The thalamocortical (TC) neurones of the sensory thalamic nuclei receive three excitatory inputs: two are the ascending input from the sensory pathway and the descending input from the cortex, and the third is the modulatory input from the brainstem activating system (Jones, 1985). The sensory and cortical inputs form synapses at different locations on the dendritic arbors of TC neurones, with the sensory input more proximal to the soma and the cortical input more distal. The sensory input to auditory, somatosensory and visual thalamic nuclei has been well characterized as being mediated by both non-NMDA and NMDA ionotropic glutamate receptors both in vitro (Scharfman, Lu, Guido, Adams & Sherman, 1990; Turner, Leresche, Guyon, Soltesz & Crunelli, 1994;Hu, Senatorov & Mooney, 1994;Kao & Coulter, 1997) and in vivo (Salt, 1986;Sillito, Murphy & Salt, 1990a;Sillito, Murphy, Salt & Moody, 1990b;Salt & Eaton, 1991). However, while the contribution of these ionotropic glutamate receptors to corticothalamic synaptic transmission has been established both in vitro and in vivo (Deschênes & Hu, 1990;Scharfman et al. 1990;Eaton & Salt, 1996;Kao & Coulter, 1997) 1. Using an in vitro slice preparation of the rat dorsal lateral geniculate nucleus (dLGN), the properties of retinogeniculate and corticothalamic inputs to thalamocortical (TC) neurones were examined in the absence of GABAergic inhibition. 2. The retinogeniculate EPSP evoked at low frequency (û 0·1 Hz) consisted of one or two fastrising (0·8 ± 0·1 ms), large-amplitude (10·3 ± 1·6 mV) unitary events, while the corticothalamic EPSP had a graded relationship with stimulus intensity, owing to its slower-rising (2·9 ± 0·4 ms), smaller-amplitude (1·3 ± 0·3 mV) estimated unitary components. 3. The retinogeniculate EPSP exhibited a paired-pulse depression of 60·3 ± 5·6 % at 10 Hz, while the corticothalamic EPSP exhibited a paired-pulse facilitation of > 150 %. This frequency-dependent depression of the retinogeniculate EPSP was maximal after the second stimulus, while the frequency-dependent facilitation of the corticothalamic EPSP was maximal after the fourth or fifth stimulus, at interstimulus frequencies of 1-10 Hz. 4. There was a short-term enhancement of the û 0·1 Hz corticothalamic EPSP (64·6 ± 9·2 %), but not the retinogeniculate EPSP, following trains of stimuli at 50 Hz. 5. The û 0·1 Hz corticothalamic EPSP was markedly depressed by the non-NMDA antagonist 1-(4-amino-phenyl)-4-methyl-7,8-methylene-dioxy-5H-2,3-benzodiazepine (GYKI 52466), but only modestly by the NMDA antagonist 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid ((RS)-CPP), and completely blocked by the co-application of GYKI 52466, 6_cyano-7-nitroquinoxaline-2,3-dione (CNQX), (RS)-CPP and (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK_801). Likewise, the corticothalamic responses to trains of stimuli (1-500 Hz) were greatly reduced by this combination of ionotropic glutamate receptor antagonists. 6. In the presence of GYKI 52466, CNQX, (RS)-CPP and MK_801, res...

