Analog signalling in mammalian cortical axons

doi:10.1016/j.conb.2008.08.006

Current Opinion in Neurobiology

Volume 18, Issue 3, June 2008, Pages 314-320

https://doi.org/10.1016/j.conb.2008.08.006 Get rights and content

In the mammalian cortex, the classic view assumes that the output information of a neuron is encoded in rather stereotyped action potentials, which provide an all-or-none or digital way of communication between cell body and axonal boutons. A role for subthreshold signal propagation within cortical axons has largely been ignored. Recent achievements of direct recordings from axonal structures in the hippocampus and neocortex extended the classic view by the observation that subthreshold-graded signals propagate down the axon over distances of up to 1 mm. At certain synapses, these analog axonal signals modulate action-potential-dependent transmitter release, thereby enabling a hybrid code of information transmission in local cortical circuits.

Introduction

The rate of information transfer at graded synapses — synapses translating presynaptic analog membrane potential fluctuations into graded tonic transmitter release — seems to be significantly higher than at synapses using presynaptic spike train coding [1, 2]. Although subthreshold electrical signals are decremental (as their conduction is largely passive), axons in small invertebrates propagate subthreshold analog signals over distances of several millimeters [3]. In mammals, analog signalling is the prevailing mode of information processing in somato-dendritic domains of neurons, whereas information transmission to postsynaptic neurons requires conversion of analog signals in axons into all-or-none action potentials, except certain sensory receptor cells using graded tonic transmitter release [4]. Although most of the synapses in the mammalian cerebral cortex are formed by nonmyelinated axon collaterals within less than a millimeter [5], the relevance of additional axonal analog signalling remained unexplored, mainly because of the electrophysiological inaccessibility of the thin mammalian cortical axons.

This review focuses on the recent discovery that analog axonal signalling plays an unexpected and significant role in information transmission in local cortical networks [6••, 7••]. It describes the results obtained in two preparations: the hippocampal mossy fiber and the neocortical layer 5 pyramidal cell axon. These cortical axons are adapted to propagate analog signals, which are generated as subthreshold membrane potential fluctuations in the dendrites of neurons, down the axon to presynaptic terminals. Cortical synapses do not act as graded potential synapses transmitting analog information directly to the postsynaptic cell, rather the analog signal modulates action-potential-dependent transmitter release. The combination of axonal analog and all-or-none signal propagation and modulation of transmitter release establishes a hybrid code of information transmission between cortical neurons [8]. The differences concerning the underlying mechanisms in the two preparations will also be described.

Section snippets

Preparations to study axonal signalling in the mammalian cortex

In the early 1990s, the invention of direct patch-clamp recordings from neocortical pyramidal dendrites in acute brain slices by Stuart et al. [9] represented a milestone for investigations of dendritic signalling and integration. Similarly, in the past few years direct recordings from axonal structures have been achieved in two areas of the cortex. First, in the hippocampus, direct recordings from presynaptic terminals of the mossy fiber, which connects the dentate gyrus granule cells with the

Active properties of mammalian cortical axons

Direct axonal recordings from either en-passant boutons or axonal blebs revealed that distal axonal action potentials in the hippocampus and neocortex are overshooting in amplitude and brief in duration at physiological temperatures (∼300 μs duration at half of the amplitude [7••, 10•, 12•]) similar to action potentials at the node of Ranvier in peripheral nerve fiber preparations (∼300 μs at 37 °C [14]), indicating the high density of voltage-gated sodium and potassium channels in cortical axons [

Analog signal propagation in mammalian cortical axons

The direct recording technique from cortical axons has led to the seminal observation that in addition to action potentials subthreshold (analog) signals passively propagate along the axon over substantial distances (∼1 mm). This has been shown first in mossy fibers by detecting subthreshold transient potential changes in distal axonal recordings with amplitude variations depending on stimulation intensity of synaptic inputs to dentate gyrus granule cell dendrites [6^••] (Figure 1a). A very

Hybrid code of information transmission by dual axonal signalling

Does dual axonal propagation of analog signals and action potentials affect synaptic transmission? Simultaneous recordings from presynaptic and postsynaptic elements at the mossy fiber–CA3 pyramidal neuron synapse (Figure 2a) showed that transient depolarizations as observed in MFBs upon activation of synapses at the dendrites of the granule cell fail to elicit transmitter release per se (Figure 2b). However, action-potential-evoked transmitter release is markedly enhanced when a transient

Mechanisms underlying hybrid information transmission

A primary mechanism underlying hybrid information transmission could be a direct interaction of the subthreshold signal with the shape of the axonal action potential. A reduction in action potential amplitude by inactivation of voltage-gated sodium channels would decrease transmitter release by less efficient activation of presynaptic voltage-gated calcium channels. This would lead to a reduced presynaptic calcium signal and thereby reduce transmitter release [15, 28], whereas broadening of the

Conclusions

The achievement to record directly from en-passant boutons and axonal blebs has advanced the research area of axonal electrical signalling in the hippocampus and neocortex. It has allowed us to gain new insights concerning density, properties and distribution of voltage-gated channels as well as the generation and properties of axonal action potentials.

