Homeostatic regulation of h-conductance controls intrinsic excitability and stabilizes the threshold for synaptic modification in CA1 neurons.

KEY POINTS: We determined the contribution of the hyperpolarization-activated cationic (h) current (Ih ) to the homeostatic regulation of CA1 pyramidal cells in vitro using chronic treatments (48 h) that either increase (picrotoxin) or decrease (kynurenate) neuronal activity. The h-conductance was found to be up- or down-regulated following chronic activity enhancement or activity deprivation, respectively. This bidirectional plasticity of Ih was found to subsequently alter both apparent input resistance and intrinsic neuronal excitability. Bidirectional homeostatic plasticity of Ih also determined EPSP waveform and EPSP summation tested at 5-30 Hz. Long-term synaptic modification induced by repetitive stimulation of the Schaffer collaterals was found to be constant across treatments in the presence of Ih but not when Ih was blocked pharmacologically. Thus, bidirectional homeostatic regulation of Ih stabilizes induction of long-term synaptic modification in CA1 pyramidal neurons that depends on EPSP summation. ABSTRACT: The hyperpolarization-activated cationic (h) current is a voltage-shock absorber, highly expressed in the dendrites of CA1 pyramidal neurons. Up-regulation of Ih has been reported following episodes of intense network activity but the effect of activity deprivation on Ih and the functional consequence of homeostatic regulation of Ih remain unclear. We determined here the contribution of Ih to the homeostatic regulation of CA1 pyramidal cell excitability. Intrinsic neuronal excitability was decreased in neurons treated for 2-3 days with the GABAA channel blocker picrotoxin (PiTx) but increased in neurons treated (2-3 days) with the glutamate receptor antagonist kynurenate (Kyn). Membrane capacitance remained unchanged after treatment but the apparent input resistance was reduced for PiTx-treated neurons and enhanced for Kyn-treated neurons. Maximal Ih conductance was up-regulated after chronic hyperactivity but down-regulated following chronic hypoactivity. Up-regulation of Ih in PiTx-treated cultures was found to accelerate EPSP kinetics and reduce temporal summation of EPSPs whereas opposite effects were observed in Kyn-treated cultures, indicating that homeostatic regulation of Ih may control the induction of synaptic modification depending on EPSP summation. In fact, stimulation of the Schaffer collaterals at 3-10 Hz induced differential levels of plasticity in PiTx-treated and Kyn-treated neurons when Ih was blocked pharmacologically but not in control conditions. These data indicate that homeostatic regulation of Ih normalizes the threshold for long-term synaptic modification that depends on EPSP summation. In conclusion, bidirectional homeostatic regulation of Ih not only controls spiking activity but also stabilizes the threshold for long-term potentiation induced in CA1 pyramidal neurons by repetitive stimulation.

Membrane potential dynamics of excitatory and inhibitory neurons in mouse barrel cortex during active whisker sensing.

Neocortical neurons can increasingly be divided into well-defined classes, but their activity patterns during quantified behavior remain to be fully determined. Here, we obtained membrane potential recordings from various classes of excitatory and inhibitory neurons located across different cortical depths in the primary whisker somatosensory barrel cortex of awake head-restrained mice during quiet wakefulness, free whisking and active touch. Excitatory neurons, especially those located superficially, were hyperpolarized with low action potential firing rates relative to inhibitory neurons. Parvalbumin-expressing inhibitory neurons on average fired at the highest rates, responding strongly and rapidly to whisker touch. Vasoactive intestinal peptide-expressing inhibitory neurons were excited during whisking, but responded to active touch only after a delay. Somatostatin-expressing inhibitory neurons had the smallest membrane potential fluctuations and exhibited hyperpolarising responses at whisking onset for superficial, but not deep, neurons. Interestingly, rapid repetitive whisker touch evoked excitatory responses in somatostatin-expressing inhibitory neurons, but not when the intercontact interval was long. Our analyses suggest that distinct genetically-defined classes of neurons at different subpial depths have differential activity patterns depending upon behavioral state providing a basis for constraining future computational models of neocortical function.

The role of hyperpolarization-activated cationic current in spike-time precision and intrinsic resonance in cortical neurons in vitro.

