Tissue Plasticity Flashcards
In which human systems is plasticity most evident?
CNS Muscle (volume, fibre type)
What is the connectome?
The pattern of neural connections in the brain and how it changes throughout life
Large number of trial connections formed and pruned during the critical period
Synaptic pruning in Muscle fibres- what is involved?
Early developmental expression changes in Ephrin A3/8 to target fast/slow neurons
Fibre terminals swell, lifting off the fibre and cause neuron retraction, leaving only one neuron innervating each fibre
Visual acuity and Pruning- what happens?
Hubel 1977
Refined early in development during a critical period lasting 3-8 months
Separation of overlapping ocular dominance columns
Covering an eye (monocular deprivation) widens the contralateral OD column, but shrinks ipsilaterally
Closure of an eye leads to a competitive disadvantage in column retraction/pruning
Differences in Layer 5 (superior colliculus/spinal cord connection pruning)
What 4 R’s occur as part of plasticity in adults
Regeneration (new neuron/synapse creation)
Rewiring
Reconnection
Reweighting (changing thresholds for synapse formation)
What 4 things make up PNNs?
Chondroitin Sulphate Proteoglycans (CSPGs)
Link Proteins
Tenascin R
Hyaluronan
What might PNNs do physiologically?
Neuroprotective role- reducing oxidative stress due to GABAergic neuronal excitability
PNN formation may be Na+ channel dependent, as it is not affected by disruption of glutamatergic system transgenically
PNNs and their relation to Visual Acuity
Pizzorusso 2002
PNNs appear at the end of development of visual acuity
- CSPGs are expressed throughout the critical period but are diffusely distributed on immunohistochemistry (IHC)
What gene might Pruning be dependent upon?
Otx1
- Transcription factor found to translocate to the nucleus at specific developmental stages
- Otx1 mutant mice are unable to refine/ prune cortical progenitors
Models of synaptic pruning
Sequential (formation then elimination)
Concurrent
Pruning has a net turnover during development
How are dendritic spines involved in plasticity
Are found on dendrites, and increase stability/ new synapse formation
Turnover very quickly
- Spines labelled with PSD-95-eGFP, and move within minutes
- in vitro, 20% of PSDs turn over in 24h in hippocampal neurons, likely to be an underestimation of in vivo
Dendritic spines are stabilised by actin which decrease length and mobility, but increase width and stability
How is actin polymerisation regulated?
Fischer 2000
AMPA and NMDA receptor activation reduces spine mobility and increases stability
Fischer 2000: selected dendritic spines with variation
Actin-eGFP imaged to investigate turnover
- NMDA receptor activation reduced mobility
- Inhibition with APV still reduced mobility (?role of AMPA)
- AMPA receptor activation reduced mobility
- Inhibition with CNQX did not affect motility
Ionic basis of actin polymerisation by AMPA/NMDA
Due to AMPA-mediated Na+ influx and NMDA mediated Ca2+ influx
-Actin polymerisation correlates strongly with Sodium molarity
Blocking Na+ channels with TTX has no effect, it is mediated by AMPA receptors
GluR2 subunit expression and spine stability
Passafaro 2003
GluR2 subunit expression associated with reduced Ca2+ permeability
- GluR2 Overexpression: Filopodia co-localised with PSD-95 were longer and more dense than controls
- N terminal domain mutation eliminated these effects
PNNs in schizophrenia
Pantazopolous 2010
Massive increases in CSPG+ glial cells in amygdalic nuceli and entorhinal cortex assc. with reductions in PNNs
-ECM-glial interactions may contribute to disturbances in neuronal migration and neurotransmission
PNNs in SCI
Lesion-dependent PNN changes may occur
- Decreases in Aggrecan, Neurocan, Phosphacan after traumatic brain injury
- Decreased Aggrecan after SC hemisection injury
Features of SCI secondary injury
Glial infiltration (microglia, astrocytes)
Cytokine upregulation
CSPG secretion from astrocytes
Factors that prevent regeneration after SCI
CSPGs
-Prevent regrowth into area, formation of dystrophic endbulbs
Semaphorin 3A (Sema3A): binds to PNNs and reduces neurite outgrowth in adult DRG cultures
Contact signalling between EphB-2 expressing fibroblasts and EphrinB2 expressing astrocytes
-Segregated following injury causing segregation
Evidence that PNNs reduce lateral mobility of Receptors
Spines labelled for GlurR1, PNNs labelled for HABP-658
GluR1 labelled areas mostly devoid of HABP (‘holes’)
Removal of PNN increased lateral mobility of GluR1 receptors on Fluorescence Loss in Photobleaching (FLIP) imaging
Chondroitinase ABC treatment in SCI
Improves neuron growth through scar, increases distal connections and fibre counts
- Improved beam walking, grid walking
- Functional recovery- pellet retrieval
- Increases neurite length following CSPG+Sema3A
Issues with chABC treatments
Breaks down all types of CSPG, include types that may be beneficial
Destroys surrounding loose ECM
May increase sprouting of normal neurons- inducing new circuitry organisation
Would require multiple injections for human use and induce a significant immune response
BDNF and Plasticity
BDNF is secreted in exercise
Has positive roles on differentiation, neurite extension, synaptic plasticity
mRNA upregulated following 7 days exercise training in the hippocampus
BDNF and Actin Polymerisation
BDNF- binds TrkB receptors which have an actin-binding cytoplasmic domain, increasing spine stability
Ca2+ influx assc. with NMDA-mediated stability also causes NF-kB activation, transcribing more BDNF- positive feedback loop
Link between exercise and Plasticity
Lungh and Sale 2015
Exercise vs. inactive control testing monocular deprivation
- Short term plasticity (measuring mean phase duration) robustly enhanced in exercise group
- May be mediated by a change in GABA inhibition, affecting excitation/inhibition balance in the visual cortex
chABC treatment and Monocular Deprivation
chABC injection into cortex
- Causes shift in Contralateral bias index (shift towards ipsilateral, non-deprived eye)
- Similar performance to as seen in the critical period compared to adults
Link protein targetting
Evidence- MD, digit innervation, NOR, memory+ age
Link protein expression controlled by Crtl1 gene
KO of Crtl1 reduces PNN formation in visual cortex on IHC
Dark rearing of animals also significantly reduced Crtl1; increased upon light
MD: contralateral bias reduced
Digit innervation: increased projection of Cholera toxin-labelled neurons from injured digit back to cuneate nucleus
NOR: Crtl1 KO mice performed better in NOR test at 24/48h
-Not improved further by chABC injection, suggesting link proteins are just as critical as CSPGs in PNNs
Age: Recovered age-associated memory deficits better in KOs
chABC in tauopathies
P301S mutants/ AAV-injected mice used as tauopathy/AD model
- chABC improved object recognition after 1 week; but returned to normal after 5
- Restored synaptic transmission changes and improved LTD in perirhinal cortex
- Did not affect tauopathy progression in terms of Western blot mRNA
Fear memory and chABC treatment
chABC in basolateral amygdala allowed erasure of fear extinction memory
