Dopamine replacement therapy reverses abnormal synchronization of pallidal neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine primate model of parkinsonism

Abstract

Previous physiological studies have revealed changes in firing rates and synchronization of pallidal neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of Parkinson's disease. Several primate and human studies have demonstrated that dopamine replacement therapy (DRT) reverses the changes in the pallidal firing rates; however, the effects of DRT on pallidal synchronization have never been explored. To do so, we recorded the simultaneous activity of pallidal neurons of a vervet monkey before and after induction of severe parkinsonism by systemic MPTP treatment. We subsequently recorded the pallidal activity before and after daily administration of oral DRT. We extended the time scale of our correlation studies to +/-5 sec to allow detection of long-duration synchronized neuronal activity. After MPTP treatment, firing rates decreased in the external segment of the globus pallidus (GP(e)) and increased in the internal segment (GP(i)). A reversal of these rate changes occurred during the "on" periods of DRT. The percentage of correlated pairs increased from 16.7% in the normal state to 46.9% after MPTP treatment and was restored to nearly normal values (25% correlated pairs) under the influence of DRT. These changes in rate and correlation were observed at both the population level and at the level of units recorded continuously before, during, and after the clinical transition from "off" to "on" periods. We conclude that changes in both pallidal discharge rates and synchronization are correlated with the clinical manifestations of parkinsonism and its pharmacological treatment.

Fig. 1.

Summary of changes in firing rates and correlation in each clinical state. A, Changes in neuronal firing rates in the GP_e and GP_i proceed in opposite directions in response to dopamine depletion and replacement. After induction of parkinsonism, neuronal firing rates decrease in the GP_e and increase in the GP_i, and the reverse occurs in response to DRT. The y-axis is the ratio between mean firing rates of GP_e and GP_ineurons. MPTP, MPTP-treated l-DOPA-naive parkinsonian monkey; DRT-off, off periods (before morning dose) of MPTP monkey undergoing daily DRT; DRT-on, on periods of MPTP monkey after DRT. B, Neuronal synchronization increases after dopamine depletion and decreases in response to dopamine replacement. Neurons from both pallidal segments are pooled. The y-axis is the percentage of correlated pairs. Clinical state definitions are the same as inA.

Fig. 2.

Discharge rates of five continuously recorded pallidal neurons during the clinical off–on transition, demonstrating an increase in discharge rate of GP_e units and a decrease in GP_i units. DRT was administered orally 35 min before onset of recording (solid arrow); clinical off–on transition began after 14 min of recording (open arrow). All units were recorded continuously through minutes 0–52, except for unit 6, which was recorded through minutes 8–46. Thex-axis is time in minutes; y-axis is the firing rate of each unit in spikes/sec.

Fig. 3.

Examples of changes in neuronal synchronization in response to DRT. A, B, Simultaneous recording from the GP_e of the MPTP monkey undergoing daily DRT in off period (A) and the same cells in on period 26 min later (B). The recordings show synchronized bursts in the off period but not in the on period. Thex-axis is time in seconds. C,D, Temporal magnification of 2 sec from thetraces shown in A and B, respectively. E, F, Cross-correlogram matrices of the units shown in A and B, demonstrating long-range cross-correlations in the off period (E) that are flattened in the on period (F). The x-axis is the offset of the cross-correlogram in seconds; y-axis is the conditional firing rate in spikes/sec. Un x, ycorresponds to unit number y in electrode numberx. E, Inset, Demonstrates how the cross-correlogram of units 2.1 and 4.1 crosses confidence lines when calculated for ±5 sec offset and does not cross the confidence lines when calculated for ±0.5 sec offset. x- andy-axes are the same as for E andF.