Homeostasis of intrinsic excitability: making the point

Many years after the original discovery of EPSP-spike (E-S) potentiation (the component of plasticity not explained by synaptic changes; Bliss & Lomo, 1973), the investigation of changes in neuronal intrinsic excitability has been revitalized by the discovery of its mechanism in single neurons in culture and in brain slices (reviewed in Nelson & Turrigiano, 2008; Maffei & Fontanini, 2009). A paper by O’Leary et al. (2010) in a recent issue of The Jouranl of Physiology is the latest in this series. Unless processes of development, ageing and various pathological states give rise to cell growth or degeneration, the neuronal elements of brain circuits remain unchanged throughout an animal's life. During their life-long activity, neurons have to face continual changes in their environment and to adapt to them. To do so they have to find the balance between two potentially contrasting requirements, that of change through learning and that of maintaining an internal equilibrium in their activity. The biological responses are to develop long-term plasticity to adapt behaviour and to generate homeostatic changes to maintain activity within a given physiological range. Plasticity in neuronal circuits appears as persistent changes in synaptic excitation in the form of long-term potentiation (LTP) and long-term depression (LTD). Both LTP and LTD can be expressed through synaptic (Bliss & Collingridge, 1993; Malenka & Bear, 2004) and non-synaptic changes (Hansel et al. 2001; Debanne 2009), the former enhancing synaptic transmission and the latter affecting neuronal intrinsic excitability. Homeostasis in neuronal excitability, although initially less explored, can also consist of synaptic changes (called synaptic scaling) and non-synaptic changes. Plasticity and homeostasis can therefore share some basic cellular mechanisms, although critical aspects differentiate the two phenomena. One main difference is that long-term plasticity is typically induced by short spike bursts in afferent fibres and then persists indefinitely after induction. Conversely, homeostatic changes are determined by protracted changes in the average level of neuronal activity, as it occurs with protracted depolarization in vitro, and at the end of a stimulus the change should be fully reversible. However, this is hard to demonstrate with experiments in vivo, e.g. with visual deprivation, due to critical developmental windows and overlap between plastic and homeostatic processes. Another important difference is related to the source of intracellular calcium needed to trigger the changes. Long-term synaptic plasticity is usually related to glutamatergic synapses and to NMDA receptors, while homeostasis of intrinsic excitability has often been shown to depend on voltage-dependent Ca2+ channels (VDCCs). However, there are case in which the same protocol can induce both changes together (Aizenmann & Linden, 2000; Armano et al. 2000). Given these complications, a simplified system is needed to define the mechanisms of homeostasis and understand its integration with plasticity. The paper by O’Leary et al. (2010) takes an important step in this direction by investigating homeostatic changes of intrinsic excitability in hippocampal neuronal cultures. Through a classical biophysical analysis of membrane excitability, the authors provide a solid demonstration of changes in resting membrane potential and subthreshold excitability rather than in the spiking mechanism. This allows us to speculate on how this mechanism integrates with synaptic LTP or LTD. By regulating the amount of current needed to reach spike threshold, the homeostatic changes provide an equal scaling for all the synapses, while the relative weight of specific transmission lines would remain determined locally by the classical LTP and LTD mechanism. In this manner, the neuron could account for its homeostatic constraints without losing efficiency in terms of synaptic memory. LTP and LTD may themselves contribute to homeostasis through heterosynaptic plasticity (Chistiakova & Volgushev, 2009). For instance, LTP can be counterbalanced by LTD in neighbouring sites, and islets of neurons undergoing LTP can be surrounded by areas undergoing LTD (Mapelli & D’Angelo, 2007). Therefore, the mechanism discovered by O’Leary et al. (2010) is just one in a complex orchestration of counterweights needed to ensure adaptation. Another important point made by O’Leary et al. (2010) is that intrinsic excitability changes were induced by VDCCs (nifedipine-sensitive L-type channels). These channels are suitable for detecting the average firing rate and therefore providing an appropriate signal for homeostasis of intrinsic excitability. Thus, the homeostasis pathway could remain segregated from the plasticity signalling pathway, which usually depends on local activation of NMDA receptors. Among the issues raised by this paper, the most compelling seems to be the exploration of natural patterns capable of inducing the homeostatic regulation of intrinsic excitability in brain slices and in vivo. Another concerns the molecular mechanisms downstream of calcium influx, which might exploit, at least in part, microdomains different from those of LTP and LTD. It also remains to be determined whether these mechanisms can be generalized or are different in different neurons or in different functional or developmental states. Of particular interest would be to understand how plasticity and homeostasis interact in various brain pathologies, in which neuronal damage forces the resilient network to readapt its neuronal and synaptic properties.