Editorial
Editorial
- M. Steriade
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- Published online by Cambridge University Press:
- 12 April 2006, p. 1
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Research Article
Interactions of synaptic and intrinsic electroresponsiveness determine corticothalamic activation dynamics
- Christine M. Pedroarena, Rodolfo Llinás
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- 12 April 2006, pp. 3-14
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The interaction between cortical input frequency and intrinsic thalamic neuron (TN) properties were investigated using intracellular recordings from mice TNs in thalamocortical (TC) slices. Excitatory postsynaptic potentials (EPSPs) of corticothalamic (CT) origin were recorded at TN membrane potentials (Vm) held, by current clamp means, between −59 and −55 mV to avoid low-threshold calcium currents (IT) activation. EPSPs elicited in ventrobasal neurons (n = 25) by stimulation in the internal capsule showed constant latency, relatively fast rise time (2.9 ± 0.56 ms) and short duration (26.6 ± 9.11 ms). EPSPs evoked by threshold stimulation (n = 10) showed similar characteristics (mean rise time, 2.74 ± 0.42 ms; mean duration, 30 ± 8.00 ms). The time course of CT synaptic facilitation was determined using pairs of stimuli. Paired-pulse facilitation (PPF) of CT EPSPs peaked at 25–30 ms stimulus intervals and decayed exponentially with an average time constant of 130 ms (n = 50). Application of the NMDA receptor blocker APV (25 μM, n = 4) did not modify PPF for any interstimulus interval studied but suppressed frequency facilitation evoked by trains of CT stimuli. We compared the number of spikes per stimulus (Fs) evoked in TNs by repetitive CT stimulation over a range of frequencies at different Vm. At hyperpolarized Vm (below −65 mV) and frequencies of stimulation ≥ 10 Hz, Fs decreased along the train while at depolarized Vm (above −59 mV) Fs increased along the train. Decremental patterns resulted from the activation of IT while facilitatory patterns emerged from superposition of synaptic and intrinsic mechanisms. At hyperpolarized Vm, steady-state Fs was maximal for frequencies ≤ 2 Hz, intermediate for frequencies between 2 and 10 Hz and zero at ≥ 10 Hz. At depolarized Vm, steady-state Fs increased with increasing frequencies (from 1 to 40 Hz).
We conclude that the CT–TN junctions are tuned to establish stable thalamocortical resonant dynamics.
Differentiation of corticothalamic and collateral thalamocortical synapses on mouse reticular nucleus neurons by EPSC amplitude and AMPA receptor subunit composition
- Xiao-Bo Liu, Sonia Bolea, Peyman Golshani, Edward G. Jones
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- 12 April 2006, pp. 15-29
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AMPA receptors mediate fast synaptic transmission at collateral synapses of corticothalamic and thalamocortical axons in the thalamic reticular nucleus (RTN). These synapses are important in generating synchrony in the thalamocortical network. Whole cell recording in the mouse thalamocortical slice preparation was combined with high-resolution immunoelectron microscopy to characterize AMPA-mediated conductances at the two synapses and to correlate these with differential expression of GluR3 and GluR4 subunits. Thalamocortical collateral (TC) synapses had larger mean EPSC amplitudes (1914 ± 1814pS) than corticothalamic (CT) synapses (400 ± 257 pS), and rise and decay times of TC EPSCs were faster and less variable than CT EPSCs, probably reflecting proximal and dispersed locations of TC and CT terminals, respectively, on RTN cells. In situ hybridization and immunocytochemical studies revealed that GluRl and GluR2 subunits are not expressed in the RTN and GluR4 subunits are expressed at higher levels than GluR3 subunits. Immunoelectron microscopy revealed gold particles representing GluR3 or GluR4 subunits concentrated at single postsynaptic densities (PSD) characteristic of CT synapses and at the two to seven split PSD segments characteristic of TC synapses. At CT synapses the number and density of GluR4 particles were 2.5 times greater than GluR3 particles. At the larger TC synapses, the number of GluR3 particles exceeded that of GluR4 particles but density of GluR4 particles was lower than at CT synapses while density of GluR3 particles was similar. Despite enrichment of GluR4 subunits at CT synapses, larger conductances prevailed at thalamocortical collateral synapses, probably reflecting both larger overall numbers of AMPA receptors and a greater number of release sites represented by the split PSDs. Variability in amplitudes of TC EPSCs may reflect variability in the number of release sites; lower variability in CT EPSC amplitudes may reflect a more constant number of release sites.
