6-cyano-7-nitroquinoxaline-2-3-dione and Parkinsonian-Disorders

Inhibitory connections among striatal projection neurons (SPNs) called "feedback inhibition," have been proposed to endow the striatal microcircuit with computational capabilities, such as motor sequence selection, filtering, and the emergence of alternating network states. These properties are disrupted in models of Parkinsonism. However, the impact of feedback inhibition in the striatal network has remained under debate. Here, we test this inhibition at the microcircuit level. We used optical and electrophysiological recordings in mice and rats to demonstrate the action of striatal feedback transmission in normal and pathological conditions. Dynamic calcium imaging with single-cell resolution revealed the synchronous activation of a pool of identified SPNs by antidromic stimulation. Using bacterial artificial chromosome-transgenic mice, we demonstrate that the activated neuron pool equally possessed cells from the direct and indirect basal ganglia pathways. This pool inhibits itself because of its own GABA release when stimuli are frequent enough, demonstrating functional and significant inhibition. Blockade of GABAA receptors doubled the number of responsive neurons to the same stimulus, revealing a second postsynaptic neuron pool whose firing was being arrested by the first pool. Stronger connections arise from indirect SPNs. Dopamine deprivation impaired striatal feedback transmission disrupting the ability of a neuronal pool to arrest the firing of another neuronal pool. We demonstrate that feedback inhibition among SPNs is strong enough to control the firing of cell ensembles in the striatal microcircuit. However, to be effective, feedback inhibition should arise from synchronized pools of SPNs whose targets are other SPNs pools.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Adrenergic Agents; Anesthetics, Local; Animals; Animals, Newborn; Bicuculline; Biophysics; Calcium; Disease Models, Animal; Electric Stimulation; Excitatory Amino Acid Antagonists; Feedback, Physiological; GABA Antagonists; gamma-Aminobutyric Acid; Green Fluorescent Proteins; In Vitro Techniques; Lidocaine; Lysine; Male; Mice; Mice, Transgenic; Monte Carlo Method; Neostriatum; Neural Inhibition; Neural Pathways; Neurons; Oxidopamine; Parkinsonian Disorders; Patch-Clamp Techniques; Pyridazines; Rats; Rats, Wistar; Reaction Time; Receptors, Dopamine D1; Receptors, Dopamine D2; Synaptic Transmission; Time Factors; Valine