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«Bonnie Gale Garcia Dissertation Submitted to the faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements ...»

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CORTICOSTRIATAL REGULATION OF MEDIUM SPINY NEURON DENDRITIC

REMODELING IN MODELS OF PARKINSONISM

By

Bonnie Gale Garcia

Dissertation

Submitted to the faculty of the

Graduate School of Vanderbilt University

in partial fulfillment of the requirements for

the degree of

DOCTOR OF PHILOSOPHY

in

Pharmacology

May, 2010

Nashville, Tennessee

Approved:

Professor Ariel Y. Deutch Professor Randy D. Blakely Professor Danny G. Winder Professor Eugenia V. Gurevich Professor P. Jeffrey Conn Copyright © 2010 by Bonnie Gale Garcia All Rights Reserved

ACKNOWLEDGEMENTS

This dissertation would not have been possible without the help of so many people in so many ways. First I would like to thank my doctoral advisor, Dr. Ariel Y.

Deutch for having faith in me and accepting me into his lab. Ariel has been a great scientific role model, instilling in me the qualities of being not only a good scientist.

I am grateful for his unwavering patience and guidance, especially with the development of my communication and writing skills, and my overall growth as a scientist throughout all these years in his laboratory.

I am grateful for the professional and personal guidance from all of my committee members. Drs. Eugenia V. Gurevich (chair), Randy D. Blakely, P. Jeff Conn, and Danny G. Winder all have made committee meetings a very valuable and pleasurable experience.

My doctoral research was conducted with the support of an NRSA predoctoral award (F31 NS060174) from the National Institutes of Neurological Disorders and Stroke.

I would also like to thank Dr. M. Diana Neely for teaching me how to prepare organotypic slice cultures and for our scientific and personal discussions. I would also like to thank Dr. Michael Bubser for showing me how to perfuse a rat, and for all his immunohistochemical expertise. I would also like to thank all members of the Deutch lab both past and present. Special thanks to Michael Bubser, Brian Mathur, and Sheila Kusnoor for insightful discussions. I thank Lorelei Reinhardt and Dr.

Dennis Schmidt who have provided much needed humor in the lab.

iii I am also grateful to Dr. Aurelio Galli who inspired me to become a scientist and join the graduate program at Vanderbilt University.

I would also like to thank my family and friends who have always been there for me. Finally I owe my deepest gratitude to my husband, Sergio Coffa,for his support especially in these last few months.

