Transcript Horizontal Transmission

Experience-Dependent Plasticity Mechanisms for
Neural Rehabilitation in Somatosensory Cortex
A Review
Kevin Fox
Presented by: Stephanie Hornyak-Borho
York University
April 2009
OUTLINE
1. Introduction
2. Anatomical pathways mediating plasticity
3. Molecular pathways mediating plasticity
4. Structural plasticity in the somatosensory cortex
5. Plasticity, stability and the role of gene expression
6. Remaining questions
OUTLINE
1. Introduction
2. Anatomical pathways mediating plasticity
3. Molecular pathways mediating plasticity
4. Structural plasticity in the somatosensory cortex
5. Plasticity, stability and the role of gene expression
6. Remaining questions
INTRODUCTION
Somatosensory cortex (SSC) serves
several key functions in the brain.
1. Integration and analysis of somatosensory
information leads to perception of these stimuli.
2. Enables planning, execution and dynamic
modulation of coordinated movement (via motor
cortex).
3. Governs the sense of body ownership and leads to
a sense of self (with insular and visual cortices).
INTRODUCTION
Cortical reorganization occurs naturally during recovery
(or partial recovery) from stroke (Nelles et al., 1999).
Treatments aimed at improving recovery from stroke is
comprised of three stages:
1. Neuroprotection
2. Neuronal Repair
3. Functional Rehabilitation
INTRODUCTION
Increasing Plasticity +
Behavioural Training =
Rehabilitation
Constraint-Induced Therapy (CIT)
(Cramer & Riley, 2008).
Functional brain mapping studies
indicate that CIT causes an
increase in remapping of arm
function in peri-infarct cortex
(Sutcliffe et al., 2007).
EXPERIENCE-DEPENDENT
PLASTICITY
INTRODUCTION
Much research in this area comes from studies in the
rodent BARREL CORTEX, which receives input from the
vibrissae.
Barrel cortex also provides a useful model for stroke
research:
Area affected by the infarct can be defined quite
accurately with reference to the barrels.
Ability to stimulate the whiskers provides an easy
method for checking whether stimulus-induced
increases in blood flow are affected by stroke.
INTRODUCTION
OUTLINE
1. Introduction
2. Anatomical pathways mediating plasticity
3. Molecular pathways mediating plasticity
4. Structural plasticity in the somatosensory cortex
5. Plasticity, stability and the role of gene expression
6. Remaining questions
ANATOMICAL PATHWAYS MEDIATING PLASTICITY
1. Pathways for Potentiation and Horizontal Transmission
2. Pathways for Depression and Vertical Transmission
ANATOMICAL PATHWAYS MEDIATING PLASTICITY
Pathways for Potentiation and Horizontal Transmission
A characteristic feature of plasticity in the SSC is the:
Horizontal spread of the body representation spared
by the injury.
Deprivation that causes a rearrangement in the
cortical map of the body surface.
ANATOMICAL PATHWAYS MEDIATING PLASTICITY
Pathways for Potentiation and Horizontal Transmission
Experience-dependent plasticity is CORTICAL in nature.
1. Lesions of the septal region lying between the edges of
two neighboring barrels have been found to be sufficient to
prevent HORIZONTAL TRANSMISSION displaying strong
evidence for INTERCOLUMNAR CONNECTIONS.
2. Horizontal pathways have been shown to form in
extragranular layers of cortex following STROKE and
PERIPHERAL AMPUTATION.
3. Layer II/III cells have large dendritic spread spanning the
same horizontal dimensions as the width of a barrel.
ANATOMICAL PATHWAYS MEDIATING PLASTICITY
Pathways for Depression and Vertical Transmission
Deprived or missing sensory pathways contract, displaying
weaker responses to stimulation in corresponding columns.
Due to minimal layer IV plasticity in older animals,
depression is likely to occur in VERTICAL PATHWAYS
projecting out of layer IV to layer II/III above and to later V
below.
Layer V cells in deprived columns also show centre
receptive field (principal whisker) depression following
whisker deprivation.
