Basal Ganglia:Parkinson disease

David G. Standaert, M.D., Ph.D.

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

Multiple Basal Ganglia circuits for multiple functions

Alexander et al., 1986

The Motor Circuit Input: the striatum (caudate and

putamen) Output: The GPi and SNpr Intrinsic nuclei:

–GPe–STN–SNpc

Human basal ganglia

CaudatePutamen

GPeGPiSTNSNcSNr

InputOutputIntrinsic

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

“Cardinal Features” ofParkinson Disease

• Tremor• Rigidity• Bradykinesia• Postural Instability

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

DMG11/1/99

Motor complications - a patient’s view

Ocular Complications of PD

Biousse et al., 2004, Neurology 62:177-180

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