Motor Systems: Cerebellum and LTD

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Motor Systems Cerebellum and LTD

• Richard Harlan, PhD
• harlanre_at_tulane.edu

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Overview

• Gross structure of cerebellum
• Cytoarchitecture of cerebellum
• Functional organization of cerebellum
• Cortico-pontine-cerebellar-thalamo-cortical
  circuit
• Cerebellum and long-term depression

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Cortical-Subcortical-Thalamo-Cortical Loops
Subcortical Structures
Cortex
Thalamus
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Motor Hierarchy and Loops
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Cortical-Subcortical-Thalamo-Cortical
Loops Involving cerebellum

Cortex
Pons


Cerebellum
Thalamus

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Overview

• Gross structure of cerebellum
• Cytoarchitecture of cerebellum
• Functional organization of cerebellum
• Cortico-pontine-cerebellar-thalamo-cortical
  circuit
• Cerebellum and long-term depression

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Cerebellar organization

• Divided into a cortex and deep nuclei
• Cortex divided into 10 lobules
• Each lobule divided into folia, running
  medial-lateral
• Cortex also divided into vermis on midline and
  hemispheres

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Deep nuclei

• Fastigial (medial, relates to vermis)
• Interposed or intermediate (two nuclei, relate to
  paravermal region of hemispheres
• Dentate (lateral and largest, relates to
  hemispheres)

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Overview

• Gross structure of cerebellum
• Cytoarchitecture of cerebellum
• Functional organization of cerebellum
• Cortico-pontine-cerebellar-thalamo-cortical
  circuit
• Cerebellum and long-term depression

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Cell types in cerebellar cortex

• Purkinje cell body, dendrites, axons, recurrent
  collaterals dendrites are flattened
  perpendicular to folia GABAergic output from
  the cortex project to deep nuclei

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Purkinje Neurons
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Cell types in cerebellar cortex

• basket GABAergic pinceaux around axon hillock of
  Purkinje cell projects to surrounding Purkinje
  cells to produce surround inhibition
• stellate stellate cells only in mol two types
  of stellate cells superficial and deep GABAergic

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Cell types in cerebellar cortex

• granule cells send parallel fibers (PF) to
  molecular layer activate dendrites of Purkinje,
  stellate, basket and Golgi cells glutamatergic
• Golgi cells inhibitory interneurons that synapse
  on mossy fiber terminals GABAergic and
  enkephalinergic

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Cerebellar Circuitry

• Two major inputs
• Climbing fibers from inferior olivary complex
  form massive excitatory contacts with Purkinje
  neurons
• Mossy fibers from several brain regions synapse
  on granule cells
• Inputs send one collateral to deep cerebellar
  nuclei and one to cerebellar cortex
• Output from cerebellar cortex is Purkinje cell
  projects to deep cerebellar neuron

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Purkinje Neurons
Perpendicular to folia
Parallel to folia
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Complex and simple spikes of Purkinje cells, as
recorded intracellularly following excitation by
climbing and mossy fibers, respectively.
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Overview

• Gross structure of cerebellum
• Cytoarchitecture of cerebellum
• Functional organization of cerebellum
• Cortico-pontine-cerebellar-thalamo-cortical
  circuit
• Cerebellum and long-term depression

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Functional divisions of the cerebellum

• Vestibulo-cerebellum flocculo-nodular lobe
  reflex control of balance
• Spinocerebellum vermis and paravermal region
  coordination of movements and muscle tone
• Cerebro-cerebellum lateral portions of
  hemispheres planning and initiation of
  movements mostly upper limbs

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Intermediate or paravermal zone
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Functional divisions of the cerebellum

• Vestibulo-cerebellum flocculo-nodular lobe
  reflex control of balance
• Spinocerebellum vermis and paravermal region
  coordination of movements and muscle tone
• Cerebro-cerebellum lateral portions of
  hemispheres planning and initiation of
  movements mostly upper limbs

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Functional divisions of the cerebellum

• Vestibulo-cerebellum flocculo-nodular lobe
  reflex control of balance
• Spinocerebellum vermis and paravermal region
  coordination of movements and muscle tone
• Cerebro-cerebellum lateral portions of
  hemispheres planning and initiation of
  movements mostly upper limbs

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Functional divisions of the cerebellum

• Vestibulo-cerebellum flocculo-nodular lobe
  reflex control of balance
• Spinocerebellum vermis and paravermal region
  coordination of movements and muscle tone
• Cerebro-cerebellum lateral portions of
  hemispheres planning and initiation of
  movements mostly upper limbs

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Cortical-Cerebellar Loop
glutamate
Motor Cortex
Pons
glu
glu
Motor Thalamus VL
glutamate
Cerebellum
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Cerebellar Crossings

