Axons are generally considered as reliable transmission cables in which stable propagation occurs once an action potential is generated. Axon dysfunction occupies a central position in many inherited and acquired neurological disorders that affect both peripheral and central neurons. Recent findings suggest that the functional and computational repertoire of the axon is much richer than traditionally thought. Beyond classical axonal propagation, intrinsic voltage-gated ionic currents together with the geometrical properties of the axon determine several complex operations that not only control signal processing in brain circuits but also neuronal timing and synaptic efficacy. Recent evidence for the implication of these forms of axonal computation in the short-term dynamics of neuronal communication is discussed. Finally, we review how neuronal activity regulates both axon morphology and axonal function on a long-term time scale during development and adulthood.

The sorting of sodium channels to axons and the formation of clusters are of primary importance for neuronal electrogenesis. Here, we showed that the cytoplasmic loop connecting domains II and III of the Na v 1 subunit contains a determinant conferring compartmentalization in the axonal initial segment of rat hippocampal neurons. Expression of a soluble Na v 1.2II-III linker protein led to the disorganization of endogenous sodium channels. The motif was sufficient to redirect a somatodendritic potassium channel to the axonal initial segment, a process involving association with ankyrin G. Thus, this motif may play a fundamental role in controlling electrical excitability during development and plasticity.

The auxiliary beta subunit is essential for functional expression of high voltage-activated Ca2+ channels. This effect is partly mediated by a facilitation of the intracellular trafficking of alpha1 subunit toward the plasma membrane. Here, we demonstrate that the I-II loop of the alpha1 subunit contains an endoplasmic reticulum (ER) retention signal that severely restricts the plasma membrane incorporation of alpha1 subunit. Coimmunolabeling reveals that the I-II loop restricts expression of a chimera CD8-I-II protein to the ER. The beta subunit reverses the inhibition imposed by the retention signal. Extensive deletion of this retention signal in full-length alpha1 subunit facilitates the cell surface expression of the channel in the absence of beta subunit. Our data suggest that the beta subunit favors Ca2+ channel plasma membrane expression by inhibiting an expression brake contained in beta-binding alpha1 sequences.

Sodium channels posses receptor sites for many neurotoxins, of which several groups were shown to inhibit sodium current inactivation. Receptor sites that bind ␣-and ␣-like scorpion toxins are of particular interest since neurotoxin binding at these extracellular regions can affect the inactivation process at intramembranal segments of the channel. We examined, for the first time, the interaction of different scorpion neurotoxins, all affecting sodium current inactivation and toxic to mammals, with ␣-scorpion toxin receptor sites on both mammalian and insect sodium channels. As specific probes for rat and insect sodium channels, we used the radiolabeled ␣-scorpion toxins AaH II and Lqh␣IT, the most active ␣-toxins on mammals and insect, respectively. We demonstrate that the different scorpion toxins may be classified to several groups, according to their in vivo and in vitro activity on mammalian and insect sodium channels. Analysis of competitive binding interaction reveal that each group may occupy a distinct receptor site on sodium channels. The ␣-mammal scorpion toxins and the anti-insect Lqh␣IT bind to homologous but not identical receptor sites on both rat brain and insect sodium channels. Sea anemone toxin ATX II, previously considered to share receptor site 3 with ␣-scorpion toxins, is suggested to bind to a partially overlapping receptor site with both AaH II and Lqh␣IT. Competitive binding interactions with other scorpion toxins suggest the presence of a putative additional receptor site on sodium channels, which may bind a unique group of these scorpion toxins (Bom III and IV), active on both mammals and insects. We suggest the presence of a cluster of receptor sites for scorpion toxins that inhibit sodium current inactivation, which is very similar on insect and rat brain sodium channels, in spite of the structural and pharmacological differences between them. The sea anemone toxin ATX II is also suggested to bind within this cluster.

In the cortex, synaptic latencies display small variations ( approximately 1-2 ms) that are generally considered to be negligible. We show here that the synaptic latency at monosynaptically connected pairs of L5 and CA3 pyramidal neurons is determined by the presynaptic release probability (Pr): synaptic latency being inversely correlated with the amplitude of the postsynaptic current and sensitive to manipulations of Pr. Changes in synaptic latency were also observed when Pr was physiologically regulated in short- and long-term synaptic plasticity. Paired-pulse depression and facilitation were respectively associated with increased and decreased synaptic latencies. Similarly, latencies were prolonged following induction of presynaptic LTD and reduced after LTP induction. We show using the dynamic-clamp technique that the observed covariation in latency and synaptic strength is a synergistic combination that significantly affects postsynaptic spiking. In conclusion, amplitude-related variation in latency represents a putative code for short- and long-term synaptic dynamics in cortical networks.

In the mammalian brain, synaptic transmission usually depends on presynaptic action potentials (APs) in an all-or-none (or digital) manner. Recent studies suggest, however, that subthreshold depolarization in the presynaptic cell facilitates spike-evoked transmission, thus creating an analogue modulation of a digital process (or analogue–digital (AD) modulation). At most synapses, this process is slow and not ideally suited for the fast dynamics of neural networks. We show here that transmission at CA3–CA3 and L5–L5 synapses can be enhanced by brief presynaptic hyperpolarization such as an inhibitory postsynaptic potential (IPSP). Using dual soma–axon patch recordings and live imaging, we find that this hyperpolarization-induced AD facilitation (h-ADF) is due to the recovery from inactivation of Nav channels controlling AP amplitude in the axon. Incorporated in a network model, h-ADF promotes both pyramidal cell synchrony and gamma oscillations. In conclusion, cortical excitatory synapses in local circuits display hyperpolarization-induced facilitation of spike-evoked synaptic transmission that promotes network synchrony.

Synaptic transmission usually depends on action potentials (APs) in an all-or-none (digital) fashion. Recent studies indicate, however, that subthreshold presynaptic depolarization may facilitate spike-evoked transmission, thus creating an analog modulation of spike-evoked synaptic transmission, also called analog-digital (AD) synaptic facilitation. Yet, the underlying mechanisms behind this facilitation remain unclear. We show here that AD facilitation at rat CA3-CA3 synapses is time-dependent and requires long presynaptic depolarization (5-10 s) for its induction. This depolarization-induced AD facilitation (d-ADF) is blocked by the specific Kv1.1 channel blocker dendrotoxin-K. Using fast voltage-imaging of the axon, we show that somatic depolarization used for induction of d-ADF broadened the AP in the axon through inactivation of Kv1.1 channels. Somatic depolarization enhanced spike-evoked calcium signals in presynaptic terminals, but not basal calcium. In conclusion, axonal Kv1.1 channels determine glutamate release in CA3 neurons in a time-dependent manner through the control of the presynaptic spike waveform.

Non-technical summary We determined here the role of the hyperpolarization-activated cationic (h) current on the temporal organization of hippocampal activity in vitro. In CA1 pyramidal neurons the h-current has three main actions. In addition to setting intrinsic resonance frequency at ∼4 Hz, the h-current determines, through two main mechanisms, the temporal precision of action potentials evoked by excitatory postsynaptic potentials or following stimulation of inhibitory postsynaptic potentials (rebound spiking). We propose that h-channels participate in the fine tuning of oscillatory activity in hippocampal and neocortical networks.Abstract Hyperpolarization-activated cyclic nucleotide modulated current (I h ) sets resonance frequency within the θ-range (5-12 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.