1. The mechanism underlying a novel form of input signal amplification and bistability was investigated by intracellular recording in rat and cat thalamocortical (TC) neurones maintained in slices and by computer simulation with a biophysical model of these neurones. 2. In a narrow membrane potential range centred around −60 mV, TC neurones challenged with small (10-50 pA), short (50-200 ms) current steps produced a stereotyped, large amplitude hyperpolarization ( > 20 mV) terminated by the burst firing of action potentials, leading to amplification of the duration and amplitude of the input signal, that is hereafter referred to as input signal amplification. 3. In the same voltage range centred around −60 mV, single evoked EPSPs and IPSPs also produced input signal amplification, indicating that this behaviour can be triggered by physiologically relevant stimuli. In addition, a novel, intrinsic, low frequency oscillation, characterized by a peculiar voltage dependence of its frequency and by the presence of plateau potentials on the falling phase of low threshold Ca¥ potentials, was recorded. 4. Blockade of pure Na¤ and K¤ currents by tetrodotoxin (1 ìÒ) and Ba¥ (0·1-2·0 mÒ), respectively, did not affect input signal amplification, neither did the presence of excitatory or inhibitory amino acid receptor antagonists in the perfusion medium. 5. A decrease in [Ca¥]ï (from 2 to 1 mÒ) and an increase in [Mg¥]ï (from 2 to 10 mÒ), or the addition of Ni¥ (2-3 mÒ), abolished input signal amplification, while an increase in [Ca¥]ï (from 2 to 8 mÒ) generated this behaviour in neurones where it was absent in control conditions. These results indicate the involvement of the low threshold Ca¥ current (IT) in input signal amplification, since the other Ca¥ currents of TC neurones are activated at potentials more positive than −40 mV. 6. Blockade of the slow inward mixed cationic current (Ih) by 4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)-pyrimidinium chloride (ZD 7288) (100-300 ìÒ) did not affect the expression of the large amplitude hyperpolarization, but abolished the subsequent repolarization to the original membrane potential. In this condition, therefore, input signal amplification was replaced by bistable membrane behaviour, where two stable membrane potentials separated by 15-30 mV could be switched between by small current steps. 7. Computer simulation with a model of a TC neurone, which contained only IT, Ih, K¤ leak current (ILeak) and those currents responsible for action potentials, accurately reproduced the qualitative and quantitative properties of input signal amplification, bistability and low frequency oscillation, and indicated that these phenomena will occur at some value of the injected DC if, and only if, the 'window' component of IT (IT,Window) and the leak conductance (gLeak) satisfy the relation (dIT,WindowÏdV)max > gLeak. 8. The physiological implications of these findings for the electroresponsiveness of TC neurones are discussed, and, as IT is widely expressed in the central nervous syste...

The action of ethosuximide (ETX) on Na+, K+, and Ca2+ currents and on tonic and burst-firing patterns was investigated in rat and cat thalamic neurons in vitro by using patch and sharp microelectrode recordings. In thalamocortical (TC) neurons of the rat dorsal lateral geniculate nucleus (LGN), ETX (0.75-1 mM) decreased the noninactivating Na+ current, INaP, by 60% but had no effect on the transient Na+ current. In TC neurons of the rat and cat LGN, the whole-cell transient outward current was not affected by ETX (up to 1 mM), but the sustained outward current was decreased by 39% at 20 mV in the presence of ETX (0.25-0.5 mM): this reduction was not observed in a low Ca2+ (0.5 mM) and high Mg2+ (8 mM) medium or in the presence of Ni2+ (1 mM) and Cd2+ (100 microM). In addition, ETX (up to 1 mM) had no effect on the low-threshold Ca2+ current, IT, of TC neurons of the rat ventrobasal (VB) thalamus and LGN and in neurons of the rat nucleus reticularis thalami nor on the high-threshold Ca2+ current in TC neurons of the rat LGN. Sharp microelectrode recordings in TC neurons of the rat and cat LGN and VB showed that ETX did not change the resting membrane potential but increased the apparent input resistance at potentials greater than -60 mV, resulting in an increase in tonic firing. In contrast, ETX decreased the number of action potentials in the burst evoked by a low-threshold Ca2+ potential. The frequency of the remaining action potentials in a burst also was decreased, whereas the latency of the first action potential was increased. Similar effects were observed on the burst firing evoked during intrinsic delta oscillations. These results indicate an action of ETX on INaP and on the Ca2+-activated K+ current, which explains the decrease in burst firing and the increase in tonic firing, and, together with the lack of action on low- and high-threshold Ca2+ currents, the results cast doubts on the hypothesis that a reduction of IT in thalamic neurons underlies the therapeutic action of this anti-absence medicine.

