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J Physiol. 2008 Apr 15;586(8):2121-42. doi: 10.1113/jphysiol.2008.151118. Epub 2008 Feb 21.

D2-like dopamine receptor-mediated modulation of activity-dependent plasticity at GABAergic synapses in the subthalamic nucleus.

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Northwestern University, Department of Physiology, Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, IL 60611, USA.


Reciprocally connected glutamatergic subthalamic nucleus (STN) and GABAergic external globus pallidus (GP) neurons normally exhibit weakly correlated, irregular activity but following the depletion of dopamine in Parkinson's disease they express more highly correlated, rhythmic bursting activity. Patch clamp recording was used to test the hypothesis that dopaminergic modulation reduces the capability of GABAergic inputs to pattern 'pathological' activity in STN neurons. Electrically evoked GABA(A) receptor-mediated IPSCs exhibited activity-dependent plasticity in STN neurons, i.e. IPSCs evoked at frequencies between 1 and 50 Hz exhibited depression that increased with the frequency of activity. Dopamine, the D(2)-like dopamine receptor agonist quinpirole and external media containing a low [Ca(2+)] reduced both the magnitude of IPSCs evoked at 1-50 Hz and synaptic depression at 10-50 Hz. Dopamine/quinpirole also reduced the frequency but not the amplitude of miniature IPSCs recorded in the presence of tetrodotoxin. D(1)-like and D(4) agonists were ineffective and D(2/3) but not D4 receptor antagonists reversed the effects of dopamine or quinpirole. Together these data suggest that presynaptic D(2/3) dopamine receptors modulate the short-term dynamics of GABAergic transmission in the STN by lowering the initial probability of transmitter release. Simulated GABA(A) receptor-mediated synaptic conductances representative of control or modulated transmission were then generated in STN neurons using the dynamic clamp technique. Dopamine-modulated transmission was less effective at resetting autonomous activity or generating rebound burst firing than control transmission. The data therefore support the conclusion that dopamine acting at presynaptic D(2)-like receptors reduces the propensity for GABAergic transmission to generate correlated, bursting activity in STN neurons.

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