• symptoms are ipsilateral to lesion
• some outputs are ipsilateral fastigial and
  vestibular nuclei
• crossed outputs are double crossed outputs from
  interposed and dentate n. are crossed
  (decussation of superior cerebellar peduncle),
  but output from targets are also crossed (e.g.
  rubrospinal, corticospinal, corticobulbar)
• climbing fibers are always crossed
• mossy fibers old are ipsilateral, new are
  contralateral

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Cerebellar Problems

• Vestibulocerebellum loss of balance, swaying,
  truncal and gait ataxia
• Spinocerebellum and cerebrocerebellum
  (neocerebellar syndrome)

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Neocerebellar Syndrome

• ataxia intermittent or jerky movements lateral
  lesions cause ataxia in limbs, medial lesions
  cause gait ataxia, but not upper limb ataxia
• dysmetria deficit in judging distances, e.g.
  past-pointing
• adiadochokinesis clumsiness in rapidly
  alternating movements
• asynergy decomposition of movements
• hypotonia weakness, flacidness and fatigue
• intention tremor tremor at end of a movement
• nystagmus lateral eye movements with fast and
  slow components

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Overview

• Gross structure of cerebellum
• Cytoarchitecture of cerebellum
• Functional organization of cerebellum
• Cortico-pontine-cerebellar-thalamo-cortical
  circuit
• Cerebellum and long-term depression

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Major players in LTD in cerebellar cortex

• AMPA and mGluRs
• Ca
• PKC
• NO

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Cell types in cerebellar cortex

• Purkinje PKC g and some have PKC d no NMDA
  receptors, but mGluR1 and AMPA receptors (GluR2
  and 2/3, perhaps GluR1) at PF synapses no nNOS

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Cell types in cerebellar cortex

• basket GABAergic pinceaux around axon hillock of
  Purkinje cell projects to surrounding Purkinje
  cells to produce surround inhibition PKC d in
  pinceau
• stellate stellate cells only in mol two types
  of stellate cells superficial and deep
  superficial cells have PKC bI GABAergic

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Cell types in cerebellar cortex

• granule cells send parallel fibers (PF) to
  molecular layer activate dendrites of Purkinje,
  stellate, basket and Golgi cells glutamatergic
  much nNOS here PKC bII perhaps mGluR1a in
  granule cells and PF
• Golgi cells inhibitory interneurons that synapse
  on mossy fiber terminals GABAergic and
  enkephalinergic

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LTD in Purkinje cells

• A. phenonemon long-term decrease in EPSP (or
  EPSC) amplitude following paired activation of
  "inputs" from CF and PF (or two sets of PF)
  initiation phase independent of protein
  synthesis, while maintenance phase requires
  postsynaptic protein synthesis

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LTD in Purkinje cells

• B. major preparations studied
• 1. in vivo
• 2. acute slices
• 3. dissociated cells in culture

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LTD in Purkinje cells required factors

• 1. glutamate acting on AMPA and mGluR1 receptors
  no LTD in mGluR1 knockout mice LTD can be
  rescued by intracellular activation of IP3, and
  this can be blocked by PKC antagonist LTD can
  also be rescued by mGluR1a transgene under
  control of Purkinje cell-specific promoter in
  knockout mice
• 2. increase in intracellular Ca, through VGCC
  and perhaps release of stored Ca or activation
  of Na-Ca exchanger link to mGluR1 receptors
• 3. activation of PKC link to mGluR1 receptors
  and Ca

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LTD in Purkinje cells important factors

• 1. NO production, although this is controversial
  and may be a product of cell culture how does
  this work?
• 2. activation of soluble guanylyl cyclase in PC,
  leading to increased cGMP, activation of
  G-substrate, and inhibition of phosphatases

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LTD in Purkinje cells important factors

• 3. phosphorylation of AMPA receptors, especially
  GluR2 at ser-880 via PKC this produces reduction
  in affinity of GluR2 for GRIP, disruption of
  GluR2 clustering, and internalization of GluR2
  application of peptides that interfere with
  clathrin-mediated endocytosis blocks LTD
  intracellular infusion of peptides that disrupt
  interaction between GluR2 and PDZ domain proteins
  (GRIP/ABP) and PICK1 blocks LTD

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LTD in Purkinje cells important factors

• 4. activation of PLA2 to produce arachidonic
  acid link to PKC
• 5. activation of CRF receptors, which are linked
  to activation of PKC

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LTD in Purkinje cells important factors

• 6. induction of c-Fos and c-Jun procedures which
  induce LTD increase IEG production these
  transcription factors may be important for
  maintenance phase
• 7. late phase of LTD blocked by transfection of
  dominant negative inhibitor of CREB, and by
  pharmacological inhibition of CaMKIV, but not PKA
  or MAPK cascades

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Functional significance of LTD

• A. adaptation in vestibulo-ocular reflex, and
  potentially in other examples of motor learning
• B. why LTD rather than LTP? LTP occurs at mossy
  fiber-granule cell synapse and at granule
  cell-Purkinje cell synapse (mediated by PKA,
  which can activate NO release)