1. Nitric Oxide (NO) and How it Regulates Motor Function
Connor Culley, Derek Emerson, Domenick Stumpo

2. Point of Paper
To analyze the role of Nitric Oxide and the integration of dopaminergic and glutamatergic neurotransmission in the Striatum and what their roles are in Parkinson's Disease

3. Nitric Oxide (NO) Short lived Soluble Penetrate cell membranes
Can be dangerous in high concentrations
Neuronal communications
Modulation of blood vessel relaxation
Immune response
Neuro-development within CNS
Release and uptake of neuro-transmitters
Synaptic plasticity
EVOKES RELEASE OF DOPAMINE AND EFFECTS ITS TRANSPORTERS
CONTROL OF MENTAL AND MOTOR FUNCTION

4. NO Synthesis in Brain Synthesized by Nitric Oxide Synthase
Requires O2, NADPH, and L-arginine
Cant be stored
Synthesized by four enzymes
Constitutive
Neuronal NOS (Short lasting increase)
Endothelial NOS (Short lasting increase)
Mitochondrial NOS
Inducible (iNOS) (produce long lasting amounts)
nNOS is the predominant source of NO in neurons

5. nNOS Inhibitors
Multitude of studies have looked at results of nNOS inhibitors
Conclusions are controversial
nNOS reduces movement in rodents on drugs
It can also induce catalepsy in other rodents
Shows that NO modulates motor function through
Dopaminergic
Serotoninergic
Cholinergic transmission

6. NO in Parkinson's Parkinson's
Loss of Dopamine producing neurons in substantial nigra pars compacta (SNc)
Severe depletion of Dopamine producing neurons in Corpus Striatum
NO synthesizing neurons, and expression of nNOS mRNA decreases in putamen
nNOS mRNA is higher in subthalamic nucleus
NO in cerebrospinal fluid is very low

7. Striatum NOS cells only make up 5% of all cells in the Striatum
Axons of these cells create a network that allows these cells to influence the whole of the striatum
nNOS is expressed highly in the Striatum
Interacts and controls almost 95% of Striatum neurons (MSNs)
MSNs interact with dopaminergic and glutamatergic transmission
nNOS controls these through the interactions with MSNs

8. Glutamate and DA role in the synthesis of NO
Dopamine modulates nNOS activity in the Striatum via both facilitatory and inhibitory signaling
Facilitatory is D1 receptor stimulation
Inhibitory is D2 receptor stimulation
In Parkinson Disease the function of the dopaminergic system is decreased
NO synthesis is disrupted

9. The Role of NO-sGC-cGNP signaling in the regulation of output pathways in the Striatum
The MSNs in the Striatum are the target for dopaminergic innervations
These neurons are regulated by two pathways
Direct
Inhibitory control of substantia nigra
D1 receptors
Indirect
Increased activity of glutamatergic neurons, excites substantia nigra
D2 receptors

10. The Role of NO-sGC-cGNP signaling in the regulation of output pathways in the Striatum
DA release stimulates production of cAMP
Increases nNOS activity, upregulation of cGMP production
NO acts via cGMP to regulate ion channels, protein kinases and nucleotide phosphodiesterase's(PDEs)
L-dopa affects level of cyclic nucleotides in Striatum differently.
Dyskinetic Rats
Severe decreases in in cAMP and cGMP levels in the cortex, striatum, and globus pallidus
Non-Dyskinetic Rats
cAMP increased in cortex and striatum, but decreased in globus pallidus
Pretreatment with PDEs inhibitor reduced severity of L-dopa induced dyskinesias, prevented significant drop in cyclic nucleotides
Possibly by restoring synaptic plasticity

11. Summary Further studies are clearly needed
Disturbances in nitrergic transmissions can lead to PD
Understanding the NO-sGC-cGMP pathway during L-dopa therapy can help prevent L-dopa induced dyskinesia
These studies may help in finding new treatments for PD