Differential control of high-voltage activated Ca2+ current components by a Ca2+-dependent inactivation mechanism in thalamic relay neurons
- Sven Meuth, Thomas Budde, Hans-Christian Pape
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- 12 April 2006, pp. 31-38
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Ca2+-dependent inactivation of Ca2+ channels represents a feedback mechanism to limit the influx of Ca2+ into cells. Since large Ca2+ transients are present in thalamocortical relay neurons and Ca2+-dependent mechanisms play a pivotal role for thalamic physiology, the existence of this inactivation mechanism and the involvement of different Ca2+ channel subtypes was investigated. The use of subtype-specific antibodies revealed the expression of α1A–α1E channel proteins on the cell body and proximal dendrites of acutely isolated cells from the rat dorsolateral geniculate nucleus (dLGN). In addition, subtype-specific channel blocking agents were used in whole cell patch clamp experiments: nifedipine (1–5 μM; L-type) blocked 35 ± 3%, ω-conotoxin GVIA (1 μM; N-type) blocked 27 ± 8%, and ω-conotoxin MVIIC (4 μM; P/Q-type) blocked 33 ± 5% of the total HVA Ca2+ current. The blocker-resistant current constituted about 12 ± 3% of the total Ca2+ current. The degree of Ca2+ current inactivation was assessed by using a two-pulse protocol. Under control conditions the post-pulse I/V was U-shaped with 35 ± 4% of the current undergoing inactivation. Inclusion of BAPTA to the internal pipette solution reduced the degree of inactivation to 15 ± 1%. When L- and P/Q-type current was blocked, the degree of inactivation was lowered to 20 ± 2 and 27 ± 3%, respectively. In the presence of ω-agatoxin TK (35 ± 6%) and ω-conotoxin GVIA (32 ± 1%) there was no change in inactivation. These data suggest that Ca2+-dependent inactivation is involved in the fine tuning of Ca2+ entry into relay neurons mediated by L- and Q-type channels locally operated by Ca2+ beneath the plasma membrane.
Dendritic organization in thalamocortical neurons and state-dependent functions of inhibitory synaptic inputs
- M. Neubig, A. Destexhe
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- 12 April 2006, pp. 39-52
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GABA-ergic thalamic reticular neurons function generically or singularly in a state-dependent manner: during quiet sleep they synchronously and rhythmically inhibit thalamocortical neurons (TCNs) via bursts, thereby eliciting the low-threshold Ca2+ potentials in TCNs that are crucial to oscillatory network behavior in the thalamo-reticulo-cortical system; during wakefulness they shape the flux of ascending sensory information by inhibiting TCNs with asynchronous and arrhythmic single-spikes. To investigate how the reticulo-thalamic synapses, which occur throughout TCN dendrites, are able to effect such disparate functions, we have: (1) used a 1416 compartment model of a 3D reconstructed TCN; (2) triggered dendritic miniature (TTX-independent) and unitary (single-afferent) conductance-based synaptic events, and (3) recorded axial currents and voltage transients in all 1416 compartments simultaneously. For synapses at all dendritic locations, more than 79% of the charge transfer reached the soma, where it dispersed into other dendritic trees to return to the extracellular space. In accord, dendritic synapses in 80% of the arbor induced voltage responses that were severely attenuated at the soma (>75% loss). Spatio-temporal aspects of distributed postsynaptic responses were examined as well. Except for synapses in the 13 most proximal compartments, the amplitude and phase of the voltage responses degraded rapidly within a focal region that did not extend beyond the host tree, and was limited most often to a subtree. The bulk response (outside the focal region) was highly synchronous and uniform. Interestingly, there were not 1403 different focal regions, but only 20, each clearly distinct from the rest and sharply delineated. Structural attributes of the arbor determined their boundaries. Boundaries were invariant when the analysis was repeated on rescaled versions (length, diameter) of the reconstructed arbor. Unitary events also induced focal/bulk structures for both burst and single-spike triggers – paradigms that correspond to single-afferent drives during quiet sleep and arousal, respectively. Such qualities differ dramatically from previously proposed motifs of dendritic clustering, each of which carried nonlinear sensitivities to parameter values. We propose that dendritic clustering underlies the role of reticulo-thalamic synapses in the early processing of ascending sensory information and that bulk responses contribute robustness to the induction and maintenance oscillations in the thalamo-reticulo-cortical network.
Contribution of intrinsic and synaptic factors in the desynchronization of thalamic oscillatory activity
- I. Timofeev, M. Bazhenov, T.J. Sejnowski, M. Steriade
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- 12 April 2006, pp. 53-69
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The interplay between the intrinsic properties of thalamocortical (TC) neurons and synaptic potentials was investigated in vivo, in decorticated and intact-cortex cats, as well as in computational models to elucidate the possible mechanisms underlying the disruption of the spindle oscillation, a network phenomenon. We found that the low-threshold spikes (LTSs) in TC neurons were graded in their amplitude and latency to peak when elicited by current pulses or synaptic potentials from physiological levels of hyperpolarization. IPSPs could either delay or shunt the LTSs. Although the onset of spindles was rhythmic and did not include rebound LTSs, the end of spindles was highly aperiodic suggesting that desynchronization could contribute to the spindle termination. The desynchronization could have several sources, the main of which are (a) intrinsically generated rebound LTSs in TC neurons that occur with different delays and keep thalamic reticular (RE) neurons relatively depolarized, and/or (b) out-of-phase firing of cortical neurons due to intracortical processes that would result in depolarization of both TC and RE neurons. The present study suggests that an active cortical network participates in disrupting the spindle activities. We propose that the progression of spindles contains at least three different phases, with different origins: (a) the onset is generated by RE neurons that impose their activity onto TC neurons, without participation of cortical neurons; (b) the middle part is produced by the interplay between RE and TC neurons, with potentiation from the cortical network; and (c) the waning of spindles is due to the out-of-phase firing of TC and particularly cortical neurons that participate in the spindle termination.