OUTLINE
1. Introduction
2. Anatomical pathways mediating plasticity
3. Molecular pathways mediating plasticity
4. Structural plasticity in the somatosensory cortex
5. Plasticity, stability and the role of gene expression
6. Remaining questions
MOLECULAR PATHWAYS MEDIATING PLASTICITY
1. Mechanisms for Potentiation
a) NMDA and metabotropic glutamate receptors (mGluRs)
b) Calcium/calmodulin-dependent kinase type II (CaMKII)
c) Nitric oxide synthase (NOS)
2. Mechanisms for Depression
a) Protein Kinase A (PKA) and GluR1
b) Cannabinoid receptor-dependent mechanisms
MOLECULAR PATHWAYS MEDIATING PLASTICITY
Mechanisms for Potentiation
a) NMDA and metabotropic glutamate receptors (mGluRs)
NMDA receptors are involved in LTP and some forms of LTD,
therefore, may be involved in both potentiation and depression
mechanisms in vivo.
NMDA receptors play a role in synaptic plasticity of the layer IV to
II/III pathway, and reveals a role for mGluRs.
LTP is restored in this pathway if NMDA
receptors are antagonized, which could
indicate that NMDA-dependent LTD is
enhanced in spared columns and overwrites
any LTP that might occur.
MOLECULAR PATHWAYS MEDIATING PLASTICITY
Mechanisms for Potentiation
b) Calcium/calmodulin-dependent kinase type II (CaMKII)
Appears to be necessary for LTP in the hippocampus and
neocortex due to its ability to phosphorylate AMPA
receptors.
Experience-dependent potentiation in the barrel cortex has
been found to be dependent on CaMKII, raising the
possibility this is related to LTP mechanisms.
CaMKII retains a ‘memory’ of past synaptic activity by
phosphorylating itself (threonine-286 site), prolonging its
activity.
MOLECULAR PATHWAYS MEDIATING PLASTICITY
Mechanisms for Potentiation
c) Nitric oxide synthase (NOS)
LTP and experience-dependent plasticity
in the cortex appear to be strongly dependent
on the neuronal form of NOS.
NOS is the source of the retrograde messenger NO,
implicated in LTP in the hippocampus, and a substrate for
phosphorylation by CaMKII.
NOS is required for plasticity in the layer IV to II/III pathway,
and when blocked, prevents pre-synaptic potentiation
leaving the post-synaptic component intact.
MOLECULAR PATHWAYS MEDIATING PLASTICITY
1. Mechanisms for Potentiation
a) NMDA and metabotropic glutamate receptors (mGluRs)
b) Calcium/calmodulin-dependent kinase type II (CaMKII)
c) Nitric oxide synthase (NOS)
2. Mechanisms for Depression
a) Protein Kinase A (PKA) and GluR1
b) Cannabinoid receptor-dependent mechanisms
MOLECULAR PATHWAYS MEDIATING PLASTICITY
Mechanisms for Depression
a) Protein Kinase A (PKA) and GluR1
Inhibition of PKA does not affect the magnitude of LTP in the
columnar IV to II/III pathway in mouse barrel cortex.
However, following whisker deprivation, LTP is larger in
magnitude and sensitive to inhibition of PKA
(DESATURATION).
Mechanisms involved in PKA-dependent potentiation could
also act via the GluR-1 subunit of the AMPA channel (ser845).
MOLECULAR PATHWAYS MEDIATING PLASTICITY
Mechanisms for Depression
b) Cannabinoid receptor-dependent depression mechanisms
Blocking cannabinoid receptors prevents LTD induction.
This form of plasticity requires pre-synaptic NMDA
receptors.
Due to the fact that pre-synaptic receptors only occur in
cortex early in life, it is possible that cannabinoid-dependent
depression is limited to early life.
