Acute dopamine receptor blockade in substantia nigra pars reticulata: a possible model for drug-induced Parkinsonism

Dopamine (DA) depletion modifies the firing pattern of neurons in the substantia nigra pars reticulata (SNr), shifting their mostly tonic firing toward irregularity and bursting, traits of pathological firing underlying rigidity and postural instability in Parkinson’s disease (PD) patients and animal models of Parkinsonism (PS). Drug-induced Parkinsonism (DIP) represents 20–40% of clinical cases of PS, becoming a problem for differential diagnosis, and is still not well studied with physiological tools. It may co-occur with tardive dyskinesia. Here we use in vitro slice preparations including the SNr to observe drug-induced pathological firing by using drugs that most likely produce it, DA-receptor antagonists (SCH23390 plus sulpiride), to compare with firing patterns found in DA-depleted tissue. The hypothesis is that SNr firing would be similar under both conditions, a prerequisite to the proposal of a similar preparation to test other DIP-producing drugs. Firing was analyzed with three complementary metrics, showing similarities between DA depletion and acute DA-receptor blockade. Moreover, blockade of either nonselective cationic channels or Cav3 T-type calcium channels hyperpolarized the membrane and abolished bursting and irregular firing, silencing SNr neurons in both conditions. Therefore, currents generating firing in control conditions are in part responsible for pathological firing. Haloperidol, a DIP-producing drug, reproduced DA-receptor antagonist firing modifications. Since acute DA-receptor blockade induces SNr neuron firing similar to that found in the 6-hydroxydopamine model of PS, output basal ganglia neurons may play a role in generating DIP. Therefore, this study opens the way to test other DIP-producing drugs. NEW & NOTEWORTHY Dopamine (DA) depletion enhances substantia nigra pars reticulata (SNr) neuron bursting and irregular firing, hallmarks of Parkinsonism. Several drugs, including antipsychotics, antidepressants, and calcium channel antagonists, among others, produce drug-induced Parkinsonism. Here we show the first comparison between SNr neuron firing after DA depletion vs. firing found after acute blockade of DA receptors. It was found that firing in both conditions is similar, implying that pathological SNr neuron firing is also a physiological correlate of drug-induced Parkinsonism.

Distinguishing the Causes of Firing with the Membrane Potential Slope

In this letter, we aim to measure the relative contribution of coincidence detection and temporal integration to the firing of spikes of a simple neuron model. To this end, we develop a method to infer the degree of synchrony in an ensemble of neurons whose firing drives a single postsynaptic cell. This is accomplished by studying the effects of synchronous inputs on the membrane potential slope of the neuron and estimating the degree of response-relevant input synchrony, which determines the neuron's operational mode. The measure is calculated using the normalized slope of the membrane potential prior to the spikes fired by a neuron, and we demonstrate that it is able to distinguish between the two operational modes. By applying this measure to the membrane potential time course of a leaky integrate-and-fire neuron with the partial somatic reset mechanism, which has been shown to be the most likely candidate to reflect the mechanism used in the brain for reproducing the highly irregular firing at high rates, we show that the partial reset model operates as a temporal integrator of incoming excitatory postsynaptic potentials and that coincidence detection is not necessary for producing such high irregular firing.

Interspike Interval Analyses Reveal Irregular Firing Patterns at Short, But Not Long, Intervals in Rat Head Direction Cells

Previous studies have shown that a subset of neurons in the rat anterodorsal thalamus discharge as a function of the animal's head direction (HD) in the horizontal plane, independent of the animal's location and behavior. These cells have consistent firing properties across a wide range of conditions and cell discharge appears highly regular when listened to through a loudspeaker. In contrast, interspike interval (ISI) analyses on cortical cells have found that cell firing is irregular, even under constant stimulus conditions. Here, we analyzed HD cells from the anterodorsal thalamus, while rats foraged for food pellets, to determine whether their firing was regular or irregular. ISIs were measured when the animal's HD was maintained within ±6° of the cell's preferred firing direction. ISIs were highly variable with a mean coefficient of variation (CV) of 0.681. For each cell, the CV values at HDs ±24° away from the cell's preferred direction were similar to the coefficient measured at the cell's preferred direction. A second recording session showed that cells had similar coefficients of variation as the first session, suggesting that the degree of variability in cell spiking was a characteristic property for each cell. There was little correlation between ISIs and angular head velocity or translational speed. ISIs measured in HD cells from the postsubiculum and lateral mammillary nuclei showed higher CV values. These results indicate that despite the appearance of regularity in their firing, HD cells, like cortical cells, have irregular ISIs. In contrast to the irregular firing observed for ISIs, analyses over longer time intervals indicated that HD cell firing was much more regular, more nearly resembling a rate code. These findings have implications for attractor networks that model the HD signal and for models proposed to explain the generation of grid cell signals in entorhinal cortex.