in the subthalamic nucleus
Author: Fan, Kai Yoon
ISNI:       0000 0004 2728 6010
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2012
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The reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN) occupy pivotal positions in cortico-basal ganglia-thalamo-cortical networks essential for normal voluntary movement. In both idiopathic and experimental PD characterized by degeneration of midbrain dopamine neurons, the GPe and STN exhibit hypo- and hyper-activity, respectively, and hypersynchronous rhythmic burst firing (< 30 Hz). Deep brain stimulation (DBS) of STN (> 60 Hz) suppresses the pathological oscillations and improves motor impairments, although the therapeutic mechanisms are unclear. Given the GPe potently patterns STN activity, the decorrelated nature of GPe-STN network is intriguing. Therefore, the main objective of this thesis is to study the regulation of GPe-STN input in health, PD and DBS, using complementary anatomical, molecular, electrophysiological and computational modelling approaches. Studies comparing GPe-STN transmission in control and 6-OHDA-lesioned rodents revealed that following chronic dopamine depletion the GPe-STN projections strengthened remarkably through proliferation in the number of functional synaptic connections. The enhanced GPe-STN transmission is predicted to increase the capability of the GPe to generate synchronous rhythmic burst firing in the parkinsonian STN. Recent optogenetic studies showed that high-frequency driving of afferents expressing channelrhodopsin-2 (ChR2) in the STN of Thy1-ChR2 transgenic mice rescued parkinsonian symptoms. Characterization of the mouse line revealed ChR2 expression in not only glutamatergic but GABAergic afferents in the STN, implying DBS may exert its therapeutic effects through manipulation of GPe-STN transmission. The work from this thesis also demonstrates that GABAergic inhibition in STN neurons activates HCN channel currents that limit synaptic hyperpolarisation and deinactivation of low-voltage-activated Ca2+ channels, hence reducing the propensity of rebound burst firing. Uniform HCN channel distribution across the somatodendritic axis most effectively counteracts the GABAergic inhibition. These results suggest that HCN channels in STN neurons may partly underlie the decorrelated nature of GPe-STN activity and prevent excessive burst firing observed in PD.
Supervisor: Holley, Matthew ; Bevan, Mark Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available