1 PATHOPHYSIOLOGY OF THE CEREBELLUM Department of Pathophysiology Faculty of Medicine in Pilsen Charles University Department of Pathophysiology Faculty of Medicine in Pilsen Charles University

2 STRUCTURE OF THE CEREBELLUM Cortex- stratum moleculare (A) - stratum gangliosum (B) - stratum granulosum (C) White matter Cerebellar nuclei- nc. dentatus - nc. emboliformis - nc. globosus - nc. fastigii A B C

3 excitatory synapse inhibitory synapse climbing fibre mossy fibre stratum moleculare stratum gangliosum stratum granulosum cerebellar nuclei white matter stellate cell basket cell Purkinje cell granule cells efferent cerebellar pathways

4 FUNCTION OF THE CEREBELLUM 1.Archicerebelum (vestibulocerebellum): - equilibrium maintenance, head and eye movement coordination 2.Paleocerebelum (spinocerebellum): - muscle tone regulation 3.Neocerebelum (corticocerebellum): - movement coordination

5 CAUSATIONS OF CEREBELLAR DISORDERS 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)

6 MANIFESTATIONS OF CEREBELLAR DISORDERS – EXTINCTION SYNDROME Cerebellar ataxia: posture disorders – titubations, falls (especially rearwards – independent on head position), posture with wide basisposture disorders – titubations, falls (especially rearwards – independent 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 musclesspeaking disorders – because of adiadochokinesis of orofacial muscles Tremor – intention (during goal-directed movements) Disorders of muscular tone – hypertonia of trunk extensors and hypotonia of limb muscles Defects of cognitive functions

7 MANIFESTATIONS OF CEREBELLAR DISORDERS – IRRITATION SYNDROME Opposite to the extinction syndrome, similar to parkinsonism 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

8 Animal model of cerebellar disorder: 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

9 Cerebellum of Lurcher mutant mice Nissl staining +/+ Nissl staining +/Lc anticalbindin +/+ (P21) anticalbindin +/Lc (P21)

10 Apoptosis of Purkinje cells in Lurcher mutant mice Fluorescent doublestaining: Lucifer Yellow, DiD oil (Kröger a Wagner, 1998)

11 excitatory synapse inhibitory synapse climbing fibre mossy fibre stratum moleculare stratum gangliosum stratum granulosum cerebellar nuclei white matter stellate cell basket cell Purkinje cell granule cells efferent cerebellar pathways

12 excitatory synapse inhibitory synapse climbing fibre mossy fibre stratum moleculare stratum gangliosum stratum granulosum cerebellar nuclei white matter stellate cell basket cell Purkinje cell granule cells efferent cerebellar pathways

13 MOTOR 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

14 Mouse model of cerebellar ataxia

15 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 BAR

16 HORIZONTAL BAR

17 LADDER 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

18 LADDER

19 BRIDGE 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

20 BRIDGE

21 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 ROTAROD

22 ROTAROD

23 EVALUATION OF MOTOR COORDINATION TESTS Mean success rate in motor coordination tests in wild type (WT) and Lurcher mutant mice (Lc) - in % of trials barladderrotarod

24 THE END