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1. Intracellular sharp electrode current clamp and discontinuous single electrode voltage clamp recordings were made from thalamocortical neurones (n = 57) of the cat ventrobasal thalamus in order to investigate the mechanism underlying anomalous rectification. 2. Under current clamp conditions, voltage-current (V-I) relationships in a potential range of -55 to -110 mV demonstrated anomalous rectification with two components: fast rectification, which controlled the peak of negative voltage deviations, and time-dependent rectification. Time-dependent rectification was apparent as a depolarizing sag generated during the course of negative voltage deviations, was first formed at potentials in the range -60 to -70 mV, and was sensitive to 3 mM Cs+ (n = 6). Similarly, under voltage clamp conditions, instantaneous and steady-state I-V relationships demonstrated anomalous rectification. A slowly activating inward current with an activation threshold in the range of -65 to -70 mV formed time-dependent rectification. This current was sensitive to Cs+ (3 mM) (n = 3) and had properties similar to the slow inward mixed cationic current (Ih). 3. 4-(N-Ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)-pyrimidinium++ + chloride (ZD 7288) (100-300 microM) irreversibly blocked time-dependent rectification mediated by Ih (n = 23 of 25 neurones), and led to a hyperpolarization of the resting membrane potential (6.8 +/- 0.5 mV). In the presence of ZD 7288, V-I and I-V relationships, exhibited fast anomalous rectification, first activated from potential more negative than -80 mV. 4. Ba2+ (100 microM) (n = 8), in the continuous presence of ZD 7288, reversibly linearized peak V-I and instantaneous I-V relationships over a potential range of -70 to -120 mV, and led to a membrane depolarization (13.3 +/- 4.2 mV) or tonic inward current (192 +/- 36 pA). 5. The co-application of ZD 7288 and Ba2+ revealed a depolarizing sag in negative voltage deviations under current clamp conditions, or a large inward current with kinetics two to three times slower than those of Ih under voltage clamp conditions. This novel form of time-dependent rectification was first apparent at potentials more negative than about -85 mV, was sensitive to 5 mM Cs+ (n = 4), and is termed Ih,slow. Ih,slow tail currents reversed between -65.3 and -56.6 mV (with potassium acetate electrodes, n = 3) or -57.6 and -50.3 mV (with KCl electrodes, n = 3). 6. Computer simulations confirmed that the pattern of anomalous rectification in thalamocortical neurones of the cat ventrobasal thalamus is mediated by the concerted action of Ih and a Ba(2+)-sensitive current with properties similar to an inwardly rectifying K+ current (IKIR).

