Parkinsons Disease 4222004 1 Illustrations from Principles of

Parkinson’s Disease 4/22/2004 1

Illustrations from Principles of Neural Science by E. R. Kandel, J. H. Schwartz, and T. M. Jessell Mc. Graw-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 4/22/2004 2

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: 2963 -2976, 2002. [2] D. Plenz and S. T. Kitai, A basal pacemaker formed by the subthalamic nucleus and the external globus pallidus, Nature 400: 677 -682, 1999. 4/22/2004 3

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: 8559 -8571, 2000. [4] P. Brown, A. Oliviero, P. Mazzone, A. Isola, P. Tonali, and V. Di. Lazzaro, Dopamine dependency of oscillations between subthalamic nucleus and pallidum in Parkinson’s disease, J. Neurosci. 21: 1033 -1038, 2001. 4/22/2004 4

[1] Dependence on internal Ca 2+ In pituitary gonadotropes, Gn. RH 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, DCm , and measure [Ca 2+]i and DCm simultaneously. 4/22/2004 5

[1], Figure 1, page 82 4/22/2004 6

Based on micrographs by others, they estimate about 10, 000 secretory vesicles in a single rat gonadotrope, of which 6001000 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 Gn. HR. Increase in [Ca 2+]i is necessary for exocytosis: application of Gn. RH 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 Gn. RH. When extracellular Ca 2+ was removed, application of Gn. RH still produced both [Ca 2+]i oscillations and exocytosis. 4/22/2004 7

[1] Conclusions 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 4/22/2004 8

[2] Local / global changes in [Ca ]i 2+ 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. M, but in exocytosis, the local concentration may rise to tens or hundreds of m. 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. 4/22/2004 9

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. 4/22/2004 10

When stimulated by Gn. RH, the anterior pituitary gland secretes the reproductive hormones LH and FSH. The Gn. RH 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. M and exocytosis begins to occur when [Ca 2+]i reaches. 03 m. 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. 4/22/2004 11

[2], Figure 1, page 863 4/22/2004 12

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. 4/22/2004 13