Low-threshold Calcium Channels Research Articles

Role of Cav3.2 Low-Threshold Calcium Channel in Mechanosensitivity and Neuropathic Pain

Les fibres nerveuses peuvent être divisées en trois catégories, jouant chacune leur rôle dans différents types de sensations. Ces fibres ainsi que les récepteurs qu’elles expriment jouent un rôle crucial dans les pathologies liées aux perceptions thermiques, chimiques, nociceptives et mécaniques. Dans cette étude, les auteurs ont porté leur intérêt sur les fibres nerveuses Aδ et C, connues pour leurs rôles dans la mécanoception, et une sous-famille de ces fibres plus particulièrement, les fibres exprimant des récepteurs mécaniques à faible seuil d’activation (low-threshold mechanoreceptor or LTMRs). Sachant que les canaux calciques Cav 3.2, de type T, sont connus pour leur rôle dans la transmission d’informations sensorielles, leur prévalence ainsi que leur activité dans les LTMRs ont été évaluées via l’utilisation de souris génétiquement modifiées. Cette étude montre que les canaux Cav3.2 sont impliqués dans la transmission d’informations mécanique et thermique au froid, et donc potentiellement dans les douleurs neuropathiques. En outre, les canaux Cav3.2 ont été détectés le long des axones des fibres LTMRs, suggérant un rôle important de ces canaux dans la vitesse de conduction.

Thalamic Reticular Nucleus Parvalbumin Neurons Regulate Sleep Spindles and Electrophysiological Aspects of Schizophrenia in Mice

The thalamic reticular nucleus (TRN) is implicated in schizophrenia pathology. However, it remains unclear whether alterations of TRN activity can account for abnormal electroencephalographic activity observed in patients, namely reduced spindles (10–15 Hz) during sleep and increased delta (0.5–4 Hz) and gamma-band activity (30–80 Hz) during wakefulness. Here, we utilized optogenetic and reverse-microdialysis approaches to modulate activity of the major subpopulation of TRN GABAergic neurons, which express the calcium-binding protein parvalbumin (PV), and are implicated in schizophrenia dysfunction. An automated algorithm with enhanced efficiency and reproducibility compared to manual detection was used for sleep spindle assessment. A novel, low power, waxing-and-waning optogenetic stimulation paradigm preferentially induced spindles that were indistinguishable from spontaneously occurring sleep spindles without altering the behavioral state, when compared to a single pulse laser stimulation used by us and others. Direct optogenetic inhibition of TRN-PV neurons was ineffective in blocking spindles but increased both wakefulness and cortical delta/gamma activity, as well as impaired the 40 Hz auditory steady-state response. For the first time we demonstrate that spindle density is markedly reduced by (i) optogenetic stimulation of a major GABA/PV inhibitory input to TRN arising from basal forebrain parvalbumin neurons (BF-PV) and; (ii) localized pharmacological inhibition of low-threshold calcium channels, implicated as a genetic risk factor for schizophrenia. Together with clinical findings, our results support impaired TRN-PV neuron activity as a potential cause of schizophrenia-linked abnormalities in cortical delta, gamma, and spindle activity. Modulation of the BF-PV input to TRN may improve these neural abnormalities.

Endocannabinoid 2-AG and intracellular cannabinoid receptors modulate a low-threshold calcium spike-induced slow depolarizing afterpotential in rat thalamic paraventricular nucleus neurons

In rat paraventricular thalamic nucleus (PVT) neurons, activation of low-threshold calcium (Ca2+) channels triggers a low-threshold spike (LTS) which may be followed by slow afterpotentials that can dramatically influence action potential patterning. Using gluconate-based internal recording solutions, we investigated the properties of a LTS-induced slow afterdepolarization (sADP) observed in a subpopulation of PVT neurons recorded in brain slice preparations. This LTS-induced sADP required T-type Ca2+ channel opening, exhibited variable magnitudes between neurons and a voltage dependency with a maximum near −50mV. The area under the sADP remained stable during control monitoring, but displayed gradual suppression in media where strontium replaced Ca2+. The sADP was suppressed following bath application of 2-APB or ML204, suggesting engagement of transient receptor potential canonical (TRPC)-like channels. Further investigation revealed a reversible suppression during bath applications of membrane permeable cannabinoid receptor (CBR) blockers rimonabant, AM630 or SR144528 suggesting the presence of both CB1Rs and CB2Rs. Similar results were achieved by intracellular, but not bath application of the membrane impermeant CB1R blocker hemopressin, suggesting an intracellular localization of CB1Rs. Data from pharmacologic manipulation of endocannabinoid biosynthetic pathways suggested 2-arachidonlyglycerol (2-AG) as the endogenous cannabinoid ligand, derived via hydrolysis of diacylglycerol (DAG), with the latter formed from the pathway involving phosphatidylcholine-specific phospholipase D and phosphatic acid phosphohydrolase. The sADP suppression observed during recordings with pipettes containing LY294002, a PI3-kinase inhibitor, suggested a role for PI3kinase in the translocation of these TRPC-like channels to the plasma membrane. Drug-induced attenuation of the availability of 2-AG influences the number of action potentials that surmount the LTS evoked in PVT neurons, implying an ongoing intracellular CBR modulation of neuronal excitability during LTS-induced bursting behavior.