1. Intracellular and patch-clamp recordings were obtained from thalamocortical (TC) cells in the rat and cat dorsal lateral geniculate nucleus (dLGN) in vitro to study the role of N-methyl-D-aspartate (NMDA) and non-NMDA receptors in the synaptic potential and burst firing evoked by electrical stimulation of the optic tract. 2. At membrane potentials more positive than -65 mV, the sensory synaptic potential consisted of a fast EPSP that was followed by a smaller, slower component. At membrane potentials more negative than -65 mV, this slower component became more prominent owing to the presence of a low-threshold (LT) Ca2+ potential, which in turn evoked a high-frequency (> 150 Hz) burst of action potentials. The lower, but not the upper limit of the range of membrane potential over which burst firing occurred was dependent on the amplitude of the fast EPSP. 3. The non-NMDA receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 5-10 microM) and 1-(4-amino-phenyl)-4-methyl-7,8-methylene-dioxy-5H-2,3- benzodiazepine (GYKI 52466, 100 microM) greatly depressed the fast EPSP, abolished the burst firing generated by the LT Ca2+ potential, and left a relatively small, slow EPSP, which was sensitive to the NMDA antagonist DL-2-amino-5-phosphonovaleric acid (DL-AP5, 50-100 microM). 4. In the absence of CNQX or GYKI 52466, DL-AP5 depressed the slow but not the fast EPSP. DL-AP5 also increased the latency of the first action potential evoked by the LT Ca2+ potential or even abolished the LT Ca2+ potential and associated burst firing. The latter effect was only present when this type of firing occurred within a small membrane potential range. 5. DL-AP5 had no effect on the properties of the LT Ca2+ current IT, indicating that its effect on the burst firing was not mediated by a direct action on IT. 6. The response of TC cells to high-frequency (100 Hz) stimulation consisted of an initial burst firing response, followed by a sustained depolarization that could reach firing threshold. This sustained depolarization was markedly depressed by DL-AP5 but not by CNQX. 7. These results demonstrate that with low-frequency stimulation of the sensory afferents, the generation of TC cell output in the rat and cat dLGN is mainly controlled by non-NMDA receptors, while the contribution of NMDA receptors is limited to the burst firing generated by the LT Ca2+ potential, and depends on the membrane potential range over which this type of firing occurs.(ABSTRACT TRUNCATED AT 400 WORDS)

1. The morphological (n = 66) and electrophysiological (n = 41) properties of eighty-six thalamocortical (TC) neurones and those of one interneurone in the cat ventrobasal (VB) thalamus were examined using an in vitro slice preparation. The resting membrane potential for thirty-seven TC neurones was −61·9 ± 0·7 mV, with thirteen neurones exhibiting delta oscillation with and without DC injection. 2. The voltage-current relationships of TC neurones were highly non-linear, with a mean peak input resistance of 254·4 MÙ and a mean steady-state input resistance of 80·6 MÙ between −60 and −75 mV. At potentials more positive than −60 mV, outward rectification led to a mean steady-state input resistance of 13·3 MÙ. At potentials more negative than −75 mV, there was inward rectification, consisting of a fast component leading to a mean peak input resistance of 14·5 MÙ, and a slow time-dependent component leading to a mean steadystate input resistance of 10·6 MÙ. 3. Above −60 mV, three types of firing were exhibited by TC neurones. The first was an accelerating pattern associated with little spike broadening and a late component in the spike after-hyperpolarization. The second was an accommodating or intermittent pattern associated with spike broadening, while the third was a burst-suppressed pattern of firing also associated with spike broadening, but with broader spikes of a smaller amplitude. All TC neurones evoked high frequency (310-520 Hz) burst firing mediated by a low threshold Ca¥ potential. 4. Morphologically TC neurones were divided into two groups: Type I (n = 31 neurones) which had larger soma, dendritic arbors that occupied more space, thicker primary dendrites and daughter dendrites that followed a more direct course than Type II (n = 35). The only electrophysiological differences were that Type I neurones (n = 16) had smaller peak input and outward rectification resistance and spike after-hyperpolarization, but greater peak inward rectification resistance, and exhibited delta oscillation less often than Type II (n = 13). 5. The morphologically identified interneurone exhibited no outward rectification, only moderate inward rectification, and no high frequency firing associated with the offset of negative current steps below −55 mV. This interneurone had a regular accommodating firing pattern, but the spike after-hyperpolarization had a late component, unlike the accommodating firing in TC neurones. 6. Therefore, the differentiation of TC neuronal types in the cat VB thalamus based on their morphology was reflected by differences in peak input resistance, outward rectification and spike after-hyperpolarization, which could be accounted for by their difference in soma size. More importantly, the firing pattern of the majority of TC neurones in the cat VB thalamus were different from those of TC neurones in other sensory thalamic nuclei. 7. Thalamocortical neurones in the cat VB thalamus were also clearly distinguishable from the interneurone based on the presence of their prominent outward rectification, pea...

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