title: A continuous high frequency stimulation of the subthalamic nucleus determines a suppression of excitatory synaptic transmission in nigral dopaminergic neurons recorded in vitro.
abstract: High frequency stimulation of the subthalamic nucleus (HFS-STN) has been successfully introduced to treat symptoms of advanced Parkinson's disease (PD) (rigidity, tremor and akinesia). In spite of its extensive clinical practice, little is known at cellular level about the effects of a continuous train of electrical stimuli (>100 Hz) delivered in the STN. In this manuscript we examine the synaptic responses of substantia nigra pars compacta (SNpc) dopaminergic cells, upon continuous HFS-STN delivered in a rat brain slice preparation. We report that HFS-STN, delivered at frequencies resembling those used during DBS (100-130 Hz), caused synaptic responses in SNpc dopaminergic neurons, which summated progressively, until they reached a plateau within few tens of ms. However, if the HFS was maintained, a rapid fading of the synaptic response was observed, with an almost complete loss after 10s. Accordingly, the postsynaptic excitability, evaluated by the tonic firing rate of the SNpc dopaminergic neurons, remained unaltered during a continuous HFS-STN. Upon HFS termination, there was a rapid recovery of synaptic function. Neither a converging synaptic input, evoked by intranigral stimulation, nor the depolarizing responses to locally-applied AMPA, were affected during HFS. The loss of synaptic response by continuous HFS-STN was not prevented by inhibition of AMPA receptor desensitization, nor by antagonists of a variety of neurotransmitter receptors, known to depress synaptic transmission in the SNpc. We conclude that a HFS in the STN, with patterns resembling in vivo DBS, induces a rapid and input-specific suppression of the synaptic transmission from STN to SNpc dopaminergic neurons, that is maintained during an ongoing stimulation. The deficit of transmission between the STN and the SNpc could have a role in the therapeutic effects of the DBS procedure.
authors: Università degli Studi di Roma Tor Vergata, Rome, Italy.
authors: Ada
authors: A
authors: Ledonne
authors: Dalila
authors: D
authors: Mango
authors: Giorgio
authors: G
authors: Bernardi
authors: Nicola
authors: N
authors: Berretta
authors: Nicola Biagio
authors: NB
authors: Mercuri
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D001581:Benzothiadiazines / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D001703:Biophysics; D059290:Dopaminergic Neurons / Q000502:physiology*; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D009434:Neural Pathways / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000166:cytology*; D020531:Subthalamic Nucleus / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D001581:Benzothiadiazines; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D058787:GABA-A Receptor Antagonists; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C004639:cyclothiazide; D001640:Bicuculline