The mechanisms of late-onset synaptic responses in a realistic model of Unipolar Brush Cells

Unipolar brush cells (UBCs) are excitatory glutamatergic interneurons of the cerebellar granular layer receiving both primary and secondary vestibular inputs through mossy fibers (excitatory input) and Golgi cell axon (inhibitory input). When injected with progressively increasing depolarizing currents from a negative membrane potential, the UBC generates a burst sustained by a calcium spike and then a protracted discharge with shorter latency and spike frequency adaptation. The intrinsic excitability of UBCs is determined by an H current and by Low Voltage activated and High Voltage activated calcium currents [2,3]. Fast inactivating T-type Calcium channels generate low-threshold spikes and L-type Calcium channel sustain tonic firing. The H current (activated between -60 mV and -80 mV) produces a slow hyperpolarization characterized by a “sag” in response to a hyperpolarizing step and an afterhyperpolarization at the end of a depolarizing step. Here we present a biologically realistic multi-compartmental mathematical model of the UBC realized with the NEURON-PYTHON simulator. According to literature [1-4], ionic channels are distributed among compartments (soma, dendrite, initial segment and axon). The model can reproduce the excitable properties of UBCs in currentclamp and voltage-clamp modes. The response to mossy fiber inputs was reproduced using synaptic models of AMPA and NMDA synaptic receptors. The model is also capable of reproducing the late onset response recently reported for this cellular type [5] by exploiting the interaction between cAMP, TRPC, and H current. This model, in addition to confirm the prim ary role of the aforementioned currents in UBC’s electroresponsiveness, will prove a valuable tool for investigating the UBC’s function in the cerebellar network.

Low-threshold calcium currents contribute to locomotor-like activity in neonatal mice

In this study, we examined the contribution of a low-threshold calcium current [I(Ca(T))] to locomotor-related activity in the neonatal mouse. Specifically, the role of I(Ca(T)) was studied during chemically induced, locomotor-like activity in the isolated whole cord and in a genetically distinct population of ventromedial spinal interneurons marked by the homeobox gene Hb9. In isolated whole spinal cords, cycle frequency was decreased in the presence of low-threshold calcium channel blockers, which suggests a role for I(Ca(T)) in the network that produces rhythmic, locomotor-like activity. Additionally, we used Hb9 interneurons as a model to study the cellular responses to application of low-threshold calcium channel blockers. In transverse slice preparations from transgenic Hb9::enhanced green fluorescent protein neonatal mice, N-methyl-d-aspartate-induced membrane potential oscillations in identified Hb9 interneurons also slowed in frequency with application of nickel when fast, spike-mediated, synaptic transmission was blocked with TTX. Voltage-clamp and immunolabeling experiments confirmed expression of I(Ca(T)) and channels, respectively, in Hb9 interneurons located in the ventromedial spinal cord. Taken together, these results provide support that T-type calcium currents play an important role in network-wide rhythm generation during chemically evoked, fictive locomotor activity.

