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PATHOPHYSIOLOGY OF THE CEREBELLUM

PATHOPHYSIOLOGY OF THE CEREBELLUM

Department of PathophysiologyFaculty of Medicine in Pilsen

Charles University

Department of PathophysiologyFaculty of Medicine in Pilsen

Charles University

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STRUCTURE OF STRUCTURE OF THE THE CEREBELLUMCEREBELLUM

• Cortex - stratum moleculare (A)- stratum gangliosum (B)- stratum granulosum (C)

• White matter

• Cerebellar nuclei - nc. dentatus- nc. emboliformis- nc. globosus- nc. fastigii

AA

BB

CC

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excitatory synapse inhibitory synapse

climbing fibre

mossy fibre

stratum moleculare

stratum gangliosum

stratum granulosum

cerebellarnuclei

white matter

stellatecell

basketcell

Purkinjecell

granulecells

efferent cerebellarpathways

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FUNCTION OF THE CEREBELLUMFUNCTION OF THE CEREBELLUM

1. Archicerebelum (vestibulocerebellum): - equilibrium maintenance, head and eye movement coordination

2. Paleocerebelum (spinocerebellum):- muscle tone regulation

3. Neocerebelum (corticocerebellum):- movement coordination

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CAUSATIONS OF CEREBELLAR CAUSATIONS OF CEREBELLAR DISORDERSDISORDERS

• inborn developmental defects – often accompanied with affections of the brain-stem

• trauma• intoxications - acute or chronic ethanol intoxication• vascular causations – ischemia, hemorrhagia• cerebellar tumours• sclerosis multiplex• inflammations – cerebelitis• hereditary spinocerebelar degenerations

A) autosomal recessive: - Friedreich‘s ataxia- ataxia treleangiectatica- abetalopoproteinemia- ataxia with isolated vitamin-E deficiency

B) autosomal dominant: - spinocerebelar ataxia SCA1 – SCA 7- episodic ataxia type 1 and 2 (EA-1, EA-

2)

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MANIFESTATIONS OF CEREBELLAR MANIFESTATIONS OF CEREBELLAR DISORDERSDISORDERS

– EXTINCTION SYNDROME– EXTINCTION SYNDROMECerebellar ataxia:Cerebellar ataxia:

• posture disorders – titubations, falls (especially rearwards – posture disorders – titubations, falls (especially rearwards – independent on head position), posture with wide basisindependent on head position), posture with wide basis

• ambulation disorders – wobble, retropulsions and propulsionsambulation disorders – wobble, retropulsions and propulsions

• hypermetriahypermetria

• movement coordination disordersmovement coordination disorders

• adiadochokinesisadiadochokinesis

• speaking disorders – because of adiadochokinesis of orofacial speaking disorders – because of adiadochokinesis of orofacial musclesmuscles

Tremor Tremor –– intention (during goal-directed movement intention (during goal-directed movementss))

Disorders of muscular toneDisorders of muscular tone – – hypertonia of trunk extensors and hypertonia of trunk extensors and hypotonia of limb muscleshypotonia of limb muscles

Defects of cognitive functionsDefects of cognitive functions

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MANIFESTATIONS OF CEREBELLAR MANIFESTATIONS OF CEREBELLAR DISORDERSDISORDERS

– IRRITATION SYNDROME– IRRITATION SYNDROME

Opposite to the extinction syndrome, similar to Opposite to the extinction syndrome, similar to parkinsonismparkinsonism

• increased plastic tone of flexorsincreased plastic tone of flexors

• flexion holding of the trunk and limbsflexion holding of the trunk and limbs

• static tremorstatic tremor

• hypokinesis or akinesishypokinesis or akinesis

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Animal model of cerebellar Animal model of cerebellar disorder: Lurcher mutant micedisorder: Lurcher mutant mice

Animal model of cerebellar Animal model of cerebellar disorder: Lurcher mutant micedisorder: Lurcher mutant mice

Heterozygots (+/Lc) – Lurcher mutants:

• complete loss of cerebellar Purkinje cells within 3 months of postnatal life - excitotoxic apoptosis

• secondary decrease of number of cerebellar granule cells and inferior olivary neurons

• cerebellar ataxia, deterioration of cognitive functions, higher CNS excitability, higher sensitivity to neurotoxic agents

Unaffected homozygos (+/+) - wild type: completely healthy

Affected homozygots (Lc/Lc): not viable

- a natural model of olivocerebellar degeneration, a mutation of the 2-glutamate receptor gene- used for investigation of consequences of the neurodegeneration and of therapeutic methods

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Cerebellum of Lurcher mutant miceCerebellum of Lurcher mutant mice

Nissl staining +/+Nissl staining +/+ Nissl staining +/LcNissl staining +/Lc

anticalbindin +/+ (P21)anticalbindin +/+ (P21) anticalbindin +/Lc (P21)anticalbindin +/Lc (P21)

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Apoptosis of Purkinje cells in Lurcher mutant miceApoptosis of Purkinje cells in Lurcher mutant mice

Fluorescent doublestaining: Lucifer Yellow, DiD oil (Kröger a Wagner, 1998)

1 3

2 4

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excitatory synapse inhibitory synapse

climbing fibre

mossy fibre

stratum moleculare

stratum gangliosum

stratum granulosum

cerebellarnuclei

white matter

stellatecell

basketcell

Purkinjecell

granulecells

efferent cerebellarpathways

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excitatory synapse inhibitory synapse

climbing fibre

mossy fibre

stratum moleculare

stratum gangliosum

stratum granulosum

cerebellarnuclei

white matter

stellatecell

basketcell

Purkinjecell

granulecells

efferent cerebellarpathways

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MOTOR COORDINATION TESTSMOTOR COORDINATION TESTS

Fall – ability to land on all four limbs

Horizontal bar – ability to hold on a horizontal wire

Ladder – ability to hold on a slanting ladder

Bridge – ability to hold on a narrow horizontal bridge

Rotarod – ability to hold on a rotating cylinder

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Mouse model of cerebellar ataxiaMouse model of cerebellar ataxia

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• The mouse is hang with its frontal limbs on a horizontal wire.

• Criterion of the success trial: to stay on the bar for 60 s, or to leave the apparatus actively

HORIZONTAL BARHORIZONTAL BAR

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HORIZONTAL BARHORIZONTAL BAR

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LADDERLADDER

• The mouse is placed into the middle of a slanting ladder (head up position).

• Criterion of the success trial: to stay on the ladder for 60 s, or to leave the apparatus actively

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LADDERLADDER

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BRIDGEBRIDGE

• The mouse is placed transversally into the middle of a narrow horizontal bridge.

• Criterion of the success trial: to stay on the bar for 120 s, or to leave the apparatus actively

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BRIDGEBRIDGE

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• The mouse is placed on a rotating cylinder (head in the direction of rotation).

• Criterion of the success trial: to stay on the bar for 60 s, or to leave the apparatus actively

ROTARODROTAROD

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ROTARODROTAROD

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EVALUATION OF MOTOR EVALUATION OF MOTOR COORDINATION TESTSCOORDINATION TESTS

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hrazda žebřík rotarod

% WT Lc

Mean success rate in motor coordination tests in wild type (WT) and Lurcher mutant mice (Lc) - in % of trials

bar ladder rotarod

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THE ENDTHE END