Surgical control of the human thalamocortical dysrhythmia: I. Central lateral thalamotomy in neurogenic pain
- D. Jeanmonod, M. Magnin, A. Morel, M. Siegemund
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- 12 April 2006, pp. 71-79
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Reactualization of the medial thalamotomy, performed since the fifties in cases of neurogenic pain, has been guided by the discovery of low threshold calcium spike bursts at frequencies in the delta-theta range in the posterior part of the central lateral (CL) nucleus. This thalamic rhythmicity is transmitted to the cortex through thalamocortical resonant properties, giving rise to the thalamocortical dysrhythmia, proposed to be the mechanism of neurogenic pain as well as other central nervous system (CNS) dysfunctions. Magnetic resonance- and microelectrode-guided stereotactic CL thalamotomy was implemented in 96 patients suffering from chronic therapy-resistant peripheral or central neurogenic pain (mean age: 56 ± 15 years; pain duration before surgery: 7.5 ± 8 years). At a mean follow-up of 3 years, 9 months ± 2 years, 9 months, 53% of the patients benefited from a relief superior to 50% (complete relief in 18.7%). Further analysis of the results demonstrated a significant difference between patients suffering from intermittent as compared with continuous pain. Patients with continuous pain showed only a mean relief of 20.4 ± 25.8% in contrast to the 66 ± 39.2% obtained for patients with intermittent (episodic or paroxysmal) pain manifestations. This was confirmed by the pre- and postoperative visual analogue scale scores showing a significant decrease (59.2%) only in the patient group with intermittent pain. Allodynia was suppressed in 57.3% of the patients. Parameters such as the preoperative pain duration or the site of the causal lesion did not affect the surgical outcome. In 28 patients suffering from unilateral continuous pain, the addition of an ipsilateral CL thalamotomy provided a further significant pain relief. A suppression of drug intake was observed in 31.6% of the patients. Complications occurred in 11.5% of the patients and led to a long term significant disability in only one case. In conclusion, CL thalamotomy is a safe neurosurgical option for neurogenic pain, especially for patients suffering from intermittent pain or allodynia. Its limitation in cases of continuous pain indicates the necessity to explore other stereotactic targets outside of the medial thalamus.
Surgical control of the human thalamocortical dysrhythmia: II. Pallidothalamic tractotomy in Parkinson's disease
- M. Magnin, D. Jeanmonod, A. Morel, M. Siegemund
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- 12 April 2006, pp. 81-89
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Following earlier stereotactic experiences, we re-explored the possibilities of a therapeutic lesion of the pallidothalamic tract in the fields H1 and H2 of Forel in patients with parkinsonian signs. The physiopathological rationale of the pallidothalamic tractotomy (PTT) is based on the presence in the parkinsonian brain of a state of thalamic overinhibition due to an increased output of the internal pallidum. This causes the development of a thalamocortical dysrhythmia characterized by increased low frequencies in the relevant thalamic and frontal cortical areas. The fields of Forel are strategically placed to control this thalamic overinhibition, as they give passage to the majority of the pallidothalamic fibres. Magnetic resonance- and microelectrode-guided stereotactic PTT was proposed to 21 parkinsonian patients (mean age: 60 ± 10 years; mean Hoehn and Yahr in on-condition: 3.5 ± 1; mean disease duration: 11 ± 5 years). At a follow-up of 14 ± 6 months and in on-medication condition, a significant (P < 0.001) postoperative improvement of the motor part of the UPDRS (64.6%) and of the activities of daily living (ADL; 75.8%) was observed. Rest tremor, on-chorea and rigidity were reduced by 77.9, 92.2 and 82.3%, respectively. Distal and axial hypobradykinesias showed an improvement of 72.9 and 64%, respectively. Gait and postural stability also improved (57.5 and 66%, respectively) but at a lower level of significance (P < 0.005). Voice was not statistically influenced. L-dopa intake was decreased by 52.2% (P < 0.001) and 33% of the patients could be freed from treatment. In conclusion, PTT is an effective treatment for chronic therapy-resistant Parkinson's disease, improving symptoms in both on- and off-conditions.
Instructions to Authors
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- 12 April 2006, pp. 91-93
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