Modeling UBC intrinsic excitability

Unipolar brush cells (UBCs) are excitatory glutamatergic interneurons of the cerebellar granular layer receiving both primary and secondary vestibular inputs through mossy fibers (excitatory input) and Golgi axon (inhibitory input). The brush like structure of the dendrite allows to form a giant synapses in the glomerulus and to produce an all or none post synaptic response with short delay and protracted kinetics. The excitable response of UBCs can be either a tonic discharge or a high-frequency burst of action potentials. When injected with progressively increasing depolarizing currents from a negative membrane potential, the UBC generates a burst sustained by a calcium spike (Figure ​(Figure1,1, +20pA) and then a protracted discharge with shorter latency and spike frequency adaption (Figure ​(Figure1,1, +25pA). The intrinsic excitability of UBCs is determined by an H current and by Low Voltage activated and High Voltage activated calcium currents [2,3]. Fast inactivating T-type Calcium channels generate low-threshold spikes and L-type Calcium channel sustain tonic firing. The H current (activated between -60mV and -80mV) produces a slow hyperpolarization characterized by a “sag” in response to a hyperpolarizing step (Figure ​(Figure1,1, -16pA) and an afterhyperpolarization at the end of a depolarizing step. Figure 1 Excitable response of the UBC model to step-current injection.

Low-threshold calcium channel subunit Cav3.3 is specifically localized in GABAergic neurons of rodent thalamus and cerebral cortex

Relatively little is known about the subcellular localization of low threshold Ca²+ channels (T-channels) in the brain. Using immunocytochemical labeling and preembedding immunoperoxidase and silver-enhanced immunogold electron microscopy, we localized T-channel subunit Ca(v) 3.3 in rodent cerebral cortex and thalamus. Double immunofluorescent staining demonstrated that Ca(v) 3.3-labeled neurons in cerebral cortex are a subgroup of GABAergic interneurons that coexpress calbindin and in half of the cases parvalbumin. In the thalamus, virtually all reticular nucleus (RTN) neurons were immunopositive for Ca(v) 3.3, while neurons in dorsal thalamic nuclei were nonimmunoreactive. At the electron microscopic (EM) level, in cortical layers IV-V and RTN neurons, Ca(v) 3.3 immunoreactivity was mainly associated with membranes of dendrites but with some localization in cytoplasm. None was found in axon terminals. In cortex, ≈73% of immunogold particles were present in close proximity to synaptic contacts (<0.5 μm from the postsynaptic density), while 27% were distributed along membranes at extrasynaptic sites (>0.5 μm from the postsynaptic density). In RTN, ≈57% particles were evenly distributed along perisynaptic membranes and the remaining 43% of particles were diffusely localized at extrasynaptic membranes. The density of particles along the dendritic membranes of cortical neurons was 40% higher than in RTN neurons. These results suggest that Ca(v) 3.3 plays a role in regulating GABAergic neurons whose actions underlie thalamocortical rhythmicity.

Nonlinear Influence of T-Channels in anin silicoRelay Neuron

Thalamic relay cells express distinctive response modes based on the state of a low-threshold calcium channel (T-channel). When the channel is fully active (burst mode), the cell responds to inputs with a high-frequency burst of spikes; with the channel inactive ( tonic mode), the cell responds at a rate proportional to the input. Due to the T-channel's dynamics, we expect the cell's response to become more nonlinear as the channel becomes more active. To test this hypothesis, we study the response of an in silico relay cell to Poisson spike trains. We first validate our model cell by comparing its responses with in vitro responses. To characterize the model cell's nonlinearity, we calculate Poisson kernels, an approach akin to white noise analysis but using the randomness of Poisson input spikes instead of Gaussian white noise. We find that a relay cell with active T-channels requires at least a third-order system to achieve a characterization as good as a second-order system for a relay cell without T-channels.

The Back and Forth of Dendritic Plasticity

Synapses are located throughout the often-elaborate dendritic tree of central neurons. Hebbian models of plasticity require temporal association between synaptic input and neuronal output to produce long-term potentiation of excitatory transmission. Recent studies have highlighted how active dendritic spiking mechanisms control this association. Here, we review new work showing that associative synaptic plasticity can be generated without neuronal output and that the interplay between neuronal architecture and the active electrical properties of the dendritic tree regulates synaptic plasticity.

