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.

The spinal localization of the forelimb locomotor generators and their interactions with other spinal segments were investigated on in vitro brainstem-spinal cord preparations of new-born rats. Superfusion of the cervicothoracic cord (C1-T4) with high K+/low Mg2+ artificial cerebrospinal fluid (aCSF) evoked rhythmic motor root activity that was limited to low cervical (C7, C8) and high thoracic (T1) spinal levels. This activity consisted of synchronous, homolateral bursts and a typical alternating bilateral pattern. Rhythmic activity with similar locomotor-like characteristics could be induced with either serotonin (5-HT, 5 microm), N-methyl-d-aspartate (NMDA, 5 microm), kainate (10 microm) or a "cocktail" of 5-HT (5 microm) and NMDA (5 microm). During 5-HT/NMDA perfusion of the cervicothoracic cord, induced bursting was no longer restricted to C7-T1 levels, but also occurred at cervical C3-C5 levels and with C5-C8 homolateral alternation. Spinal transections between C6 and C7 cervical segments did not abolish rhythmic activity in C7-T1, but suppressed locomotor-like rhythmicity at C3-C5 levels. Reduced regions comprising the C7-C8 or C8-T1 segments maintained rhythmicity. Superfusion of the whole cord with 5-HT/NMDA induced ventral root bursting with similar frequencies at all recorded segments (cervical, thoracic and lumbar). After isolation, the T3-T10 cord was unable to sustain any rhythmic activity while cervical and lumbar segmental levels continued to burst, albeit at different frequencies. We also found that the faster caudal and the slower rostral locomotor generators interact to produce coordinated locomotor-like activity in all segments of the intact spinal cord. In conclusion, C7-T1 spinal levels display a strong motor rhythmogenic ability; with the lumbar generators, they contribute to coordinated rhythmic activity along the entire spinal cord of a quadrupedal locomoting mammal.

No abstract

Striatonigral and striatopallidal neurons form distinct populations of striatal projection neurons. Their discharge activity is imbalanced after dopaminergic degeneration in Parkinson's disease. Striatal projection neurons receive massive cortical excitatory inputs from bilateral intratelencephalic (IT) neurons projecting to both the ipsilateral and contralateral striatum and from collateral axons of ipsilateral neurons that send their main axon through the pyramidal tract (PT). Previous anatomical studies in rats suggested that IT and PT inputs preferentially excite striatonigral and striatopallidal neurons, respectively. Here we used electrophysiological criteria to identify them with antidromic stimulations. We show that the spontaneous discharge activity of IT neurons is depressed, whereas that of PT neurons is not affected in the rat cortex ipsilateral to 6-hydroxydopamine injection. However, our functional experiments do not support the hypothesis of a differential cortical input to striatal pathways. Firstly, although the conduction velocity of PT neurons is 4.6 times faster than that of IT neurons, identified striatopallidal and striatonigral neurons exhibit identical latencies of their spike responses to electrical stimulation of the ipsilateral cortex. Secondly, although PT neurons are ipsilateral, both striatal populations exhibit similar sensitivity to the stimulation of the ipsilateral and contralateral cortex. We suggest that IT neurons provide the main excitatory input to both striatal populations and that the corticostriatal PT input is weaker. Therefore, our functional data do not support our previous hypothesis that the deficit of IT neurons associated with the dopaminergic depletion might contribute to the striatal imbalance. This imbalance might rather result from intrinsic striatal mechanisms.

There is a debate as to what modifications of neuronal activity underlie the clinical manifestations of Parkinson's disease and the efficacy of antiparkinsonian pharmacotherapy. Previous studies suggest that release of GABAergic striatopallidal neurons from D2 receptor-mediated inhibition allows spreading of cortical rhythms to the globus pallidus (GP) in rats with 6-hydroxydopamine-induced nigrostriatal lesions. Here this abnormal spreading was thoroughly investigated. In control urethane-anaesthetized rats most GP neurons were excited during the active part of cortical slow waves ('direct-phase' neurons). Two neuronal populations having opposite phase relationships with cortical and striatal activity coexisted in the GP of 6-hydroxydopamine-lesioned rats. 'Inverse-phase' GP units exhibited reduced firing coupled to striatal activation during slow waves, suggesting that this GP oscillation was driven by striatopallidal hyperactivity. Half of the pallidonigral neurons identified by antidromic stimulation exhibited inverse-phase activity. Therefore, spreading of inverse-phase oscillations through pallidonigral axons might contribute to the abnormal direct-phase cortical entrainment of basal ganglia output described previously. Systemic administration of the D2 agonist quinpirole to 6-hydroxydopamine-lesioned rats reduced GP inverse-phase coupling with slow waves, and this effect was reversed by the D2 antagonist eticlopride. Because striatopallidal hyperactivity was only slightly reduced by quinpirole, other mechanisms might have contributed to the effect of quinpirole on GP oscillations. These results suggest that antiparkinsonian efficacy may rely on other actions of D2 agonists on basal ganglia activity. However, abnormal slow rhythms may promote enduring changes in functional connectivity along the striatopallidal axis, contributing to D2 agonist-resistant clinical signs of parkinsonism.

No abstract

D 2 -like antagonists potentiate dopamine release. They also inhibit dopamine uptake by a mechanism yet to be clarified. Here, we monitored dopamine uptake in the striatum of anesthetized mice. The dopamine overflow was evoked by brief electrical stimulation of the medial forebrain bundle (four pulses at 100 Hz) and was monitored with carbon fiber electrodes combined with continuous amperometry. The decay phase of evoked overflows reflects dopamine half-life, which entirely depends on uptake. The D 2 -like antagonists haloperidol and eticlopride enhanced the half-life by 45% and 48%, respectively, a moderate effect as compared to the uptake blocker nomifensine (528%). Both D 2 -like antagonists did not affect dopamine uptake in mice lacking D 2 receptors. Inhibition of tonic dopamine release by gamma-butyrolactone did not mimic the enhancing effect of D 2 antagonists on dopamine half-life. However, prolonged stimulation boosted dopamine uptake and this effect was not observed after haloperidol treatment or in mice lacking D 2 receptors. Therefore, dopamine uptake is accelerated in conditions of excessive D 2 stimulation but not finely tuned in resting conditions. Inhibition of dopamine uptake by D 2 antagonists synergizes with the potentiation of dopamine release to strongly alter the phasic dopamine signaling.

No abstract