The ‘window’ component of the low threshold Ca²⁺ current produces input signal amplification and bistability in cat and rat thalamocortical neurones

Abstract

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...

Enhancement of Excitatory Synaptic Integration by GABAergic Inhibition in the Subthalamic Nucleus

“…Together, our observations and the known biophysical properties of Ca v 3 channels in STN and other neurons indicate that Ca v 3 channels do not participate in the integration of single IPSPs in STN neurons. The increase in the frequency of autonomous activity that was obtained with Ni 2ϩ application in five of six STN neurons supports the existence of Ca v 3 channel-mediated Ca 2ϩ influx during autonomous firing (Williams et al, 1997;Chemin et al, 2002). The increase in firing frequency that accompanies the blockade of an inward Ca 2ϩ current may indicate that Ca v 3 channels are functionally coupled to small and/or large conductance Ca 2ϩ -activated potassium channels (cf.…”

Neuronal Basis of the Slow (<1 Hz) Oscillation in Neurons of the Nucleus Reticularis ThalamiIn Vitro

“…10 E 2 , top plot). By performing this shift we ensured that the transient activation of I T was essentially unchanged but that I Twindow was virtually eliminated (Hutcheon et al, 1994;Williams et al, 1997) (Fig. 10 E 2 , bottom plot).…”

“…9B 4 ). In TC neurons, the instatement of a slow oscillation only occurs when I Leak is reduced below a specific threshold (Williams et al, 1997;Tó th et al, 1998;Hughes et al, 1999). To test whether some NRT neurons lack a slow oscillation because mGluR1a activation in these cells does not sufficiently reduce I Leak , we artificially induced a further suppression of this current using a dynamic-clamp system in nonoscillating NRT neurons that had been subjected to TTX (Hughes et al, 1999(Hughes et al, , 2002a) (supplemental Fig.…”

“…In TC neurons, the intrinsic slow oscillation arises when mGluR1a activation reduces the leak K ϩ current, I Leak , below a certain threshold where it can interact with the "window" component of the T-type Ca 2ϩ current, I Twindow , to produce a form of intrinsic bistability (Williams et al, 1997;Tó th et al, 1998;Hughes et al, 1999Hughes et al, , 2002a. The slow oscillation in TC neurons also relies on a Ca 2ϩ -activated, nonselective cation (CAN) current (Hughes et al, 2002a;Crunelli et al, 2005).…”

The Role of Calcium Channels in Epilepsy

“…In addition, T-type channels generate "window currents," in which, at certain potentials, a proportion of channels are open but not inactivated, leading to an inward calcium current, which contributes to membrane stability. It follows that changes in the channel milieu, which determine whether channels are open, closed, or inactivated, will influence the window current, which, in turn, will have consequences on neuronal excitability, a chain of events that may underlie seizure initiation (Williams et al 1997;Perez-Reyes 2003;Crunelli et al 2005;Contreras 2006;Cain and Snutch 2010). Finally, T-type channels also influence neuronal firing in a calcium-dependent manner by controlling intracellular calcium concentration and interacting with calcium-activated potassium channels (Simms and Zamponi 2014).…”