Niraj S. Desai, Lana C. Rutherford and Gina G. Turrigiano; Department of Biology and Center for Complex Systems, Brandeis University, 415 South Street, Waltham, Massachusetts 02454-9110, USA
During learning and development, the level of synaptic input received by cortical neurons may change dramatically. Given a limited range of possible firing rates, how do neurons maintain responsiveness to both small and large synaptic inputs? We demonstrate that in response to changes in activity, cultured cortical pyramidal neurons regulate intrinsic excitability to promote stability in firing. Depriving pyramidal neurons of activity for two days increased sensitivity to current injection by selectively regulating voltage-dependent conductances. This suggests that one mechanism by which neurons maintain sensitivity to different levels of synaptic input is by altering the function relating current to firing rate. A common feature of learning and development is that the number and/or strength of a neuron’s synapses can vary substantially over time. During development, synapses are continually being formed and eliminated1, and many learning mechanisms such as long-term potentiation and depression (LTP and LTD) rely on experience-dependent modification of synaptic strengths2. As a result, the synaptic input received by a neuron may vary over time by orders of magnitude. Although such synaptic change is crucial for the formation, maintenance and proper functioning of neural circuits, it raises the question of how cortical neurons keep from falling silent or keep their firing rates from saturating if the average synaptic input falls too low or rises too high. Without a mechanism that allows a neuron to remain responsive to its input in this most basic sense, the neuron would be unable to transmit information or to participate effectively in the correlation-based synaptic modifications needed for the development and maintenance of neural circuits1. Several possible solutions to this problem have been proposed3,4. Among these are the ideas that the ability of a synapse to undergo Hebbian modification depends upon its history of use5–7, and that global mechanisms stabilize neuronal activity by regulating either the total synaptic strength8–11 or the intrinsic excitability4,12 of a neuron. In keeping with the latter two ideas, recent studies on cortical neurons have shown that cortical firing rates are regulated by activity in a homeostatic manner10,13– 15. This is accomplished in part by scaling the strength of excitatory synapses up or down as a function of activity10, but the question of whether changes in intrinsic excitability also contribute to this homeostatic regulation of firing rates has not been addressed. The dynamics of neural circuits arise through a complex interplay between synaptic inputs and the intrinsic electrical properties of individual neurons, and the magnitude and distribution of ionic conductances can influence processes as diverse as synaptic integration16,17, the pattern and rate of firing18 and synaptic plasticity19,20. Recent experimental work on both invertebrate and vertebrate preparations has suggested that activity is important in modulating intrinsic neuronal excitability18,21–26. In invertebrate preparations, activity can switch neurons between tonic firing and burst firing modes by regulating the balance of inward and outward currents18, and in a variety of preparations, activity is important in regulating the magnitude of individual ionic conductances18,21–26. We asked whether long-lasting changes in activity influence the intrinsic excitability of cortical neurons, and whether this regulation is consistent with a role in stabilizing firing rates. We found that preventing cortical neurons from firing for two days dramatically increased their intrinsic excitability. In response to injected current, activity-deprived neurons fired much more rapidly and did so in response to smaller current injections. This increase in excitability was mediated by selective regulation of the magnitudes of sodium and persistent potassium currents; the former increased, whereas the latter decreased. These findings demonstrate that the history of activity of a cortical neuron helps to determine its intrinsic excitability. This may allow a neuron to adjust the way it transduces synaptic input to maintain its responsiveness during periods of intense change in synapse number and strength.
RESULTS
We used primary cell cultures of postnatal rat visual cortical neurons to examine effects of long-lasting changes in activity on the intrinsic electrical properties of pyramidal neurons. Over time in vitro, neurons in these cultures form excitatory and inhibitory synaptic connections and develop spontaneous activity driven by synaptic input10,13,14. Recordings were obtained after 7–9 days in vitro. To block spontaneous activity in test cultures, cultures were incubated with the sodium channel blocker tetrodotoxin (TTX). Except where noted, the duration of the activity blockade was 48 hours. The TTX was then washed out, and whole-cell patch recordings were obtained from pyramidal neurons in both treated and sister control cultures.
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