Imaging the activity of neuronal populations: when spikes don't flash and flashes don't spike

Imaging the activity of neuronal populations: when spikes don't flash and flashes don't spike

Sodium/calcium selectivity of cloned calcium T-type channels

We studied the peculiarities of permeability with respect to the main extracellular cations, Na+ and Ca2+, of cloned low-threshold calcium channels (LTCCs) of three subtypes, Cav3.1 (α1G), Cav3.2 (α 1H), and Cav3.3 (α1I), functionally expressed in Xenopus oocytes. In a calcium-free solution containing 100 mM Na+ and 5 mM calcium-chelating EGTA buffer (to eliminate residual concentrations of Ca2+) we observed considerable integral currents possessing the kinetics of inactivation typical of LTCCs and characterized by reversion potentials of −10 ± 1, −12 ± 1, and −18 ± 2 mV, respectively, for Cav3.1, Cav3.2, and Cav3.3 channels. The presence of Ca2+ in the extracellular solution exerted an ambiguous effect on the examined currents. On the one hand, Ca2+ effectively blocked the current of monovalent cations through cloned LTCCs (Kd = 2, 10, and 18 µM for currents through channels Cav3.1, Cav3.2, and Cav3.3, respectively). On the other hand, at the concentration of 1 to 100 mM, Ca2+ itself functioned as a carrier of the inward current. Despite the fact that the calcium current reached the level of saturation in the presence of 5 mM Ca2+ in the external solution, extracellular Na+ influenced the permeability of these channels even in the presence of 10 mM Ca2+. The Cav3.3 channels were more permeable with respect to Na+ (PCa/PNa ∼ 21) than Cav3.1 and Cav3.2 (PCa/PNa ∼ 66). As a whole, our data indicate that cloned LTCCs form multi-ion Ca2+-selective pores, as these ions possess a high affinity for certain binding sites. Monovalent cations present together with Ca2+ in the external solution modulate the calcium permeability of these channels. Among the above-mentioned subtypes, Cav3.3 channels show the minimum selectivity with respect to Ca2+ and are most permeable for monovalent cations.

Peculiarities of Selectivity of Three Subtypes of Low-Threshold T-Type Calcium Channels

Despite the progress in studies of the properties and functions of low-threshold calcium channels (LTCCs) [1], the mechanisms of their selectivity and permeability remain unstudied in detail. We performed a comparative analysis of the selectivity of three cloned pore-forming LTCC subunits (α1G, α1H, and α1I) functionally expressed in Xenopus oocytes with respect to bivalent alkaline-earth metal cations (Ba2+, Ca2+, and Sr2+. The relative conductivities (G) of these channels were determined according to the amplitudes of macroscopic currents (I) and potentials of zero currents (E). The currents were recorded after preliminary intracellular injection of a fast calcium buffer, BAPTA, in order to suppress the endogenous calcium-dependent chloride conductivity. Channels formed by α1G subunits demonstrated the following ratios of the amplitudes of macroscopic currents and potentials of zero current: I Ca:I Ba:I Sr = 1.00:0.75:1.12 and E Ca ≈ E Ba ≈ E Sr. For channels that were formed by α1H and α1I subunits, these ratios were as follows: I Ca:I Ba:I Sr = 1.00:1.20:1.17, E Ca ≈ E Ba ≈ E Sr and I Ca:I Ba:I Sr = 1.00:1.48: 1.45, E Ca ≈ E Ba ≈ E Sr respectively. The different macroscopic conductivities and similar potentials of zero current typical of α1G and α1I channels indicate that, probably, various bivalent cations can in a differential manner influence the stochastic parameters of functioning of these channels. At the same time, channels formed by α1H subunits are characterized by more positive potentials of zero current for Ca2+. It seems possible that the selectivity of the above channels is determined by mechanisms that mediate the selectivity of most high-threshold calcium channels (more affine binding of Ca2+ inside the pore).

Expression of RNA of Subunits of Low-Threshold Calcium Channels in the Laterodorsal Nucleus of the Rat Thalamus: an Ontogenetic Aspect

It was shown earlier that low-threshold calcium current in neurons of the laterodorsal nucleus of the rat thalamus is of a multicomponent nature, and, moreover, its composition changes in the course of postnatal development of the animal. These findings raised a question on the ontogenetic development of expression of the pore-forming subunits of low voltage-activated (LVA) calcium channels (or T-type channels). At present, three isoforms of such subunits, α 1G, α1I, and α1H, have been cloned. In our study, we examined expression of mRNA of three subunits of T-type calcium channels in the laterodorsal thalamic nucleus of 1-, 5-, 15-, and 90-day (3-month)-old Wistar rats using reverse transcription and the polymerase chain reaction (PCR). Analysis of amplificates showed that mostly RNAs coding α1G and α1I subunits are expressed in the laterodorsal nucleus of rats of all age groups, while levels of expression RNAs of α1H and α1E subunits (the latter subunit of calcium channels of R type is close in its properties to subunits of LVA channels) are considerably lower (16 or 32 times smaller than the respective values for α1G and α1I subunits). We could not find a significant dependence of the expression of subunit RNAs of the above-mentioned calcium channels on the phases of ontogenetic development. It is possible to hypothesize that the age dynamics of the recorded calcium current in neurons of the laterodorsal thalamic nucleus is not related to increases in the transcription of the corresponding genes but results from post-translational changes in α1G and α1I subunits of proteins of LVA calcium channels or age-related peculiarities of regulation.

