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Probing new targets for movement disorders

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Science  03 Aug 2018:
Vol. 361, Issue 6401, pp. 462
DOI: 10.1126/science.aau4916

Two Parkinson's patients receive deep brain stimulation (DBS) in their subthalamic nuclei. Despite accurate electrode placement, one patient is able to stand up and walk effortlessly around the room while the other breaks down into uncontrolled sobbing that only stops once the stimulator is turned off. This paradox exposes one of the major roadblocks in developing therapies for brain disorders: the elaborate and diffuse nature of neural circuits.

Physically proximal neurons are often engaged in functionally different pathways; whereas modulation of one pathway might be therapeutic, modulation of those surrounding it may produce debilitating side effects. The problem with high-amplitude electrical stimulation, as applied during DBS, is that it affects not only the activity of neurons around the electrode, but also the activity of neurons whose long extensions happen to pass by the electrode. In some cases, this leads to off-target recruitment of nontherapeutic circuits that mask or negate the potential benefits of stimulation.

Does this mean that therapeutic efficacy will forever be limited by the physical restrictions of electrical stimulation? Thanks to biology, the answer is no. Spatially, neural circuits are nearly impossible to delineate, but genetically, they are organized along well-defined road maps that can be used to deliver therapies with a high degree of specificity.

My lab studies the organization of these genetic road maps in the basal ganglia, a primary structure associated with motor symptoms in Parkinson's disease. This research into the basic biology of the basal ganglia led us to the discovery of cellular targets where focused interventions can induce long-lasting recovery of movement in a mouse model of Parkinson's disease.

The Globus Pallidus as a New Target for Therapeutic Intervention

Motor symptoms of Parkinson's disease are caused by aberrant activity of neurons in the basal ganglia, a tangle of interconnected brain nuclei that shape voluntary movement. Teasing apart the neural circuitry is not unlike the game pick-up sticks, in which a bunch of colored sticks are heaped in a pile on the floor and players must figure out how to remove them one by one, without bringing the whole pile crashing down.

Fortunately, we already know a bit about how the basal ganglia are organized. They consist of two parallel pathways that exert opposing effects on movement: The “direct pathway” facilitates movement and the “indirect pathway” suppresses movement (1, 2). The cellular architecture of the direct pathway is straightforward—signals pass directly from the input nucleus to the output nucleus. But the cellular architecture of the indirect pathway is more complex—signals pass through multiple intermediary nuclei on their way from the input nucleus to the output nucleus. One of these intermediary nuclei, the subthalamic nucleus (STN), is the primary target for DBS.

However, in fixating on the therapeutic potential of the STN, other components of the indirect pathway have become neglected, particularly the STN's neighbor, the external globus pallidus (GPe). This oversight motivated our study, which began as an investigation into the basic circuitry of the GPe and culminated in the discovery of its potential as a therapeutic node to induce long-lasting motor rescue in Parkinson's disease.

A First Attempt at Targeted Stimulation Fails

In the parkinsonian state, induced in mice by lesioning dopamine neurons with a toxin called 6-hydroxydopamine (6-OHDA), firing rates of GPe neurons are suppressed. Reversing this effect should alleviate motor deficits (1, 2). Although straightforward, this hypothesis has been challenging to test experimentally because electrical stimulation in the GPe excites fibers of passage and recruits off-target circuits.

To circumvent this problem, we used an approach called optogenetics, where recombinant DNA encoding a light-sensitive ion channel (channelrhodopsin 2, ChR2) is delivered to GPe neurons by viral transfection, effectively giving us control over neural activity with the flick of a light switch (3). However, when we used this technique to increase the firing rates of GPe neurons in parkinsonian mice, we found that this intervention had no effect on motor symptoms.

At face value, this negative result seemed to contradict long-standing assumptions about how the basal ganglia worked. But, everyone who has ever done an experiment knows that there are many reasons that they may not work. So, we felt it wise to interpret this result with a healthy dose of caution and performed a series of follow-up experiments.

First, we confirmed with in vivo recordings that GPe neurons were excited by our optogenetic stimulation (they were). Second, we confirmed that motor deficits were reversed by using an alternative optogenetic intervention—stimulating motor-facilitating “direct pathway” neurons (4) (they were).