The most surprising discovery, however, was the dual axonal signalling of analog signals and action potentials from the soma to presynaptic

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

This work was supported by the Hertie-Foundation and the Max-Planck-Society.

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These studies showed that beyond the digital component of the AP, as an all or none phenomenon, there is an important analog component to the AP that is its morphology (waveform), which modulates the synaptic transmission, subsequently affecting the postsynaptic reponse. This analogous component of the AP waveform is governed by the level of subthreshold potential of the axon upon the AP is conducted [32,53–55]. Given that the spike-dependent neurotransmitter release is highly dependent on presynaptic calcium concentration, the relationship between calcium and neurotransmitter release is extremely nonlinear (a power-law relationship of 3rd to 5th between calcium concentration and exocytosis) [17,19,20].
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Increasing evidence shows, however, that the shape of the presynaptic action potential can be modulated which in turn modifies the neurotransmitter release. It led to the emergence of the concept of hybrid Analog-Digital modulation of synaptic transmission in mammalian axons in which the shape of the action potential considered as a digital signal is modulated by the analog context in which it is triggered [13–16]. Moreover, the presynaptic voltage-gated Ca2+ channels (Cav) opening is steeply dependent on action potential waveform [17] and, at both glutamatergic and GABAergic terminals, vesicle fusion is supralinearly dependent on Ca2+ entry [18,19•].
Axons link distant brain regions and are usually considered as simple transmission cables in which reliable propagation occurs once an action potential has been generated. Safe propagation of action potentials relies on specific ion channel expression at strategic points of the axon such as nodes of Ranvier or axonal branch points. However, while action potentials are generally considered as the quantum of neuronal information, their signaling is not entirely digital. In fact, both their shape and their conduction speed have been shown to be modulated by activity, leading to regulations of synaptic latency and synaptic strength. We report here newly identified mechanisms of (1) safe spike propagation along the axon, (2) compartmentalization of action potential shape in the axon, (3) analog modulation of spike-evoked synaptic transmission and (4) alteration in conduction time after persistent regulation of axon morphology in central neurons. We discuss the contribution of these regulations in information processing.
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In the mammalian cortex, axons are highly ramified and link an enormous number of neurons over large distances. The conventional view assumes that action potentials (APs) are initiated at the axon initial segment in an all-or-none fashion and are then self-propagated orthodromically along axon collaterals without distortion of the AP waveform. By contrast, recent experimental results suggest that the axonal AP waveform can be modified depending on the activation states of the ion channels and receptors on axonal cell membranes. This AP modulation can regulate neurotransmission to postsynaptic neurons. In addition, the latest studies have provided evidence that cortical axons can integrate somatic burst firings and promote activity-dependent ectopic AP generation, which may underlie the oscillogenesis of fast rhythmic network activity. These seminal observations indicate that axons can perform diverse functional operations that extend beyond the prevailing model of axon physiology.
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View full text

Analog signalling in mammalian cortical axons

Introduction

Section snippets

Preparations to study axonal signalling in the mammalian cortex

Active properties of mammalian cortical axons

Analog signal propagation in mammalian cortical axons

Hybrid code of information transmission by dual axonal signalling

Mechanisms underlying hybrid information transmission

Conclusions

References and recommended reading

Acknowledgements

TINS

Neuron

Neuron

Neuron

J Neurosci

Brain Res

J Neurosci

Nat Neurosci

The rate of information transfer at graded-potential synapses

Nature

Information theory and neural coding

Nat Neurosci

Impulse-coded and analog signalling in single mechanoreceptor neurons

Science

Recurrent excitation in neocortical circuits

Science

Combined analog and action potential coding in hippocampal mossy fibers

Science

Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential

Nature

Neural coding: hybrid analog and digital signalling in axons

Curr Biol

Patch-clamp recordings from the soma and dendrites of neurons in brain slices using infrared video microscopy

Pflügers Arch