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Letter to the Editor - Synchronous oscillations and gap junction: An approach to understanding PD resting tremors

Yedidya Saiman
Yeshiva University

Letters to the Editor are accepted from any reader, and may address any topic dealing with science or undergraduate issues. They are published at the editor’s discretion. To submit a Letter to the Editor, please write to eic@jyi.org.

To the Editor—

The National Parkinson Foundation reports that in America alone, Parkinson’s disease (PD) afflicts nearly 1,500,000, with 60,000 new cases reported annually. Varying rates in other countries vastly increase the toll. Instances of Parkinson’s disease are expected to increase dramatically as the average age and life expectancy of many populations increase. The average age of PD onset is estimated at 60, crippling many people who are otherwise still healthy and active. Moreover, many patients struggle with depression about their symptoms and the realization that they will never return to good health. Treatments include delivery of levadopa (L-dopa), a dopamine (DA) precursor, or other drugs that alter the brain’s dopamine levels. In more severe cases, a number of surgical procedures reducing the outflow of the basal ganglia can ease the symptoms; however, no cure exists.

It is generally accepted that normal functioning neurons in the basal ganglia always remain uncorrelated, representing parallel circuitry (Bergman et al., 1999). A key network within the basal ganglia is comprised of the reciprocally connected glutamatergic neurons of the subthalamic nucleus (STN) and GABAergic neurons of the external globus pallidus (Bevan et al., 2002). This network, which is heavily influenced by the cerebral cortex, has been shown to sustain low frequency oscillations even in the absence of cortical activation, leading it to be considered by Plenz and Kital (1999) as “the central pacemaker of the basal ganglia,” with far-reaching implications for basal ganglia function and dysfunction. As the only glutamatergic dependent nucleus within the basal ganglia, the STN exerts a direct excitatory influence over basal ganglia outflow. During voluntary or passive movement the STN-GP neurons display intricate spatiotemporal changes in activity correlating with the complex nature of motor activity (Bevan et al., 2002). Furthermore, these neurons fire irregularly, and their activity is uncorrelated under normal conditions (Wilson et al., 2004).

Current research reports two physiological changes within the basal ganglia of both animal models of Parkinson’s disease and parkinsonian patients. The loss of DA function induces overactivity in GABAergic neurons projecting from the striatum to the GPe, reducing its inhibitory influence toward the STN which, in turn, provides a stronger excitation of basal ganglia output neurons in the internal globus pallidus (GPi) and susbstantia nigra pars reticulata (SNR). This increased GABAergic outflow from the basal ganglia leads to increased inhibition of thalamocortical neurons, thereby decreasing cortical excitability; a pathophysiological condition that underlies some of the parkinsonian symptoms. The basal ganglia networks, and in particular the STN-GPe connections, lose their ability to retain specific and segregated neuronal activity. In brief, the parallel processing of basal ganglia circuitry breaks down. This is accompanied by the emergence of synchronized oscillatory burst discharges at low frequencies correlating to resting tremors. The increased synchrony within the basal ganglia could promote synchrony within the cortex compromising motor control (Brown & Marsden, 1998). The origination of the low frequency oscillations is unknown, though it has been hypothesized that they are either abnormal representations of rhythms generated in the cerebral cortex during quiet wakefulness, or an amplification of idling rhythms from the thalamocortical, midbrain, or brainstem circuits, that effectively suppress higher frequency rhythms apparent during movement (Bevan et al., 2002).

Another physiological change found in animal models of PD is a 4-7 fold increase in dye coupling incidence and the development of a DA depolarization block within the basal ganglia (Onn & Grace, 1999). Dye coupling results from gap junctions spanning the dendrites of neighboring neural cells which allow free passage of electrical current and small molecules. While gap junctions are prevalent in the immature brain and thought to be involved in cellular network organization, there is a marked decrease of gap junction frequency in the mature brain (Perez Velazquez & Carlen, 2000). Onn and Grace (1995; 1999) have shown that gap junction conductance is upregulated in the basal ganglia upon administration of DA antagonist apomorphine and that this correlates with the development of DA cell depolarization block upon administration of antipsychotic drugs.

Gap junctions have been described as “low pass filters [or] ohmic resistors that connect two cytoplasms,” (Perez Velazquez & Carlen, 2000) lending them as suitable controllers of rhythmic oscillations, which require extremely fast electronic coupling between synchronized neurons. Perez Velazquez and Carlen (2000) have developed theoretical computer models describing gap junctions’ role in synchronized neuron firing during seizures, a state comparable to that in PD. Currently, there is no literature linking the physiological changes observed in PD brains with the regulatory influences of dopamine on fast electronic coupling in the basal ganglia. However, the correlation of increased dye coupling following dopamine antagonist application combined with increased synchronous neuron firing in dopamine depleted PD brains makes this an attractive working hypothesis. A deeper understanding of the physiology that links brain regions may shed light on the causes of PD and allow for the development of a cure and preventive measures.

Such research will work towards extending the active lives of hundreds of thousands of people crippled by Parkinson’s disease. The research may have more general applications as a greater understanding of brain function will gradually increase insight into brain dysfunction, leading to the development of treatment for other dopamine-dependent debilitating diseases such as depression and drug addiction.

References

Bergman H, Feingold A, Nini A, Raz A, Slovin H, Abeles M, and Vaadia E. (1998). Physiological aspects of information processing in the basal ganglia of normal and parkinsonian primates. Trends Neurosci. 21:32-8.

Bevan MD, Magill PJ, Terman D, Bolam JP, and Wilson CJ. (2002). Move to the rhythm: oscillations in the subthalamic nucleus-external globus pallidus network. Trends Neurosci. 25:525-31.

Brown P, and Marsden CD. (1999). What do the basal ganglia do? Lancet. 351:1801-1804.

Magill PJ, Bolam JP, and Bevan MD. (2001). Dopamine regulates the impact of the cerebral cortex on the subthalamic nucleus-globus pallidus network. Neuroscience. 106:313-330.

Onn SP, and Grace AA. (1995). Repeated treatment with haloperidol and clozapine exerts differential effects on dye coupling between neurons in subregions of striatum and nucleus accumbens. Journal of Neuroscience. 15:7024-7036.

Onn SP, and Grace AA. (1999). Alterations in electrophysiological activity and dye coupling of striatal spiny and aspiny neurons in dopamine-denervated rat striatum recorded in vivo. Synapse. 33:1-15.

Plenz D, and Kital ST. (1999). A basal ganglia pacemaker formed by the subthalamic nucleus and external globus pallidus. Nature. 400:677-682.

Perez Velazquez JL, and Carlen PL. (2000). Gap junctions, synchrony and seizures. Trends Neurosci. 23:68-74.

Wilson CL, Puntis M, and Lacey MG. (2004). Overwhelmingly asynchronous firing of rat subthalamic nucleus neurones in brain slices provides little evidence for intrinsic interconnectivity. Neuroscience. 123:187-200.