–  –  –

ACKNOWLEDGMENTS

LIST OF FIGURES

LIST OF ABBREVIATIONS

Chapter I. INTRODUCTION The striatum and movement

Diseases of the basal ganglia

Striatal cell morphology

Defining MSNs by non-morphological criteria

Interneurons

Synaptic architecture of MSNs

Regulation of MSNs

II. CORTICOSTRIATAL PROJECTION

Introduction

Striatal afferents from M1 cortex

Methods

Results

Discussion

III. DOPAMINE DEPLETION-INDUCED SPINE LOSS

Introduction

Methods

Results

Discussion

IV. DECORTICATION ATTENUATES DENDRITIC SPINE LOSS

Introduction

Methods

Results

Discussion

vV. MODULATION OF CORTICAL GLUTAMATE ATTENUATES SPINE LOSS

Introduction

Methods

Results

Discussion

VI. CONCLUSIONS Introduction

Relation to motor deficits in parkinsonism

REFERENCES

–  –  –

1. Illustration of the dorsal and ventral striatum of the rat

2. Schematic illustrating dopaminergic innervation of the striatum

3. Medium spiny neuron reconstruction

4. Schematic illustrating medium spiny neuron afferents

5. Schematic illustrating medium spiny neuron synaptic triad

6. Dopamine D2 receptor localization on the striatal triad

7. Corticostriatal tract tracing using an anterograde tracer deposited into the motor cortex (IP)

8. Corticostriatal tract tracing using an anterograde tracer deposited into the motor cortex (IF)

9. Fluorogold-positive cells in the cortex using a retrograde tracer deposited into the striatum

10. Sholl analysis of spine density as function of distance from the soma

11. Control spine density as a function of distance from soma

12. Tyrosine hydroxylase immunoreactivity in the striatum and substantia nigra (IHC)

13. Tyrosine hydroxylase immunoreactivity in the striatum as measured by western blot

14. Golgi-impregnated MSNs from sham and dopamine denervated animals

15. Time course of dopamine depletion-induced dendritic spine loss

–  –  –

17. Dopamine denervation effects on neuronal dendritic field as assessed by longest dendrite

18. Schematic illustrating the morphologies of dendritic spines





19. Dopamine denervation alters MSN spine types

20. Schematic illustrating M1 and non-M1recipient zones of striatum analyzed

21. Characterization of motor cortex lesions

22. FluoroJade C stain for degenerating cells

23. Cortical lesions in vivo reverse spine loss

24. Photomicrographs of representative MSN dendrites from each treatment group

25. Cortical lesions in vivo prevent dendritic spine loss

26. Cortical lesions cause compensatory corticostriatal sprouting

27. Representative organotypic triple slice culture stained with toluidine blue

28. mGluR 2/3 agonist prevents MSN spine loss in vitro in dopamine denervated cultures

29. Representative photomicrographs of ballistically-labeled dendrites from each culture treatment condition

30. mGluR 2/3 antagonist, blocks the effects of LY379268 on preventing spine loss

31. mGluR 5 antagonist does not prevent spine loss in dopamine denervated cultures

–  –  –

mGluR Metabotropic Glutamate Receptor MPP+ 1-methyl-4-phenyl-2,3-dihydropyridinium Ion MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine MSN Medium Spiny Neuron NMDA N-methyl-D-aspartate

–  –  –

The striatum and movement. The collection of nuclei referred to as the ―basal ganglia‖ was previously called the great cerebral nucleus by David Ferrier in 1876 (see Swanson 2000). The basal ganglia are an ill-defined group of subcortical nuclei, which consist of the neostriatum (caudate nucleus and putamen), globus pallidus, substantia nigra, and subthalamic nucleus. The striatum is the largest nucleus of the basal ganglia and is so named because it has a striated appearance due to the dense fiber bundles of axons that course through the region (Willis T et al. 1965). This ‖striped‖ structure was first illustrated by Andreas Vesalius in 1543 and later described by the seventeenth century physician, Thomas Willis, who designated the structure ―corpus

striatum‖ in 1664 (Sarikcioglu et al. 2008). Willis noted:

―These bodies, if they should be dissected along the middle, appear marked, with medullar streak, as it were rays or beams;

which sort of chamferings or streaks have a double aspect or tendency; to wit, some descend from the top of this body, as if they were tracts from the brain into the oblong marrow; and others ascend from the lower part, and meet aforesaid, as if they were paths of spirits from the oblong marrow into the brain.

And it is worth observation, that in the whole head besides there is no part found chamfered or streaked after the like manner.‖ In primates the striatum is composed of the caudate nucleus and the putamen, the two nuclei being separated by the white matter of the internal capsule. However in rodents a single structure is observed, with fascicles of

–  –  –

striatum is functionally divided into the dorsal striatum and the ventral striatum (see Figure 1). Whereas the dorsal striatum is implicated in voluntary movement, as well as habit-based learning, the ventral striatum plays an important role in the translation of motivation to movement.

Modulation of movement processes is mainly what the striatum is known for, but it also plays important roles in procedural learning and reward pathways.

The basal ganglia were suggested to be involved in movement at the beginning of the 20th century, based on the observation that damage to these structures resulted in movement disorders (Wilson SAK 1914; Mettler R and Mettler C 1942; Mettler FA 1945; Divac et al. 1967; Denny-Brown D and Yanagisawa N 1972). Simplistically, the motor cortex sends information to the basal ganglia and the cerebellum; both areas of the brain send information back to the cortex via the thalamus.

Diseases of the basal ganglia. Disturbances in the basal ganglia result in a myriad of movement disorders, both hypokinetic and hyperkinetic. Hyperkinetic disorders, or disorders of increased motor function, include Huntington’s disease (HD), dystonia, and hemiballismus. HD is a genetic, neurodegenerative disease in which striatal MSNs degenerate as a result of a mutation in the Huntington protein. Dystonia involves sustained muscle contractions that cause twisting and abnormal postures. Hemiballismus (―half jumping‖) is a rare disorder usually

–  –  –

nucleus.