OUTLINE
1. Introduction
2. Anatomical pathways mediating plasticity
3. Molecular pathways mediating plasticity
4. Structural plasticity in the somatosensory cortex
5. Plasticity, stability and the role of gene expression
6. Remaining questions
STRUCTURAL PLASTICITY IN THE SSC
1. Dendritic Spine Plasticity
2. Effect of Experience in Cortical Pre-Synaptic Structure
3. Dendritic Plasticity
STRUCTURAL PLASTICITY IN THE SSC
Dendritic Spine Plasticity
Most (+) synapses are located at
dendritic spines making them a major
site for plasticity in the cortex.
Can be gauged by how rapidly new
spines appear and disappear, which is
an AGE-DEPENDENT PROCESS, is
modulated by SENSORY
EXPERIENCE, and display a faster
turnover rate in the peri-infarct area.
STRUCTURAL PLASTICITY IN THE SSC
Dendritic Spine Plasticity
STRUCTURAL PLASTICITY IN THE SSC
Effect of Experience in Cortical Pre-Synaptic Structure
In addition to dendritic spines, axons are presumed to show
plasticity.
Changes in spines are presumed to occur alongside
changes in pre-synaptic terminals.
Newly-formed spines make contact with pre-synaptic
boutons and form synapses.
Axonal arbours are largely stable in barrel cortex over long
periods of time, however, some classes of axons reshape
often and branches can elongate and retract by tens of
microns/month.
STRUCTURAL PLASTICITY IN THE SSC
Effect of Experience in Cortical Pre-Synaptic Structure
Sensory experience affects the morphology of intracortical
axons.
Peripheral nerve lesions also affects intracortical axon
trajectories in mature animals.
Correspond with findings in monkey SSC, where long-term
digit amputation, arm amputation and even wrist fracture can
alter distribution of intracortical axons.
STRUCTURAL PLASTICITY IN THE SSC
Dendritic Plasticity
Lesion-induced plasticity also affects dendrites in the
cortex.
EXAMPLE: Denervation of vibrissae follicles causes a reorientation of dendritic arbours in layer III and layer IV of adult
rats.
Tailby et al., 2005, Proc. Natl. Acad. Sci., Vol. 102
OUTLINE
1. Introduction
2. Anatomical pathways mediating plasticity
3. Molecular pathways mediating plasticity
4. Structural plasticity in the somatosensory cortex
5. Plasticity, stability and the role of gene expression
6. Remaining questions
PLASTICITY, STABILITY AND GENE EXPRESSION
1. Epigenetic Mechanisms for Providing Synaptic Stability
2. Experience-Dependent Gene Expression
Effects of HDAC (histone deacetylase) inhibitor trichostatin on
plasticity, and the role of CREB as an example of gene expression
leads to lasting changes in synaptic transmission.
PLASTICITY, STABILITY AND GENE EXPRESSION
Epigenetic Mechanisms for Providing Synaptic Stability
Several molecules present at the synapse directly involved
in synaptic transmission are continuously turned over and
recycled.
1. GluR2
1. PKA
1. HDAC
PLASTICITY, STABILITY, AND GENE EXPRESSION
Experience-Dependent Gene Expression
CREB regulates transcription when it is caused to dimerize
following phosphorylation of PKA.
Appears to be required for late-phase protein-dependent
aspects of plasticity (hippocampal LTP).
Inducible cAMP early repressor (ICER) is a (-) feedback
gene that requires CREB for activation, but then acts to
reduce any further CREB expression.
BDNF (maturation of silent synapses) and neuritin-1
(CPG15) (regulates growth of axonal and dendritic arbours)
are genes associated with plasticity that have promoters
that bind to CREB.
OUTLINE
1. Introduction
2. Anatomical pathways mediating plasticity
3. Molecular pathways mediating plasticity
4. Structural plasticity in the somatosensory cortex
5. Plasticity, stability and the role of gene expression
6. Remaining questions
REMAINING QUESTIONS
Differential plasticity mechanisms (e.g.,
hippocampal vs. neocortical).
Inhibitory plasticity mechanisms.
Molecular mechanisms that control spine growth
and retraction.
Bias towards mechanisms in younger animals.
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