Excitability Of Medium Spiny Neurons Research Articles

Heterosynaptic Dopamine Neurotransmission Selects Sets of Corticostriatal Terminals

Dopamine input to the striatum is required for voluntary motor movement, behavioral reinforcement, and responses to drugs of abuse. It is speculated that these functions are dependent on either excitatory or inhibitory modulation of corticostriatal synapses onto medium spiny neurons (MSNs). While dopamine modulates MSN excitability, a direct presynaptic effect on the corticostriatal input has not been clearly demonstrated. We combined optical monitoring of synaptic vesicle exocytosis from motor area corticostriatal afferents and electrochemical recordings of striatal dopamine release to directly measure effects of dopamine at the level of individual presynaptic terminals. Dopamine released by either electrical stimulation or amphetamine acted via D2 receptors to inhibit the activity of subsets of corticostriatal terminals. Optical and electrophysiological data suggest that heterosynaptic inhibition was enhanced by higher frequency stimulation and was selective for the least active terminals. Thus, dopamine, by filtering less active inputs, appears to reinforce specific sets of corticostriatal synaptic connections.

Modulation of GABAergic transmission in the striatopallidal system by adenosine A2A receptors: a potential mechanism for the antiparkinsonian effects of A2A antagonists.

The selective localization of adenosine A2A receptors to the striatopallidal system suggested a new therapeutic approach to the management of Parkinson's disease (PD). The results of behavioral studies using A2A receptor-specific agents in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys highlight the therapeutic potential of A2A antagonists as a novel treatment for PD. However, little is known about the role of A2A receptors in basal ganglia function or their pathophysiologic role in PD. Recently, the authors found that presynaptic A2A receptors modulate GABAergic synaptic transmission in the striatum and globus pallidus (GP), suggesting an A2A receptor-mediated dual modulation of the striatopallidal system. Striatal A2A receptors may increase the excitability of medium spiny neurons (MSNs) by modulating an intrastriatal GABAergic network. In addition, pallidal modulation occurs at striatopallidal MSN terminals located at the GP, enhancing GABA release onto GP projection neurons and directly suppressing their activity. Blockade of these modulatory functions by A2A antagonists could counteract excessive striatopallidal neuronal activity provoked by striatal dopamine depletion in patients with PD, leading to a reversal of parkinsonian motor deficits.