4/22/20041 Parkinson’s Disease

4/22/20042 Illustrations from Principles of Neural Science by E. R. Kandel, J. H. Schwartz, and T. M. Jessell McGraw-Hill, Fourth Edition, 2000 (Chapter 43) Figure 43-1 p. 854 Signaling between BG and other parts Figure 43-2 p. 855 Basal ganglia and nearby structures Figure 43-6 p. 861 Circuitry in the system Figure 43-7 p. 863 Surgical interventions

4/22/20043 Articles on B.G., STN, & Parkinson’s [1] D. Terman, J. Rubin, A.C. Yew, and C.J. Wilson, Activitiy patterns in a model of the subthalamopallidal network of the basal ganglia, J. Neurosci. 22: , [2] D. Plenz and S.T. Kitai, A basal pacemaker formed by the subthalamic nucleus and the external globus pallidus, Nature 400: , 1999.

4/22/20044 Articles on B.G., STN, & Parkinson’s [3] A. Raz, E. Vaadia, and H. Bergman, Firing patterns and correlations of spontaneous discharge of pallidal neurons…., J. Neurosci. 20: , [4] P. Brown, A. Oliviero, P. Mazzone, A. Isola, P. Tonali, and V. DiLazzaro, Dopamine dependency of oscillations between subthalamic nucleus and pallidum in Parkinson’s disease, J. Neurosci. 21: , 2001.

4/22/20045 [1] Dependence on internal Ca 2+ In pituitary gonadotropes, GnRH induces rhythmic oscillations in Ca 2+ concentrations. These oscillations trigger exocytosis, releasing LH and FSH into the circulatory system. Where is the calcium that triggers the exocytosis coming from? Does each increase in [Ca 2+ ] i trigger exocytosis? In [1], Tse, et al., used high temporal resolution capacitance measurements to monitor cell membrane capacitance,  C m, and measure [Ca 2+ ] i and  C m simultaneously.

4/22/20046 [1], Figure 1, page 82

4/22/20047 Based on micrographs by others, they estimate about 10,000 secretory vesicles in a single rat gonadotrope, of which are within a vesicle diameter of the cell membrane. They estimate that more than 540 vesicles were released in a single 10-second application of GnHR. Increase in [Ca 2+ ] i is necessary for exocytosis: application of GnRH when the Ca 2+ is chelated does not produce exocytosis. Exocytosis did occur when caged photolysis of IP 3 triggered [Ca 2+ ] i without presence of GnRH. When extracellular Ca 2+ was removed, application of GnRH still produced both [Ca 2+ ] i oscillations and exocytosis.

4/22/20048 Hormone stimulated exocytosis is tightly coupled to an oscillatory release of Ca 2+ from intracellular stores that leads to micromolar increases in [Ca 2+ ] i Each increase in [Ca 2+ ] i can result in a burst of exocytosis Propose that each [Ca 2+ ] i elevation rapidly releases the most readily available vesicles, others are mobilized during the decrease of [Ca 2+ ] i Oscillations of [Ca 2+ ] i have the advantage of reducing toxic effects of high [Ca 2+ ] i yet maintaining a secretory output comparable to sustained elevation of [Ca 2+ ] i [1] Conclusions

4/22/20049 Depending on the spatial relationship between the intracellular stores of Ca 2+ and the site of the exocytosis, the Ca 2+ signal can be very local or spread through the entire cell. During physiological stimulation, the average concentration of the intracellular Ca 2+, [Ca 2+ ] i seldom rises beyond a few  M, but in exocytosis, the local concentration may rise to tens or hundreds of  M. While formerly believed to not be the case for release of Ca 2+ from intracellular stores, this point of view is no longer tenable. [2] Local / global changes in [Ca 2+ ] i

4/22/ First, more sensitive imaging has detected a local gradient during release of Ca 2+ from intracellular stores. Second, new studies of Ca 2+ dependence of exocytosis show that low levels of [Ca 2+ ] i are insufficient to trigger exocytosis. intracellular stores. Pancreatic acinar cells, pituitary gonadotropes, and pituitary corticotropes behave differently in the dependence on local gradients of [Ca 2+ ] i for exocytosis.

4/22/ When stimulated by GnRH, the anterior pituitary gland secretes the reproductive hormones LH and FSH. The GnRH acts via a G-protein coupled receptor stimulating the release of Ca 2+ from IP 3 sensitive stores. The peak [Ca 2+ ] i reaches 1 to 3  M and exocytosis begins to occur when [Ca 2+ ] i reaches.03  M and each burst of Ca 2+ triggers a burst of exocytosis. By using the photolysis of caged IP 3 to trigger the release of the Ca 2+, it is possible to more closely follow the rate of exocytosis.

4/22/ [2], Figure 1, page 863

4/22/ The study provides evidence that in the pituitary gonadotropes, the IP 3 sensitive stores are probably quite close to the sites of exocytosis. The fact that the rate of exocytosis falls before the peak of the [Ca 2+ ] i is probably due to the dissipation of the Ca 2+ away from the site of exocytosis as the SERCA pumps start to operate before the more general [Ca 2+ ] i has peaked. Since the residual Ca 2+ must be cleared before a second increase can begin, which expends energy in the form of ATP to fuel the SERCA pumps, this may lead to a more energy efficient mechanism for hormone secretion.