The Low Threshold Calcium Spike: A Unique Global Cellular Signal

The low threshold calcium spike (LTS), first described by Per Andersen and John Eccles, is a distinctive hallmark of thalamocortical (TC) and thalamic reticular nucleus (TRN) neurons. Although, as a result of numerous elegant studies, it has been known for a number of years that LTS depend on T-type voltage gated calcium channels (T VGCC) the precise mechanism underlying the ability of these neurons to produce LTS has remained unknown. Previous work, including our own (Errington et al., 2010, 2012) suggested that much of the T-conductance underlying the LTS was found in the dendrites of TC and TRN neurons. Therefore we asked the question: how do these dendritic T channels produce the LTS? If T VGCC are located in the dendrites it is logical to predict that LTS might be initiated locally in the dendrites before spreading to the soma as occurs with voltage gated calcium channel dependent spikes in the apical dendrite of cortical pyramidal neurons. On the other hand, action potentials, mediated by voltage gated sodium channels, typically initiate in the axon initial segment close to the soma before backpropagating either actively or passively into the dendritic tree. The answer to this question could only be obtained by recording the membrane potential in the dendrites of TC and TRN neurons during the LTS. By targeting dendrites using 2-photon fluorescence, we were able, for the first time, to make recordings directly from the thin (see above) dendrites of TC neurons (up to the tip ~ 160 um) and TRN (up to 200 um from the soma). Overcoming this technical challenge has opened up a new understanding of the function of thalamic dendrites.ltsanimationTS

Simulation of the somatic and dendritic membrane potential during a low threshold spike in a thalamocortical neuron (in the absence of sodium conductance).

We found that, rather than having a focal initiation zone, LTS are generated as a whole cell spike that requires the concerted activation of T VGCC throughout the dendritic tree. This is made possible by the fact that TC and TRN neurons are very electrontonically compact so that the entire dendritic tree can be simultaneously depolarized with little difference between voltage amplitude and phase in different cellular compartments. To test a number of predictions arising from our work we used the Neuron simulation environment to produce a multi-compartmental model of a dorsal lateral geniculate thalamocortical neuron. This model was based on new data obtained by performing dendritic patch clamp recordings and  accurately reproduces the firing and synaptic integration properties of thalamocortical neurons. The model was used in our papers published in The Journal of Neuroscience (Connelly et al., 2015, 2016) and can be found at the ModelDB repository. Consistent with our dendritic recording and calcium imaging data a uniform distribution of T VGCC throughout the dendritic tree reproduced in our model TC neuron produced the firing and dendritic voltage and calcium transients observed experimentally. The global nature of the LTS is apparent in the animation above which shows a simulated LTS in our model (in the absence of sodium conductance).AP_slowanimation_newTS

Simulation of the somatic and dendritic membrane potential during a tonic action potential in a thalamocortical neuron (slowed down relative to the LTS above).

In the thalamus, the firing of LTS is strongly associated with the behavioural state and LTS are much more frequently observed during states of low-vigilance and most regularly during non-REM sleep where the occur rhythmically and play a major role in generation of key brain EEG rhythms including slow waves, delta oscillations and sleep spindles.