Download - PATHOPHYSIOLOGY OF THE CEREBELLUM
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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