Cerebellar Disease

Question 1

How does cerebellar hypoplasia occur in cats?

Answer 1

• a congenital condition that may be caused by teratogenic ‘in utero’ influences (ie. viral infection)
• feline panleukopaenia virus is well known for infecting the cerebellum either in utero or in the neonatal period
• the cerebellum develops in late gestation and the early neonatal period, with the external germinal layer developing for up to 9-10 weeks after birth
• cerebellar hypoplasia is mainly a granuloprival disease, with the cerebellar external germinal layer most targeted

Question 2

What is the function of the cerebellum?

Answer 2

• to monitor motor commands and sensory feedback in real time and to adjust the former to ensure smooth coordinated movement

Question 3

describe the anatomy of the cerebellum

Answer 3

• motor commands are relayed through pontine and olivary nuclei via the middle and caudal peduncles respectively
• proprioceptive movement is monitored through afferents in the caudal peduncle
• pontine and proprioception afferents form mossy fibres in the granule layer while olivary afferents from the climbing fibres - both send branches to the cerebellar roof nuclei

Question 4

what is a mossy fibre?

Answer 4

• a mossy fibre is made up of pontine and proprioceptive afferents
• each mossy fibre synapses on hundreds of granule cells and thousands of granule cells converge on each Purkinje cell via the parallel fibres

Question 5

what cells form the inhibitory interneurons in the cerebellar circuit?

Answer 5

• stellate
• golgi
• basket cells

Question 6

describe the efferent pathway of the cerebellar

Answer 6

• Purkinje cells are the sole efferent from the cortex
• through roof nuclei to modify motor systems through the rostral peduncle and feedback to the olivary nuclei
• Purkinje cells of the flocculus and nodulus project directly to the vestibular nuclei

Question 7

describe the development of the cerebellum

Answer 7

• cerebellum develops from the rhombencephalon
• most of the neural tube is expanding in a medial-lateral direction, a portion of the rostral rhombencephalon rotates ~90 degrees so that the cells form the rhombic lips which proliferate caudally and medially to form the cerebellum –> as they do so they cover the remnant of the open neural tube, the roof plate

Question 8

What is ‘reelin’?

Answer 8

• a signalling molecule secreted from Bergman’s radial glia
• reelin directs the migration and development of the Purkinje cells from this same layer
• the name comes from mutant mice missing the protein which have disordered cerebellar development and a ‘reeling’ gait (cerebellar ataxia)

Question 9

What is Dandy-Walker-Like Syndrome?

Answer 9

• a mutation in a receptor for the reelin signal in Eurasia dogs leads to a migration failure of the cells in the rhombic lip to the midline and abnormal development of the vermis.

Question 10

what cell does panleukopaenia virus target during late gestation?

Answer 10

• it targets and destroys rapidly multiplying external granule cells

Question 11

what is Spectrin?

Answer 11

• it is a structural protein that stabilises membrane proteins in the synapse
• mutations in the gene coding for spectrin prevents the normal maintenance of the synapse and a neonatal onset cerebellar ataxia in Beagles

Question 12

what is calpain?

Answer 12

• calpain is a protease involves in remodelling of proteins and spectrin is a substrate for calpain activity
• a mutation in calpain would impair the maintenance of proteins like spectrin and leads to a later, juvenile onset ataxia in Parson Russell Terriers

Question 13

what mutation affects the recycling of proteins that are damaged and need to be replaced? (Gordon Setters, old english sheepdogs)

Answer 13

mutations in the autophagy protein RAB24

Question 14

what process mediates the menace response?

Answer 14

• a learned response mediated by climbing fibre synapses that signal the Purkinje cell that synapses need to be strengthened or weakened in order to anticipate what motor response is needed to a specific sensory stimulus
• this process is the long-term potentiation/depression of synaptic strength that is thought to mediate all learning

Question 15

what is the ‘anticipatory response’?

Answer 15

• dampens the oscillations
• feedback systems tend to oscillate as adjustments overshoot the intended goal and then need to be adjusted in the opposite direction
• these oscillations can be dampened by building anticipation into the control mechanism so that the response is adjusted as it occurs to avoid overshooting the goal
• without this anticipation, oscillations produce tremors

Question 16

what pathway mediates the anticipatory response?

Answer 16

• mGLUR1 glutamate receptor on the Purkinje cell dendrites
• through G-protein mediated second messengers, AMPA receptors are phosphorylated, internalized and degraded
• this weakens the strength of the synapse as the cerebellum learns to not make that error again

• when a movement error is detected, climbing fibres synapse on mGLUR1 receptors on the Purkinje cell dendrites

Question 17

what is affected in Coton de Tulear pups with neonatal ataxia?

Answer 17

• they show neonatal ataxia from their first attempts to walk because they have a mutation affecting the mGLUR1 receptor that prevents that half of the error correction system so affected pups can never learn a motor skill
• there are no histological changes on necropsy

Question 18

What is idiopathic cerebellitis? “little white shakers”

Answer 18

• a presumed autoimmune disease in dogs characterised by an acute onset of cerebellar tremors that usually respond to corticosteroid therapy
• in human medicine a number of targets for autoantibodies have been identified in autoimmune cerebellar ataxias; mGLUR1 and 2, AMPA receptor, GABAergic functions on voltage gated ion channels

Question 19

what mutation is found in Norweigen Buhunds?

Answer 19

• a mutation in the gene for a protein (KCNIP4) which usually prolongs inhibitory effects of the potassium channel
• these channels now inactivate quickly –> increased activity of the granule cells, disrupting the precise timing needed for normal cerebellar function

Question 20

how do voltage gated potassium channels affect movement?

Answer 20

• they decrease neuronal excitability through outward potassium currents that hyperpolarize the cell membrane
• the A-type channels are rapidly inactivating channels found in the heart and on small dendrites in the CNS (such as those on the granule cell) where channels modulate their excitability
• results in precise timing needed for normal cerebellar function and smooth motion

Question 21

What is the role of the KCNIP4-K+ channel interacting protein?

Answer 21

• a potassium channel interacting protein in the granule cell dendrite modulates excitability of the synapse by preventing rapid interaction of the voltage-gated channel decreasing excitation of the dendrite

Question 22

Explain why mutations in KCNJ10 in terriers, chihuahuas, Belgian Malinois causes spinocerebellar ataxia with myokymia and seizures

Answer 22

KCNJ10 gene is responsible for the Kir4.1 channel found in astrocytes which have a more negative resting potential than neurons –> these channels can buffer extracellular potassium by redistributing it into the blood
- mutations in this gene mean that the astrocytes cannot buffer adequately –> increased K+ results in a shifted equilibrium potential to a more depolarize state increasing the probability of the AP generation
–> creates a cycle of hyperexcitability

Question 23

how does potassium move during neuronal depolarisation?

Answer 23

• when the neuron depolarizes, potassium moves out of the cell to repolarize the neuron, increasing extracellular potassium
• inwardly rectifying potassium channels (Kir) preferentially conduct potassium ions into the cell

Question 24

what is the prognosis for little white shaker syndrome?

Answer 24

• excellent, most dogs clinically begin to improve in 3 days and signs resolve in 1 - 3 weeks
• relapses can occur

Question 25

how do you treat idiopathic generalised tremor syndrome?

Answer 25

• immunosuppressive doses of corticosteroids; tapering over 2 week intervals