Novel modes of rhythmic burst firing at cognitively-relevant frequencies in thalamocortical neurons

Abstract

It is now widely accepted that certain types of cognitive functions are intimately related to synchronized neuronal oscillations at both low (alpha/theta) (4-7/8-13 Hz) and high (beta/gamma) (18-35/30-70 Hz) frequencies. The thalamus is a key participant in many of these oscillations, yet the cellular mechanisms by which this participation occurs are poorly understood. Here we describe how, under appropriate conditions, thalamocortical (TC) neurons from different nuclei can exhibit a wide array of largely unrecognised intrinsic oscillatory activities at a range of cognitively-relevant frequencies. For example, both metabotropic glutamate receptor (mGluR) and muscarinic Ach receptor (mAchR) activation can cause rhythmic bursting at alpha/theta frequencies. Interestingly, key differences exist between mGluR- and mAchR-induced bursting, with the former involving extensive dendritic Ca2+ electrogenesis and being mimicked by a non-specific block of K+ channels with Ba2+, whereas the latter appears to be more reliant on proximal Na+ channels and a prominent spike afterdepolarization (ADP). This likely relates to the differential somatodendritic distribution of mGluRs and mAChRs and may have important functional consequences. We also show here that in similarity to some neocortical neurons, inhibiting large-conductance Ca2+-activated K+ channels in TC neurons can lead to fast rhythmic bursting (FRB) at approximately 40 Hz. This activity also appears to rely on a Na+ channel-dependent spike ADP and may occur in vivo during natural wakefulness. Taken together, these results show that TC neurons are considerably more flexible than generally thought and strongly endorse a role for the thalamus in promoting a range of cognitively-relevant brain rhythms.

Figure 1. mGluR-activation induces HT bursting at α/θ frequencies in TC neurons

A. Top: intracellular recordings form a cat LGN TC neuron in vitro showing basic burst (left) and tonic (right) modes of firing following the injection of a brief positive current step elicited from −70 mV and −60 mV, respectively. Bottom: application of the mGluR agonist, trans-ACPD (100 μM), brings about a third mode of firing termed HT bursting. B. Whole-cell patch clamp recording from a rat VB TC neuron in vitro exhibiting HT bursting in the presence of 25 μM trans-ACPD. The underlined sections are expanded below and show HT bursting at two different levels of steady injected current as indicated. C. Top: intracellular recording of mGluR-induced HT bursting in a cat LGN TC neuron in vitro. The trace to the right is an enlargement of a single HT burst which shows evidence of dendritic Ca²⁺ spike involvement as well as small spike ADPs (see arrowheads). Bottom: following a block of action potentials with 1 μM TTX, dendritic Ca²⁺ spikes become clearly evident. D. Intracellular recording of a cat LGN TC neuron in vitro in the presence of 0.5 mM Ba²⁺ showing activity that is essentially indistinguishable from mGluR-induced HT bursting. Again, the underlined sections are expanded below and show Ba²⁺-induced bursting at two distinct levels of steady injected current as indicated.

Figure 2. HT bursting can also be instated by mAchR activation but with distinct properties to those induced by mGLuR-activation

A. Left traces: intracellular recordings from an LGN TC neuron in control conditions in vitro at different levels of steady injected current show conventional tonic firing. Right traces: following Cch application the output of the neuron at depolarized membrane potentials becomes characterised by rhythmic HT bursts. B. left traces: HT bursting in another LGN TC neuron induced by Cch application in vitro. Right traces: addition of the mAchR antagonist pirenzipine (Pzp) converts HT bursting to conventional tonic firing. The enlarged traces below reveal that mAchR-induced HT bursting is dependent on a prominent spike ADP which, unlike that present following mGluR activation (Fig.1C, top right), can drive additional action potentials. Note, however, the clear lack of involvement of dendritic Ca²⁺ spikes. Modified and reproduced from Lörincz et al. (2008) with permission.

Figure 3. The differences between mGluR- and mAchR-induced HT bursting can be explained by a distinct somatodendritic receptor distribution

Proposed scheme to explain the difference between mGluR- and mAchR-induced HT bursting. Top: mGluR1a receptors are located at distal sites, presumably close to the Ca²⁺ channels that underlie dendritic spike generation. Thus, suppression of K⁺ channels in this region facilitates the generation of Ca²⁺ spikes which then propagate to the soma where they interact with proximal Na⁺ channels to produce bursts of action potentials. Note that because the domain of influence of mGluR1a activation extends to the soma (red shaded bar), activating these receptors is able to depolarize the neuron sufficiently close to action potential threshold to facilitate bursting. Bottom: mAchRs are located at more proximal sites and are therefore unable to trigger distal Ca²⁺ spikes. However, they are ideally situated to enhance dendritic Na⁺ channel-dependent events, hence the appearance of a prominent spike ADP following activation of these receptors.

Figure 4. Inihition of BK channels leads to rhythmic bursting at ~40 Hz in TC neurons

A. Response of a TC neuron in the rat LGN in vitro to a positive current pulse in control conditions (top), following 100 nM Ibtx application (middle) and after Ibtx washout (bottom). Ibtx reversibly induces rhythmic burst firing at 30–40 Hz. In each panel, the underlined sections are enlarged below as indicated. B. A closer inspection of the response of the neuron shown in A following Ibtx application reveals that burst activity arises from the progressive build up of a spike ADP. C. Top trace: activity of a TC neuron from the cat LGN in control conditions in vitro after depolarization with steady current reveals conventional tonic firing. Bottom trace: after recording for 30 mins with 50 mM EGTA in the electrode, at the same level of injected current this neuron exhibits rhythmic burst firing at 40–50 Hz. Again, this bursting is associated with a prominent spike ADP as shown by the enlarged section below.

Figure 5. The spike ADP underlying rhythmic bursting at ~40 Hz in TC neurons is dependent on Na⁺ channels

Top trace: response of a rat LGN TC neuron in vitro to a positive current step during application of 100 nM Ibtx showing rhythmic bursting at 20–60 Hz. Middle trace: after 10 minutes of TTX treatment the neuron reverts to a pattern of single spike activity. The enlarged sections to the right show that this is due to a preferential suppression of the spike ADP by TTX. Bottom trace: after 20 minutes TTX abolished all action potential output.

Figure 6. TC neurons recorded from the LGN of naturally waking cats can exhibit brief periods of rhythmic bursting at ~50 Hz

Single unit recording of a TC neuron from the cat LGN during natural wakefulness. The underlined sections are enlarged below and reveal episodes of rhythmic bursting at 40–60 Hz.