Multiple determinants in voltage-dependent P/Q calcium channels control their retention in the endoplasmic reticulum.

Surface expression level of voltage-dependent calcium channels is tightly controlled in neurons to avoid the resulting cell toxicity generally associated with excessive calcium entry. Cell surface expression of high voltage-activated calcium channels requires the association of the pore-forming subunit, Cavalpha, with the auxiliary subunit, Cavbeta. In the absence of this auxiliary subunit, Cavalpha is retained in the endoplasmic reticulum (ER) through mechanisms that are still poorly understood. Here, we have investigated, by a quantitative method based on the use of CD8 alpha chimeras, the molecular determinants of Cavalpha2.1 that are responsible for the retention, in the absence of auxiliary subunits, of P/Q calcium channels in the ER (referred to here as 'ER retention'). This study demonstrates that the I-II loop of Cavalpha2.1 contains multiple ER-retention determinants beside the beta subunit association domain. In addition, the I-II loop is not the sole domain of calcium channel retention as two regions identified for their ability to interact with the I-II loop, the N- and C-termini of Cavalpha2.1, also produce ER retention. It is also not an obligatory determinant as, similarly to low-threshold calcium channels, the I-II loop of Cavalpha1.1 does not produce ER retention in COS7 cells. The data presented here suggests that ER retention is suppressed by sequential molecular events that include: (i). a correct folding of Cavalpha in order to mask several internal ER-retention determinants and (ii). the association of other proteins, including the Cavbeta subunit, to suppress the remaining ER-retention determinants.

Low-threshold potassium channels and a low-threshold calcium channel regulate Ca 2+ spike firing in the dendrites of cerebellar Purkinje neurons: a modeling study

Various types of voltage-gated ion channels are distributed along the dendrites of neurons in the central nervous system. We have recently shown experimentally that the dendrites of cerebellar Purkinje neurons contain low-threshold voltage-gated Ca 2+ channels and low-threshold voltage-gated K + channels. Although we found that these channels are involved in regulating the onset of Ca 2+-dependent action potentials in the dendrites, we were unable to identify which of the known types of low-threshold Ca 2+ channels and K + channels were responsible, since there was no reliable method of discriminating between them. Here, we have built a detailed compartmental model of a Purkinje neuron by incorporating two types of low-threshold Ca 2+ channel (T-type and class-E, or R-type) and two types of low-threshold K + channel (A-type and D-type), in addition to another eight voltage-gated channel types, using a compartmental model neuron simulator. The model reproduces the basic features of the depolarization-induced responses of Purkinje neurons, such as fast Na + spikes in the soma, Ca 2+ spikes in the dendrites, the slow onset of Ca 2+ spikes, repetitive Ca 2+ spikes in the presence of TTX, the marked shortening of Ca 2+ spike onset in the presence of 4-aminopydridine, and the longer Ca 2+ spike onset in the presence of Ni 2+. Our model shows that the D-type K + channel and the class-E Ca 2+ channel regulate the onset of depolarization-induced Ca 2+ spikes in Purkinje neurons. These channels might be involved in integrating synaptic inputs in Purkinje neurons.

Oscillations and long-lasting correlations in a model of the lateral geniculate nucleus and visual cortex.

We have previously developed a model of the corticogeniculate system to explore cortically induced synchronization of lateral geniculate nucleus (LGN) neurons. Our model was based on the experiments of Sillito et al. Recently Brody discovered that the LGN events found by Sillito et al. correlate over a much longer period of time than expected from the stimulus-driven responses and proposed a cortically induced slow covariation in LGN cell membrane potentials to account for this phenomenon. We have examined the data from our model, and we found, to our surprise, that the model shows the same long-term correlation. The model's behavior was the result of a previously unsuspected oscillatory effect, not a slow covariation. The oscillations were in the same frequency range as the well-known spindle oscillations of the thalamocortical system. In the model, the strength of feedback inhibition from the cortex and the presence of low-threshold calcium channels in LGN cells were important. We also found that by making the oscillations more pronounced, we could get a better fit to the experimental data.

