basal ganglia: parkinson disease - uab school of optometry...
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Key Points
• Basal ganglia circuits are loops that regulatebehavior
• The striatum (caudate and putamen) is the inputof the basal ganglia. It integrates glutamate anddopamine input, and uses GABA for output
• Parkinson disease caused degeneration ofneurons, leading to loss of the dopamine input
• The cause of most cases of Parkinson diseaseis unknown
• Most treatments for Parkinson disease arebased on replacing dopaminergic stimulation
Basal Ganglia are Circuits that regulate motor behavior
Cortex
BasalGanglia Thalamus
Spinal Cord
Muscles
The Motor Circuit Input: the striatum (caudate and
putamen) Output: The GPi and SNpr Intrinsic nuclei:
–GPe–STN–SNpc
The StriatumSources of afferent input:–The cerebral cortex (glutamatergic)–The SNpc (dopaminergic)
Cellular composition–90% Projection neurons: medium sized GABA neurons
with spiny dendrites–10% Interneurons:»cholinergic»NOS, somatostatin»GABA, calcium binding proteins
Striatal Neurons Spiny neurons
•GABA•D1, D2 receptors
Giant aspiny neurons•cholinergic
Small and medium aspiny•NOS/somatostatin•GABA, Ca++ bindingproteins
Wilson, 1990
Afferents to Medium Spiny Neurons
•Glutamatergiccorticostriatal inputs tothe heads of spines•Dopaminergic inputsto the shafts of spinesand dendrites•Cholinergic and GABAinputs to the dendritesand soma
Smith and Bolam, 1990
Striatal efferentsTo the GPi/SNpr–GABAergic–D1 Receptors–Substance P
To the GPe–GABAergic–D2 Receptors–Enkephalin
GPe
D1SP
D2ENK
STRIATUM
-
-
GABA
GABA
GPi/SNpr
SS
AChGABA
BASAL GANGLIA ANATOMY
CEREBRAL CORTEX
GPe STN
SNpcGPi/SNpr
D1SP SS
AChD2
ENK
STRIATUM VA/VLTHALAMUS
GLU
GLU
GABA
DA++
+
-
--
-
GABA GLU
GLU
TOSPINALCORD,BRAINSTEM
+
GABA
GABA-
+
GABA
ParkinsonDisease
Described byJames Parkinson,1817Affects 3% of the
population over theage of 65 yearsAbout 500,000
patients in the US
What causes PD?• Genetics
– Most cases arenot genetic inorigin
– Rare families withinherited PD
– Genetic causemore likely inearly onset cases
• Risk Factors– Male Gender– Environment
SmokingCaffeine
Well water and rural livingPesticides, toxins
Pathology of Parkinson’s Disease
Normal Parkinson’sDepigmentation of thesubstantia nigra parscompactaFormation of LewyBodies
Feany Lab
Striatum: Inputs, outputs, and interneurons
Glutamate
Dopamine
GABA GABA
AchD1 D2
Activated bydopamine
Inhibited bydopamine
PARKINSON’S DISEASE
CEREBRAL CORTEX
GPe STN
SNpcGPi/SNpr
D1SP SS
AChD2
ENK
STRIATUM VA/VLTHALAMUS
GLU
GLU
GABA
DA++
+
-
--
-
GABA GLU
GLU
TOSPINALCORD,BRAINSTEM
+
GABA
GABA-
+
GABA
Levodopa Therapy for Parkinson Disease
Most effective treatment is levodopa (also calledL-DOPA, L-dihydroxyphenylalanine)
Works by replacing biosynthetic precursor:
tyrosine L-DOPA DATH AADC
Most important limitation of treatment is thedevelopment of “complications of levodopatherapy” - wearing off and dyskinesias
Key Points
• Basal ganglia circuits are loops that regulatebehavior
• The striatum (caudate and putamen) is the inputof the basal ganglia. It integrates glutamate anddopamine input, and uses GABA for output
• Parkinson disease caused degeneration ofneurons, leading to loss of the dopamine input
• The cause of most cases of Parkinson diseaseis unknown
• Most treatments for Parkinson disease arebased on replacing dopaminergic stimulation
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