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PATHOPHYSIOLOGY OF THE CEREBELLUM Department of Pathophysiology Faculty of Medicine in Pilsen Charles University 1 STRUCTURE OF THE CEREBELLUM • Cortex - stratum moleculare (A) - stratum gangliosum (B) - stratum granulosum (C) • White matter B A C • Cerebellar nuclei - nc. dentatus - nc. emboliformis - nc. globosus - nc. fastigii 2 stellate cell stratum moleculare basket cell Purkinje cell stratum gangliosum granule cells stratum granulosum efferent cerebellar pathways white matter mossy fibre cerebellar nuclei climbing fibre excitatory synapse inhibitory synapse 3 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 4 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) 5 MANIFESTATIONS OF CEREBELLAR DISORDERS – EXTINCTION SYNDROME Cerebellar ataxia: • posture disorders – titubations, falls (especially rearwards – independent on head position), posture with wide basis • ambulation disorders – wobble, retropulsions and propulsions • hypermetria • movement coordination disorders • adiadochokinesis • speaking 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 6 MANIFESTATIONS OF CEREBELLAR DISORDERS – IRRITATION SYNDROME Opposite to the extinction syndrome, similar to parkinsonism • increased plastic tone of flexors • flexion holding of the trunk and limbs • static tremor • hypokinesis or akinesis 7 Animal model of cerebellar disorder: Lurcher mutant mice - 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 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 8 Cerebellum of Lurcher mutant mice Nissl staining +/+ Nissl staining +/Lc anticalbindin +/+ (P21) anticalbindin +/Lc (P21) 9 Apoptosis of Purkinje cells in Lurcher mutant mice Fluorescent doublestaining: Lucifer Yellow, DiD oil (Kröger a Wagner, 1998) 1 3 2 4 10 stellate cell stratum moleculare basket cell Purkinje cell stratum gangliosum granule cells stratum granulosum efferent cerebellar pathways white matter mossy fibre cerebellar nuclei climbing fibre excitatory synapse inhibitory synapse 11 stellate cell stratum moleculare basket cell Purkinje cell stratum gangliosum granule cells stratum granulosum efferent cerebellar pathways white matter mossy fibre cerebellar nuclei climbing fibre excitatory synapse inhibitory synapse 12 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 13 Mouse model of cerebellar ataxia 14 HORIZONTAL BAR • 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 15 HORIZONTAL BAR 16 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 17 LADDER 18 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 19 BRIDGE 20 ROTAROD • 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 21 ROTAROD 22 EVALUATION OF MOTOR COORDINATION TESTS Mean success rate in motor coordination tests in wild type (WT) and Lurcher mutant mice (Lc) - in % of trials % WT Lc 100 90 80 70 60 50 40 30 20 10 0 bar hrazda ladder žebřík rotarod rotarod 23 THE END 24