title: High frequency stimulation of the subthalamic nucleus leads to presynaptic GABA(B)-dependent depression of subthalamo-nigral afferents.
abstract: Patients with akinesia benefit from chronic high frequency stimulation (HFS) of the subthalamic nucleus (STN). Among the mechanisms contributing to the therapeutic success of HFS-STN might be a suppression of activity in the output region of the basal ganglia. Indeed, recordings in the substantia nigra pars reticulata (SNr) of fully adult mice revealed that HFS-STN consistently produced a reduction of compound glutamatergic excitatory postsynaptic currents at a time when the tetrodotoxin-sensitive components of the local field potentials had already recovered after the high frequency activation. These observations suggest that HFS-STN not only alters action potential conduction on the way towards the SNr but also modifies synaptic transmission within the SNr. A classical conditioning-test paradigm was then designed to better separate the causes from the indicators of synaptic depression. A bipolar platinum-iridium macroelectrode delivered conditioning HFS trains to a larger group of fibers in the STN, while a separate high-ohmic glass micropipette in the rostral SNr provided test stimuli at minimal intensity to single fibers. The conditioning-test interval was set to 100 ms, i.e. the time required to recover the excitability of subthalamo-nigral axons after HFS-STN. The continuity of STN axons passing from the conditioning to the test sites was examined by an action potential occlusion test. About two thirds of the subthalamo-nigral afferents were occlusion-negative, i.e. they were not among the fibers directly activated by the conditioning STN stimulation. Nonetheless, occlusion-negative afferents exhibited signs of presynaptic depression that could be eliminated by blocking GABA(B) receptors with CGP55845 (1 µM). Further analysis of single fiber-activated responses supported the proposal that the heterosynaptic depression of synaptic glutamate release during and after HFS-STN is mainly caused by the tonic release of GABA from co-activated striato-nigral afferents to the SNr. This mechanism would be consistent with a gain-of-function hypothesis of DBS.
authors.affiliation: Cluster of Excellence NeuroCure, Department of Experimental Neurology, University Medicine Charité, Berlin, Germany.
authors.forename: Anton
authors.initials: A
authors.lastname: Dvorzhak
authors.affiliation: Department of Experimental Neurology, University Medicine Charité, Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Gertler
authors.affiliation: Department of Experimental Neurology, University Medicine Charité, Berlin, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Harnack
authors.affiliation: Cluster of Excellence NeuroCure, Department of Experimental Neurology, University Medicine Charité, Berlin, Germany.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Grantyn
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000344:Afferent Pathways / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D003213:Conditioning, Psychological; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D018698:Glutamic Acid / Q000494:pharmacology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D015640:Ion Channel Gating / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D009473:Neuronal Plasticity / Q000187:drug effects*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology*; D018079:Receptors, GABA / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology*; D020531:Subthalamic Nucleus / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D018079:Receptors, GABA; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid