The hyperpolarization-activated cation current (Ih) plays an important role in determining membrane potential and firing characteristics of neurons and therefore is a potential target for regulation of intrinsic excitability. Here we show that an increase in AMPAreceptor-dependent synaptic activity induced by ␣-latrotoxin or glutamate application as well as direct depolarization results in an increase in I h recorded from cell-attached patches in hippocampal CA1 pyramidal neurons. This mechanism requires Ca 2؉ influx but not increased levels of cAMP. Artificially increasing I h by using a dynamic clamp during whole-cell current clamp recordings results in reduced firing rates in response to depolarizing current injections. We conclude that modulation of somatic I h represents a previously uncharacterized mechanism of homeostatic plasticity, allowing a neuron to control its excitability in response to changes in synaptic activity on a relatively short-term time scale.T he intrinsic excitability of neurons determines the translation from synaptic input to axonal output. Regulation of intrinsic excitability may therefore constitute a form of cellular plasticity that controls the dynamic range of the input-output relationship. Such a mechanism of cellular plasticity may exist in parallel to synapse-specific mechanisms of plasticity like long-term potentiation and long-term depression. There is increasing evidence for the existence of mechanisms of plasticity that are not synapse-specific but act at the cellular level (1-3). Long-lasting changes in synaptic activity over several days have been shown to modulate the intrinsic voltage-gated ionic conductances that shape neuronal firing patterns (4-6). Modulation of voltagegated conductances occurring at a time scale of hours has also been reported (7,8). However, under physiological conditions, where the level of synaptic activity can change quickly, modulation of somatic voltage-gated conductances may be a potent mechanism to regulate excitability. It is unknown, however, whether such a mechanism of plasticity exists on a relatively short-term time scale.Hyperpolarization-activated cation channels (I h ) are a subset of voltage-gated channels that are important in determining intrinsic excitability. I h channels, which are permeable to both Na ϩ and K ϩ ions, operate in the subthreshold voltage range where they influence membrane potential, firing threshold, and firing patterns, as well as synaptic integration (9-14). Here we show that somatic I h channels in rat hippocampal CA1 pyramidal neurons are subject to modulation by an enhancement of synaptic activity on a time scale of tens of minutes and that this modulation reduces the excitability of these neurons. MethodsSlice Preparation and Electrophysiology. Parasaggital hippocampal slices (250 m) were prepared from 14-to 28-day-old male Wistar rats (Harlan, Zeist, The Netherlands). Experiments were conducted according to the ethics committee guidelines for animal experimentation of the University of Amsterdam. After ...

Pyramidal neurons in the subiculum typically display either bursting or regular-spiking behaviour. Although this classification into two neuronal classes is well described, it is unknown how these two classes of neurons contribute to the integration of input to the subiculum. Here, we report that bursting neurons posses a hyperpolarization-activated cation current (I h ) that is two-fold larger (conductance, 5.3 ± 0.5 nS) than in regular-spiking neurons (2.2 ± 0.6 nS), whereas I h exhibits similar voltage-dependent and kinetic properties in both classes of neurons. Bursting and regular-spiking neurons display similar morphology. The difference in I h between the two classes of neurons is not responsible for the distinct firing patterns, as neither pharmacological blockade of I h nor enhancement of I h using a dynamic clamp affects the qualitative firing patterns. Instead, the difference in I h between bursting and regular-spiking neurons determines the temporal integration of evoked synaptic input from the CA1 area. In response to stimulation at 50 Hz, bursting neurons, with a large I h , show ∼50% less temporal summation than regular-spiking neurons. The amount of temporal summation in both neuronal classes is equal after pharmacological blockade of I h . A computer simulation model of a subicular neuron with the properties of either a bursting or a regular-spiking neuron confirmed the pivotal role of I h in temporal integration of synaptic input. These data suggest that in the subicular network, bursting neurons are better suited to discriminate the content of highfrequency input, such as that occurring during gamma oscillations, than regular-spiking neurons.

SummaryMany GABAergic interneurons are electrically coupled and in vitro can display correlated activity with millisecond precision. However, the mechanisms underlying correlated activity between interneurons in vivo are unknown. Using dual patch-clamp recordings in vivo, we reveal that in the presence of spontaneous background synaptic activity, electrically coupled cerebellar Golgi cells exhibit robust millisecond precision-correlated activity which is enhanced by sensory stimulation. This precisely correlated activity results from the cooperative action of two mechanisms. First, electrical coupling ensures slow subthreshold membrane potential correlations by equalizing membrane potential fluctuations, such that coupled neurons tend to approach action potential threshold together. Second, fast spike-triggered spikelets transmitted through gap junctions conditionally trigger postjunctional spikes, depending on both neurons being close to threshold. Electrical coupling therefore controls the temporal precision and degree of both spontaneous and sensory-evoked correlated activity between interneurons, by the cooperative effects of shared synaptic depolarization and spikelet transmission.

van Welie I, du Lac S. Bidirectional control of BK channel open probability by CAMKII and PKC in medial vestibular nucleus neurons. J Neurophysiol 105: 1651-1659, 2011. First published February 9, 2011 doi:10.1152/jn.00058.2011.-Large conductance K ϩ (BK) channels are a key determinant of neuronal excitability. Medial vestibular nucleus (MVN) neurons regulate eye movements to ensure image stabilization during head movement, and changes in their intrinsic excitability may play a critical role in plasticity of the vestibulo-ocular reflex. Plasticity of intrinsic excitability in MVN neurons is mediated by kinases, and BK channels influence excitability, but whether endogenous BK channels are directly modulated by kinases is unknown. Double somatic patch-clamp recordings from MVN neurons revealed large conductance potassium channel openings during spontaneous action potential firing. These channels displayed Ca 2ϩ and voltage dependence in excised patches, identifying them as BK channels. Recording isolated single channel currents at physiological temperature revealed a novel kinase-mediated bidirectional control in the range of voltages over which BK channels are activated. Application of activated Ca 2ϩ /calmodulin-dependent kinase II (CAMKII) increased BK channel open probability by shifting the voltage activation range towards more hyperpolarized potentials. An opposite shift in BK channel open probability was revealed by inhibition of phosphatases and was occluded by blockade of protein kinase C (PKC), suggesting that active PKC associated with BK channel complexes in patches was responsible for this effect. Accordingly, direct activation of endogenous PKC by PMA induced a decrease in BK open probability. BK channel activity affects excitability in MVN neurons and bidirectional control of BK channels by CAMKII, and PKC suggests that cellular signaling cascades engaged during plasticity may dynamically control excitability by regulating BK channel open probability. phosphorylation; firing rate potentiation; vestibulo-ocular reflex; vestibular nucleus; calmodulin-dependent kinase II; protein kinase C; large conductance potassium channels PLASTICITY IN NEURONAL SPIKE output can occur via changes in synaptic strength but also via modulation of intrinsic excitability [for reviews, see Daoudal and Debanne (2003)