Taken together, these results demonstrated a need to revise long-standing assumptions about the GPe's impact on behavior and prompted a deeper investigation into its neural circuitry.

What assumptions had we made about the GPe that were incorrect? For one thing, by activating all GPe neurons at the same time, we were making an assumption that all GPe neurons were the same, even though we knew that this was not the case.

In our previous work, we had discovered that GPe neurons could be genetically subdivided into populations that differed anatomically and electrophysiologically (5). Could these genetic subdivisions provide a key to understanding what the GPe was doing functionally?

Stimulation of Parvalbumin-Enriched Cells Restores Mobility in Parkinsonian Mice

If genetic subdivisions were indicative of functional heterogeneity, we predicted that restricting ChR2 expression to a single-cell population might produce a better effect on behavior. To test this hypothesis, we repeated our behavioral rescue experiments, but this time, expressed ChR2 in only a subset of GPe neurons: those enriched with a molecule called parvalbumin (PV-GPe) (6).

Remarkably, this cell-specific intervention produced dramatically different behavioral results than global stimulation: Parkinsonian mice that had been almost completely immobile before stimulation began to move around the testing arena and by the end of stimulation, were moving at rates approximating those seen in healthy controls. The most striking feature of this behavioral rescue was that it persisted long after stimulation was turned off. Mice receiving cell-specific stimulation in the GPe continued moving for the duration of our 4-hour experiment (and possibly longer), far exceeding the therapeutic duration of current treatments, including DBS (7, 8). One possible interpretation is that this cell-specific GPe intervention wasn't simply masking motor symptoms, but rather was reinstating network function and by extension, restoring motor control.

Repairing Function, Not Masking Dysfunction

Evidence that transient interventions in the GPe can reinstate basal ganglia output comes from electrophysiological recordings. Basal ganglia output neurons normally fire constantly with great regularity, but after dopamine depletion, their firing becomes irregular and bursty (9). These aberrant firing patterns interfere with information encoding and contribute to motor impairments in Parkinson's disease (8). Cell-specific intervention in the GPe (but not global stimulation of the entire nucleus) attenuated pathological bursts and regularized firing of basal ganglia output neurons for hours after stimulation, persisting for the duration of our 4-hour experiment.

Discovering strategies to repair, not simply mask, circuit dysfunction is the next frontier in brain therapeutics. The discovery of genetically defined cell types, where targeted interventions restore basal ganglia function and rescue movement in a mouse model of Parkinson's disease, represents an important step in this direction.

Significance for Future Therapeutics

Widespread use of optogenetics in humans is still years away, so are there other ways that our work could have a clinical impact? Current stimulation protocols for DBS (high amplitude, high frequency) are delivered with the goal of overriding aberrant signals from the basal ganglia that impair movement. However, knowledge about the underlying biological circuits can be used to develop more refined, effective DBS interventions.

Six years ago, a proof-of-concept study in humans demonstrated that a modified DBS protocol (“coordinated reset,” CR-DBS), designed on the basis of predictions about basal ganglia circuitry, provides longlasting therapeutic effects (10). Although we do not yet know whether CR-DBS engages mechanisms similar to those underlying our cell-specific stimulation in the GPe, both interventions converge upon a common mechanism: restoring basal ganglia output physiology. Future work will determine whether these interventions share a common therapeutic mechanism, or whether there are multiple pathways through which long-lasting rescue can be achieved.

PHOTO: CARNEGIE MELLON UNIVERSITY

FINALIST

Aryn Gittis

Aryn Gittis received undergraduate degrees from Brandeis University and a Ph.D. from the University of California, San Diego. After completing her postdoctoral fellowship at the Gladstone Institute of Neurological Studies–University of California, San Franciso, Gittis started her lab in the Department of Biological Sciences at Carnegie Mellon University in 2012. Her research uses mouse models of Parkinson's disease combined with electrophysiology and optogenetics to understand the cellular basis of motor dysfunction and to develop novel strategies for intervention. www.sciencemag.org/content/361/6401/462

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