Size-Dependent Axonal Bouton Dynamics following Visual Deprivation In Vivo

Persistent synapses are thought to underpin the storage of sensory experience, yet little is known about their structural plasticity in vivo. We investigated how persistent presynaptic structures respond to the loss of primary sensory input. Using in vivo two-photon (2P) imaging, we measured fluctuations in the size of excitatory axonal boutons in L2/3 of adult mouse visual cortex after monocular enucleation. The average size of boutons did not change after deprivation, but the range of bouton sizes was reduced. Large boutons decreased, and small boutons increased. Reduced bouton variance was accompanied by a reduced range of correlated calcium-mediated neural activity in L2/3 of awake animals. Network simulations predicted that size-dependent plasticity may promote conditions of greater bidirectional plasticity. These predictions were supported by electrophysiological measures of short- and long-term plasticity. We propose size-dependent dynamics facilitate cortical reorganization by maximizing the potential for bidirectional plasticity

Subnetwork-Specific Homeostatic Plasticity in Mouse Visual Cortex In Vivo

SummaryHomeostatic regulation has been shown to restore cortical activity in vivo following sensory deprivation, but it is unclear whether this recovery is uniform across all cells or specific to a subset of the network. To address this issue, we used chronic calcium imaging in behaving adult mice to examine the activity of individual excitatory and inhibitory neurons in the same region of the layer 2/3 monocular visual cortex following enucleation. We found that only a fraction of excitatory neurons homeostatically recover activity after deprivation and inhibitory neurons show no recovery. Prior to deprivation, excitatory cells that did recover were more likely to have significantly correlated activity with other recovering excitatory neurons, thus forming a subnetwork of recovering neurons. These network level changes are accompanied by a reduction in synaptic inhibition onto all excitatory neurons, suggesting that both synaptic mechanisms and subnetwork activity are important for homeostatic recovery of activity after deprivation

Calcineurin signaling mediates activity-dependent relocation of the axon initial segment

The axon initial segment (AIS) is a specialised neuronal sub-compartment located at the beginning of the axon that is crucially involved in both the generation of action potentials and in the regulation of neuronal polarity. We recently showed that prolonged neuronal depolarisation produces a distal shift of the entire AIS structure away from the cell body, a change associated with a decrease in neuronal excitability. Here, we utilised dissociated rat hippocampal cultures, with a major focus on the dentate granule cell (DGC) population, to explore the signalling pathways underlying activity-dependent relocation of the AIS. Firstly, a pharmacological screen of voltage-gated calcium channels (VGCCs) showed that AIS relocation is triggered by activation of L-type Ca(v)1 VGCCs with negligible contribution from any other VGCC subtypes. Further pharmacological analysis revealed that downstream signalling events are mediated by the calcium-sensitive phosphatase calcineurin; inhibition of calcineurin with either FK506 or cyclosporin A totally abolished both depolarisation- and optogenetically-induced activity-dependent AIS relocation. Furthermore, calcineurin activation is sufficient for AIS plasticity, as expression of a constitutively active form of the phosphatase resulted in relocation of the AIS of DGCs without a depolarising stimulus. Finally, we assessed the role of calcineurin in other forms of depolarisation-induced plasticity. Neither membrane resistance changes nor spine density changes were affected by FK506 treatment, suggesting that calcineurin acts via a separate pathway to modulate AIS plasticity. Taken together, these results emphasise calcineurin as a vital player in the regulation of intrinsic plasticity as governed by the AIS