Firing rate homeostasis is gated by sleep/wake states
Professor Gina Turrigiano, Brandeis University, USA
Homeostatic mechanisms stabilise neural circuit function by keeping firing rates (FRs) within a set-point range, but whether individual neocortical neurons regulate firing around a cell-autonomous set-point, and whether this process is restricted to certain behavioural states such as sleep or wake, is unknown. I will start by discussing the mechanisms of synaptic scaling, a form of cell-autonomous homeostatic plasticity, and the role of this plasticity in generating firing rate set-points in vivo. I will then discuss new work in which we follow the process of FR homeostasis in individual visual cortical neurons in freely behaving rodents as they cycled between sleep and wake states. When FRs are perturbed by visual deprivation, over time they returned precisely to a cell-autonomous set-point, and this restoration of firing occurred selectively during periods of active waking and was suppressed by sleep. Longer natural waking periods result in more FR homeostasis, as does artificially extending the length of waking. This exclusion of FR homeostasis from sleep raises the possibility that memory consolidation or some other sleep-dependent process is vulnerable to interference from homeostatic plasticity mechanisms.
Hebbian and homeostatic plasticity and the role of TNF-α in the visual cortex
Professor Michael Stryker, University of California, San Francisco, USA
Diversity of homeostatic and Hebbian plasticity properties in cortical neurones
Professor Kevin Fox FMedSci, Cardiff University, UK
Not all neurones are created equal when it comes to plasticity. Either by virtue of their different afferent pathways or their different synaptic receptors, neurones in different layers of the cerebral cortex show different degrees and types of synaptic plasticity. For principal neurons in the adult somatosensory cortex, layer 4 is relatively aplastic while layer 2/3 and layer 5 are highly plastic. Recent studies show that the diversity does not end there. The two major subdivisions of layer 5 pyramidal cells, regular spiking (RS) and intrinsic bursting (IB) cells also show different types of plasticity and rely on Hebbian and homeostatic mechanisms to different degrees. RS neurones show experience-dependent depression following whisker trimming, which slowly recovers homeostatically back to baseline despite the maintained deprivation. The homeostatic rebound is TNFa dependent. Potentiation of spared whisker responses is absent in these cells. In contrast, IB cells do show potentiation of spared whisker responses comprising both TNF a and a-CaMKII-autophosphorylation dependent components1. As LTP is absent in aCaMKII-autophosphorylation mutants2 and synaptic upscaling is absent in TNF a knockouts3, these findings suggest the two synaptic mechanisms are distributed differently between the two cell types. In the light of these results, we looked again at plasticity in layer 2/3. Previous studies had shown that LTP and experience-dependent potentiation are absent in the barrel cortex of aCaMKII-autophosphorylation mutants2. Our present studies show that in addition, following depression of deprived whisker responses, layer 2/3 cells show a homeostatic rebound that is prevented by a soluble TNF a scavenger. In summary, all three cortical cell types show varying degrees of TNF a dependent homeostatic plasticity, but, while layer 2/3 cells show both Hebbian depression and potentiation, in layer 5 Hebbian depression and potentiation are segregated between RS and IB cells respectively.
1. S. D. Greenhill et al. 2015. Neuron 88, 539-552.
2. N. Hardingham et al. 2003.J Neurosci 23, 4428-4436.
3. D. Stellwagen, R. C Malenka. 2006. Nature 440, 1054-1059.
Rapid homeostasis by control of inhibition
Dr Daniel Feldman, University of California, Berkeley, USA
Cortical plasticity involves both Hebbian mechanisms that alter neural tuning in response to experience, and multiple homeostatic mechanisms that maintain cortical firing rates within a stable operating regime. We have investigated the circuit and cellular mechanisms for homeostasis in response to brief sensory manipulations in whisker somatosensory cortex (S1). Whisker deprivation induces a rapid homeostatic increase in local circuit excitability in L2/3 of S1 that preserves sensory-evoked spike rates despite loss of excitatory synaptic input. This occurs within 1 day of deprivation, and precedes classical changes in receptive fields and maps. These changes do not involve synaptic scaling, but instead reflect a preferential reduction in whisker-evoked inhibition in L2/3 pyramidal cells, due to reduced activation of parvalbumin (PV) interneuron circuits. Deprivation-induced disinhibition occurs in both feedforward and recurrent inhibitory networks. Sustained deprivation drives disinhibition by reducing excitatory synaptic input to L2/3 PV neurons. In contrast, brief deprivation drives rapid disinhibition by reducing intrinsic excitability of PV neurons. This is evident in elevated spike threshold, increased spike width and damped near-threshold excitability.
These findings add to a growing body of evidence that PV interneurons are a critical nexus for homeostatic plasticity in sensory cortex. This single site of plasticity in the cortical microcircuit can control average firing rate in local cortical networks, regulate sensory gain, and gate subsequent Hebbian plasticity for reorganization of the whisker map.
Homeostatic mechanisms in the mouse visual cortex in vivo
Dr Tara Keck, University College London, UK
Homeostatic synaptic scaling is thought to occur cell-wide. We used repeated in vivo two-photon imaging in mouse visual cortex after sensory deprivation to investigate the spatial extent of synaptic scaling. We used increases in spine size as a proxy for synaptic scaling in vivo in both excitatory and inhibitory neurons and found that after sensory deprivation, increases in spine size are restricted to a subset of dendritic branches, which we confirmed using immunohistochemistry. We found that the branches that had increases in spine size also had a lower spine density. Within a given dendritic branch, the degree of spine size increases was proportional to recent spine loss within that branch. Using simulations, we showed that this compartmentalised form of synaptic scaling better retained the previously established input-output relationship in the cell.