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 (ser- 845).

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 re- orientation 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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