Driven by inhibition

We study the stability and information encoding capacity of synchronized states in a neuronal network model that represents part of the thalamic circuitry. Our model neurons have a Hodgkin–Huxley-type low threshold calcium channel, display post-inhibitory rebound, and are connected via GABAergic inhibitory synapses. Noise drives both the subthreshold non-spiking as well as the above threshold regularly spiking state into a self-organized, stochastically synchronized state. Neuronal firing is organized in stochastic clusters, with individual neurons hopping from cluster to cluster. The information content of the resulting spike trains consists of two separate contributions: the spike-time jitter around cluster firing times, and the hopping from cluster to cluster.

Action Potential Backpropagation and Somato-dendritic Distribution of Ion Channels in Thalamocortical Neurons

Thalamocortical (TC) neurons of the dorsal thalamus integrate sensory inputs in an attentionally relevant manner during wakefulness and exhibit complex network-driven and intrinsic oscillatory activity during sleep. Despite these complex intrinsic and network functions, little is known about the dendritic distribution of ion channels in TC neurons or the role such channel distributions may play in synaptic integration. Here we demonstrate with simultaneous somatic and dendritic recordings from TC neurons in brain slices that action potentials evoked by sensory or cortical excitatory postsynaptic potentials are initiated near the soma and backpropagate into the dendrites of TC neurons. Cell-attached recordings demonstrated that TC neuron dendrites contain a nonuniform distribution of sodium but a roughly uniform density of potassium channels across the somatodendritic area examined that corresponds to approximately half the average path length of TC neuron dendrites. Dendritic action potential backpropagation was found to be active, but compromised by dendritic branching, such that action potentials may fail to invade relatively distal dendrites. We have also observed that calcium channels are nonuniformly distributed in the dendrites of TC neurons. Low-threshold calcium channels were found to be concentrated at proximal dendritic locations, sites known to receive excitatory synaptic connections from primary afferents, suggesting that they play a key role in the amplification of sensory inputs to TC neurons.

Synchronous clusters in a noisy inhibitory neural network.

We study the stability and information encoding capacity of synchronized states in a neuronal network model that represents part of thalamic circuitry. Our model neurons have a Hodgkin-Huxley-type low-threshold calcium channel, display postinhibitory rebound, and are connected via GABAergic inhibitory synapses. We find that there is a threshold in synaptic strength, tau(c), below which there are no stable spiking network states. Above threshold the stable spiking state is a cluster state, where different groups of neurons fire consecutively, and each neuron fires with the same cluster each time. Weak noise destabilizes this state, but stronger noise drives the system into a different, self-organized, stochastically synchronized state. Neuronal firing is still organized in clusters, but individual neurons can hop from cluster to cluster. Noise can actually induce and sustain such a state below the threshold of synaptic strength. We do find a qualitative difference in the firing patterns between small (approximately 10 neurons) and large (approximately 1000 neurons) networks. We determine the information content of the spike trains in terms of two separate contributions: the spike-time jitter around cluster firing times, and the hopping from cluster to cluster. We quantify the information loss due to temporally correlated interspike intervals. Recent experiments on the locust olfactory system and striatal neurons suggest that the nervous system may actually use these two channels to encode separate and unique information.

Effects of mibefradil on synaptic transmission in the hippocampus and on voltage-dependent currents in isolated hippocampal and thalamic neurons of the rat

The effects of a novel anti-hypertensive drug, mibefradil, on voltage-dependent currents in isolated thalamic and hippocampal neurons, as well as on synaptic transmission in the hippocampus have been studied. Mibefradil exerted a potent inhibitory action on low-threshold calcium currents in thalamic neurons (IC50=160 nM). In higher concentrations (1–20 μM), this drug blocked not only low-threshold calcium current but also voltage-dependent sodium and delayed potassium currents in pyramidal hippocampal neurons. The amplitude of population action potentials in hippocampal slices decreased by 55% in the presence of 20μM mibefradil. All of the effects of mibefradil were almost completely reversible. In our experiments, the sensitivity of low-threshold calcium channels in thalamic neurons to mibefradil was higher than that observed on other objects. The ability of mibefradil to block not only calcium currents but also other types of voltage-dependent ion conductances in hippocampal neurons may be considered an essential factor that determines the specificity of the pharmacological profile of this drug.