The Promise of New Technologies in Research
I was invited to speak at the 5th WPC about basal ganglia dysfunction in parkinsonian models focusing on the application of optogenetics, and I thought the timing was perfect to highlight our optimism about the future progress in research. Indeed, new technologies such as optogenetics and chemogenetics are making a big difference in our research, now we can manipulate a brain circuit or cell population with unprecedented selectivity. For example, a microbial opsin that reacts with light can be expressed exclusively in neurons of a particular basal ganglia circuit using transgenic models, and then we can excite or inhibit only those cells expressing the opsin with illumination of the brain region. These are excellent tools to examine the role of a circuit or pathway with high cell resolution and temporal precision, which are key to study specific pathological mechanisms, and even target them for therapeutic applications. The use of these technologies in research has ripened over the last decade, and today we have refined tools for a variety of in vivo studies in different animal models. In my laboratory, we are excited about the possibility of using optogenetics to refine our studies and dissect mechanisms of dysregulation in the basal ganglia of non-human primate models of Parkinson’s disease (PD).
Dysregulated activity of striatal neurons
Previous studies attempted to characterize changes in the activity of striatal neurons in animal models of PD. These cells (striatal projection neurons, SPNs) are modulated by dopamine inputs from nigrostriatal terminals, which degenerate in the natural disease. The loss of dopamine modulation leads to significant changes in the function of SPNs and the development of parkinsonian motor symptoms. Single cell recordings in the striatum of non-human primates have revealed that the SPN activity is increased more than 10 fold in models of chronic parkinsonism. The same pattern of pathological SPN hyperactivity was found in patients with PD during the recordings for DBS surgery. This basal hyperactivity is also associated with a pathological response of the SPN to dopamine inputs. In brief, SPNs exhibit “unstable” firing changes during the motor response to L-Dopa (“on” state). This is typically observed in a significant number of neurons after L-Dopa administration as modulation of firing frequency that is reversed at the peak-dose effect and can lead to the appearance of involuntary movement (dyskinesia). These SPN activity changes are also intimately related to the chronic progression of motor disability. The question, then, to be asked is: What causes such dysregulation that cannot be controlled by replacing the lacking dopamine in the system?
The role of glutamate
Striatal cells are in a complex biochemical environment receiving multiple and heterogenous signals, but there is substantial data to support a major role of “glutamate” in the dysregulation developed in PD. Glutamate is involved in cortico- and thalamo-striatal synapses that have shown changes in strength and plasticity after dopamine depletion. Also, there are significant changes in striatal glutamate receptors including their expression, composition, trafficking and localization after dopamine lesion and/or chronic DA replacement. Recently, the important role of glutamate signaling has been demonstrated in experiments using microinjections of glutamate AMPAR and NMDAR antagonists at the site of SPN recording in the parkinsonian primate. Following the antagonist injection that reduces the high basal SPN activity, the response to L-Dopa stabilizes with consistent changes of SPN firing frequencies during the “on” state. Results of these studies indicate that SPN hyperactivity in the “off” state (basal parkinsonian state) is largely responsible for unstable firing changes in response to LDopa. Furthermore, larger infusions of the antagonist to control the activity of a significant number of neurons reduce abnormal dyskinetic movements in the primate. The available data thus far leads to conclude that dysregulation of glutamate signaling largely contributes to the SPN dysfunction developed in PD. However, we do not know the changes specific to neuronal subtypes that form different circuits–there are two subtypes of SPNs that are modulated differentially by dopamine D1 or D2 receptors and form the direct or indirect striatal output pathways. This is of critical importance moving forward because signaling in these basal ganglia circuits may have a different impact in movement control. Therefore, we now need to characterize the distinctive mechanisms mediating glutamate dysregulation in SPN subpopulations (direct and indirect SPNs).
Refining studies with new technologies
To profile the glutamate regulation specific to dSPNs and iSPNs, we need studies in the primate model of chronic parkinsonism that exhibits similar SPN dysregulation as patients with PD. This may be possible using optogenetic tools with proven suitability for induction of opsin expression selectively in SPN subtypes. However, unlike rodents that can be truly transgenic, we have been limited by the lack of such primate models and depending on a virus injection in the target region of the brain to induce the transgene expression (an opsin in this case), which also requires adequate viral vectors for specificity to the targeted cell population. The good news is that the latest advances in optogenetics may allow a variety of primate studies including those necessary to profile the glutamate dysregulation in each SPN subtype. Clearly, the application of new technologies in research is promising significant refinements in our understanding of pathophysiology. Hopefully, studies in the near future will reveal the mechanisms associated specifically with altered signaling in striatal pathways, and thereby contribute critical information to identifying therapeutic targets. The control of glutamate dysregulation in PD depends critically on high level of precision to target selectively a striatal mechanism while sparing the brain glutamate transmission in general. We are excited about the prospect of progress in this area of research that can open windows to develop new treatments to restore function, and slow or even halt the progression of symptoms.
Christopher G. Sinon, PhD and Stella M. Papa, MD work at the Yerkes National Primate Research Center, Department of Neurology, Emory University School of Medicine. Dr. Papa presented at the 5th World Parkinson Congress in Kyoto, Japan.
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions of the World Parkinson Coalition®