Hyperpolarization-activated cyclic nucleotide modulated current (I(h)) sets resonance frequency within the θ-range (5­12 Hz) in pyramidal neurons. However, its precise contribution to the temporal fidelity of spike generation in response to stimulation of excitatory or inhibitory synapses remains unclear. In conditions where pharmacological blockade of I(h) does not affect synaptic transmission, we show that postsynaptic h-channels improve spike time precision in CA1 pyramidal neurons through two main mechanisms. I(h) enhances precision of excitatory postsynaptic potential (EPSP)--spike coupling because I(h) reduces peak EPSP duration. I(h) improves the precision of rebound spiking following inhibitory postsynaptic potentials (IPSPs) in CA1 pyramidal neurons and sets pacemaker activity in stratum oriens interneurons because I(h) accelerates the decay of both IPSPs and after-hyperpolarizing potentials (AHPs). The contribution of h-channels to intrinsic resonance and EPSP waveform was comparatively much smaller in CA3 pyramidal neurons. Our results indicate that the elementary mechanisms by which postsynaptic h-channels control fidelity of spike timing at the scale of individual neurons may account for the decreased theta-activity observed in hippocampal and neocortical networks when h-channel activity is pharmacologically reduced.

Cell-type-specific nicotinic input disinhibits mouse barrel cortex during active sensing.

Fast synaptic transmission relies upon the activation of ionotropic receptors by neurotransmitter release to evoke postsynaptic potentials. Glutamate and GABA play dominant roles in driving highly dynamic activity in synaptically connected neuronal circuits, but ionotropic receptors for other neurotransmitters are also expressed in the neocortex, including nicotinic receptors, which are non-selective cation channels gated by acetylcholine. To study the function of non-glutamatergic excitation in neocortex, we used two-photon microscopy to target whole-cell membrane potential recordings to different types of genetically defined neurons in layer 2/3 of primary somatosensory barrel cortex in awake head-restrained mice combined with pharmacological and optogenetic manipulations. Here, we report a prominent nicotinic input, which selectively depolarizes a subtype of GABAergic neuron expressing vasoactive intestinal peptide leading to disinhibition during active sensorimotor processing. Nicotinic disinhibition of somatosensory cortex during active sensing might contribute importantly to integration of top-down and motor-related signals necessary for tactile perception and learning.

Plasticity of intrinsic excitability during LTD is mediated by bidirectional changes in h-channel activity.

The polarity of excitability changes associated with induction of Long-Term synaptic Depression (LTD) in CA1 pyramidal neurons is a contentious issue. Postsynaptic neuronal excitability after LTD induction is found to be reduced in certain cases (i.e. synergistic changes) but enhanced in others (i.e. compensatory or homeostatic). We examined here whether these divergent findings could result from the activation of two separate mechanisms converging onto a single learning rule linking synergistic and homeostatic plasticity. We show that the magnitude of LTD induced with low frequency stimulation (LFS) of the Schaffer collaterals determines the polarity of intrinsic changes in CA1 pyramidal neurons. Apparent input resistance (Rin) is reduced following induction of moderate LTD (<20-30%). In contrast, Rin is increased after induction of large LTD (>40%) induced by repetitive episodes of LFS. The up-regulation of I h observed after moderate LTD results from the activation of NMDA receptors whereas the down-regulation of I h is due to activation of mGluR1 receptors. These changes in Rin were associated with changes in intrinsic excitability. In conclusion, our study indicates that changes in excitability after LTD induction follow a learning rule describing a continuum linking synergistic and compensatory changes in excitability.

Enhanced intrinsic excitability in basket cells maintains excitatory-inhibitory balance in hippocampal circuits.

The dynamics of inhibitory circuits in the cortex is thought to rely mainly on synaptic modifications. We challenge this view by showing that hippocampal parvalbumin-positive basket cells (PV-BCs) of the CA1 region express long-term (>30 min) potentiation of intrinsic neuronal excitability (LTP-IE(PV-BC)) upon brief repetitive stimulation of the Schaffer collaterals. LTP-IE(PV-BC) is induced by synaptic activation of metabotropic glutamate receptor subtype 5 (mGluR5) and mediated by the downregulation of Kv1 channel activity. LTP-IE(PV-BC) promotes spiking activity at the gamma frequency (∼35 Hz) and facilitates recruitment of PV-BCs to balance synaptic and intrinsic excitation in pyramidal neurons. In conclusion, activity-dependent modulation of intrinsic neuronal excitability in PV-BCs maintains excitatory-inhibitory balance and thus plays a major role in the dynamics of hippocampal circuits.