3 Figure 1. The striatum is divided into the dorsal striatum (caudate and putamen) shown in blue and the ventral striatum (nucleus accumbens) shown in orange.

Although illustrated is a distinct border between dorsal and ventral striatum, no such delineation truly exits in vivo. Abbreviations: CPu, caudate and putamen;

Acb, accumbens. Image from Voorn et al. 2004.

–  –  –

(PD). Parkinson’s Disease is a hypokinetic disorder, in which there is reduced motor function. The pathology of PD involves the degeneration of the pigmented dopamine cells in the substantia nigra (black substance, referring to the heavily pigmented dopamine neurons). The degeneration of the substantia nigra (SN) dopamine neurons results in a decrease in the amount of striatal dopamine (see Figure 2), and the appearance of the cardinal symptoms of PD: bradykinesia, resting tremor, and rigidity. Postural instability is also observed, but usually presents somewhat later in the course of the disease.

The gold standard of treatment for PD is administration of the dopamine precursor L-dihydroxyphenylalanine (levodopa, L-DOPA). Direct dopamine agonists have increasingly been used in the treatment of PD. Although levodopa is incredibly beneficial in treating the symptoms of PD, after 3-7 years patients develop on-off effects and abnormal involuntary movements (dyskinesias). Later in the course of PD, the full symptomatic responsive to L-DOPA treatment is decreased.

5 Figure 2. Dopaminergic innervation of the striatum (caudate and putamen).

A.) Normal nigrostriatal innervation is schematized in red. B.) In Parkinson’s disease the substantia nigra dopamine cells degenerate with a resultant loss of striatal dopamine levels illustrated by the hatched and thinned red lines). Image from Dauer et al. 2003.

–  –  –

medium-sized cells and large cells (interneurons). The cells of medium size are the projection neurons of the striatum. These cells were subsequently termed the medium spiny neurons (MSNs) by Kemp and Powell (1971), which are richly invested with dendritic spines. MSNs account for approximately 90-95% of all striatal neurons and utilize γ-aminobutyric acid (GABA) as their classical neurotransmitter (Gerfen 1992). As the name suggests, MSNs have a mediumsized soma (8-17 µm in diameter) possess dendrites that radially emanate and of which are densely studded with dendritic spines (see Figure 3), the sites of excitatory synapses.

The geometries of dendritic spines suggest that they are independent compartments that ―protect‖ dendrites from sharp, rapid rises in intracellular

calcium (Segal M 1993, 1995). Segal noted:

―I should like to take this a step further, and propose a novel function for spines: by isolating the synapse from the dendrite, the spine protects the neurons from toxic insults associated with the raised [Ca2+], that follows synaptic activity.‖ For example spines with large heads and thin necks sequester calcium in the spine head, whereas in spines with a low spine head: neck diameter ratio calcium may frequently invade the neck of the spine and the dendritic shaft (Sabatini et al. 2002; Noguchi et al. 2005).

As originally suggested by Vogt and Vogt (1920), there are several types of MSNs. Studies of Golgi-impregnated MSNs have revealed subtle differences in the location and density of dendritic spines on MSNs, with five different classes

–  –  –

so-called type I class, which possess aspiny proximal dendrites and somata with distal dendrites that are densely studded with dendritic spines. Type II MSNs differ in that their somata occasionally possess spines and their dendrites have significantly fewer spines compared to that of the type I class. Type III MSNs have less branched dendrites that are relatively aspiny and smooth. Type IV MSN somata are aspiny and have dendrites that branch repeatedly with a very sparse labeling of spines. Finally type V MSNs are similar to type IV in having aspiny somata, but differ in that the secondary dendrites branch significantly less and are very long (Chang et al. 1982). There have been no studies examining functional, genetic, or neurochemical differences between the five types of MSNs.

–  –  –

There are no data on physiological differences across the five morphologically defined MSNs. We will discuss MSNs as a single class.

Defining MSNs by non-morphological criteria. MSNs can also be defined on the basis of efferent projections, peptide content, and receptor expression. Two



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