Globus pallidus neurons dynamically regulate the activity pattern of subthalamic nucleus neurons through the frequency-dependent activation of postsynaptic GABAA and GABAB receptors.
Reciprocally connected GABAergic neurons of the globus pallidus (GP) and glutamatergic neurons of the subthalamic nucleus (STN) are a putative generator of pathological rhythmic burst firing in Parkinson's disease (PD). Burst firing of STN neurons may be driven by rebound depolarization after barrages of GABA(A) receptor (GABA(A)R)-mediated IPSPs arising from pallidal fibers. To determine the conditions under which pallidosubthalamic transmission activates these and other postsynaptic GABARs, a parasagittal mouse brain slice preparation was developed in which pallidosubthalamic connections were preserved. Intact connectivity was first confirmed through the injection of a neuronal tracer into the GP. Voltage-clamp and gramicidin-based perforated-patch current-clamp recordings were then used to study the relative influences of GABA(A)R- and GABA(B)R-mediated pallidosubthalamic transmission on STN neurons. Spontaneous phasic, but not tonic, activation of postsynaptic GABA(A)Rs reduced the frequency and disrupted the rhythmicity of autonomous firing in STN neurons. However, postsynaptic GABA(B)Rs were only sufficiently activated to impact STN firing when pallidosubthalamic transmission was elevated or pallidal fibers were synchronously activated by electrical stimulation. In a subset of neurons, rebound burst depolarizations followed high-frequency, synchronous stimulation of pallidosubthalamic fibers. Although GABA(B)R-mediated hyperpolarization was itself sufficient to generate rebound bursts, coincident activation of postsynaptic GABA(A)Rs produced longer and more intense burst firing. These findings elucidate a novel route through which burst activity can be generated in the STN, and suggest that GABARs on STN neurons could act in a synergistic manner to generate abnormal burst activity in PD.
Hallworth
Nicholas E
NE
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611-3008, USA.
Bevan
Mark D
MD
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D005071:Evoked Potentials / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D005917:Globus Pallidus / Q000166:cytology* / Q000502:physiology; D008239:Lysine / Q000031:analogs & derivatives / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009434:Neural Pathways / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010300:Parkinson Disease / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D010852:Picrotoxin / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000502:physiology*; D018080:Receptors, GABA-B / Q000502:physiology*; D020531:Subthalamic Nucleus / Q000166:cytology*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D015763:2-Amino-5-phosphonovalerate; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D008239:Lysine; D010852:Picrotoxin; D011724:Pyridazines; D011810:Quinoxalines; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; C056723:FG 9041; C049853:gabazine; C013411:biocytin