The striatum receives massive cortical excitatory inputs and is densely innervated by dopamine. Striatal projection neurons form either the direct or indirect pathways. Models of Parkinson's disease propose that dopaminergic degeneration imbalances both pathways, although direct electrophysiological evidence is lacking. Here, striatal neurons were identified by electrophysiological criteria and Neurobiotin labeling combined with either immunohistochemistry or in situ hybridization. Their spontaneous discharge activity and spike response to cortical stimulation were recorded in vivo in anesthetized rats rendered hemi-parkinsonian by 6-hydroxydopamine. We showed that striatonigral neurons (direct pathway) were inhibited whereas striatopallidal neurons (indirect pathway) were activated by dopaminergic lesion. We also identified, with antidromic stimulations, corticostriatal neurons that preferentially innervate striatonigral or striatopallidal neurons and showed that dopaminergic depletion selectively decreased the spontaneous activity of the former. Therefore, dopamine degeneration induces a cascade of imbalances that spread out of the basal ganglia and affect the whole basal ganglia-thalamo-cortical circuits.Fast-spiking GABA interneurons provide potent feedforward inhibition of striatal projection neurons. We showed here that these interneurons narrowed the time window of the responses of projection neurons to cortical stimulation. In the dopamine-depleted striatum, because the intrinsic activity of these interneurons was not altered, their feedforward inhibition worsened the striatal imbalance. Indeed, the time window of the evoked responses was narrower for striatonigral neurons and wider for striatopallidal neurons. Therefore, after dopaminergic depletion, cortical inputs and GABA interneurons might imbalance striatal projection neurons and represent two novel nondopaminergic mechanisms that might secondarily contribute to the pathophysiology of Parkinson's disease.

Discharge activities and local field potentials were recorded in the orofacial motor cortex and in the corresponding rostrolateral striatum of urethane-anesthetized rats. Striatal projection neurons were identified by antidromic activation and fast-spiking GABAergic interneurons (FSIs) by their unique characteristics: briefer spike and burst responses. Juxtacellular injection of neurobiotin combined with parvalbumin immunohistochemistry validated this identification. Spontaneous activities and spike responses to cortical stimulation were recorded during both states of cortical activity: slow waves and desynchronization. Both FSI and projection neurons spontaneously discharged synchronously with slow waves at the maximum of cortical activity, but, on average, FSIs were much more active. Cortical desynchronization enhanced FSI activity and facilitated their spike responses to cortical stimulation, whereas opposite effects were observed regarding projection neurons. Experimental conditions favoring FSI discharge were always associated with a decrease in the firing activity of projection neurons. Spike responses to cortical stimulation occurred earlier (latency difference, 4.6 ms) and with a lower stimulation current for FSIs than for projection neurons. Moreover, blocking GABA A receptors by local picrotoxin injection enhanced the spike response of projection neurons, and this increase was larger in experimental conditions favoring FSI responses. Therefore, on average, FSIs exert in vivo a powerful feedforward inhibition on projection neurons. However, a few projection neurons were actually more sensitive to cortical stimulation than FSIs. Moreover, picrotoxin, which revealed FSI inhibition, preferentially affected projection neurons exhibiting the weakest sensitivity to cortical stimulation. Thus, feedforward inhibition by FSIs filters cortical information effectively transmitted by striatal projection neurons.

No abstract

Most neurotransmitters inhibit their own release through autoreceptors. However, the physiological functions of these presynaptic inhibitions are still poorly understood, in part because their time course and functional characteristics have not been described in vivo. Dopamine inhibits its own release through D2 autoreceptors. Here, the part played by autoinhibition in the relationship between impulse flow and dopamine release was studied in vivo in real time. Dopamine release was evoked in the striatum of anesthetized mice by electrical stimulation of the medial forebrain bundle and was continuously monitored by amperometry using carbon fiber electrodes. Control experiments performed in mice lacking D2 receptors showed no autoinhibition of dopamine release. In wild-type mice, stimulation at 100 Hz with two to six pulses linearly inhibited further release, whereas single pulses were inefficient. Dopaminergic neurons exhibit two discharge patterns: single spikes forming a tonic activity below 4 Hz and bursts of two to six action potentials at 15 Hz. Stimulation mimicking one burst (four pulses at 15 Hz) promoted extracellular dopamine accumulation and thus inhibited further dopamine release. This autoinhibition was maximal between 150 and 300 msec after stimulation and disappeared within 600 msec. This delayed and prolonged time course is not reflected in extracellular DA availability and thus probably attributable to mechanisms downstream from autoreceptor stimulation. Thus, in physiological conditions, autoinhibition has two important roles. First, it contributes to the attenuation of extracellular dopamine during bursts. Second, autoinhibition elicited by one burst transiently attenuates further dopamine release elicited by tonic activity.

The spatiotemporal characteristics of the dopaminergic transmission mediated by D1 receptors were investigated in vivo. For this purpose dopamine (DA) release was evoked in the striatum of anesthetized rats by train electrical stimulations of the medial forebrain bundle (one to four pulses at 15 Hz), which mimicked the spontaneous activity of dopaminergic neurons. The resulting dopamine overflow was electrochemically monitored in real time in the extracellular space. This evoked DA release induced a delayed increase in discharge activity in a subpopulation of single striatal neurons. This excitation was attributable to stimulation of D1 receptors by released DA because it was abolished by acute 6-hydroxydopamine lesion and strongly reduced by the D1 antagonist SCH 23390. Striatal neurons exhibiting this delayed response were also strongly excited by intravenous administration of the D1 agonist SKF 82958. Whereas the DA overflow was closely time-correlated with stimulation, the excitatory response mediated by DA started 200 msec after release and lasted for up to 1 sec. Moreover, functional evidence presented here combined with previous morphological data show that D1 receptors are stimulated by DA diffusing up to 12 m away from release sites in the extrasynaptic extracellular space. In conclusion, DA released by bursts of action potentials exerts, via D1 receptors, a delayed and prolonged excitatory influence on target neurons. This phasic transmission occurs outside synaptic clefts but still exhibits a high degree of spatial specificity.