Raised Activity of L-Type Calcium Channels Renders Neurons Prone to Form Paroxysmal Depolarization Shifts

Abstract

Neuronal L-type voltage-gated calcium channels (LTCCs) are involved in several physiological functions, but increased activity of LTCCs has been linked to pathology. Due to the coupling of LTCC-mediated Ca2+ influx to Ca2+-dependent conductances, such as KCa or non-specific cation channels, LTCCs act as important regulators of neuronal excitability. Augmentation of after-hyperpolarizations may be one mechanism that shows how elevated LTCC activity can lead to neurological malfunctions. However, little is known about other impacts on electrical discharge activity. We used pharmacological up-regulation of LTCCs to address this issue on primary rat hippocampal neurons. Potentiation of LTCCs with Bay K8644 enhanced excitatory postsynaptic potentials to various degrees and eventually resulted in paroxysmal depolarization shifts (PDS). Under conditions of disturbed Ca2+ homeostasis, PDS were evoked frequently upon LTCC potentiation. Exposing the neurons to oxidative stress using hydrogen peroxide also induced LTCC-dependent PDS. Hence, raising LTCC activity had unidirectional effects on brief electrical signals and increased the likeliness of epileptiform events. However, long-lasting seizure-like activity induced by various pharmacological means was affected by Bay K8644 in a bimodal manner, with increases in one group of neurons and decreases in another group. In each group, isradipine exerted the opposite effect. This suggests that therapeutic reduction in LTCC activity may have little beneficial or even adverse effects on long-lasting abnormal discharge activities. However, our data identify enhanced activity of LTCCs as one precipitating cause of PDS. Because evidence is continuously accumulating that PDS represent important elements in neuropathogenesis, LTCCs may provide valuable targets for neuroprophylactic therapy.Electronic supplementary materialThe online version of this article (doi:10.1007/s12017-013-8234-1) contains supplementary material, which is available to authorized users.

The anticonvulsant retigabine is a subtype selective modulator of GABAA receptors

“…This, however, is beyond therapeutic concentrations, which range up to 10 μ m only . In primary cultures of dissociated rat hippocampi with well‐established synaptic contacts (i.e., at least 20 days in culture), low Mg 2+ can also be used to trigger seizure‐like activity, and the latter was reduced by retigabine in a concentration‐dependent manner with half maximal inhibition at 1 μ m (Fig. A,E).…”

“…Current clamp recordings of seizure‐like activity were performed using a Multiclamp 700B amplifier (Molecular Devices, Sunnyvale, CA, U.S.A.) as described before . The internal (pipette) solution for current clamp recordings contained (m m ): 120 potassium gluconate, 1.5 sodium gluconate, 3.5 NaCl, 1.5 CaCl 2 , 0.25 MgCl 2 , 10 2‐(4‐(2‐hydroxyethyl)‐1‐piperazinyl)‐ethansulfonic acid (HEPES), 10 glucose, and 5 ethylene glycol tetraacetic acid (EGTA) (pH was adjusted to 7.3 with KOH).…”

“…Seizure‐like activity in current clamp recordings involves enhanced discharge frequencies as well as depolarized membrane potentials and was thus quantified by determining area under the curve (AUC) values as described . Briefly, the area between the voltage trace and a baseline corresponding to the average resting membrane potential before onset of seizure‐like activity, was calculated (mV·msec) for periods of 90 s per condition.…”

Cav1.3 channels play a crucial role in the formation of paroxysmal depolarization shifts in cultured hippocampal neurons

“…A particular epileptiform discharge event for which a crucial contribution of LTCCs has been identified is the so‐called paroxysmal depolarization shift (PDS) . In its broadest sense, the PDS represents a “burst pattern of discharge generated by an abnormal depolarization of neuronal membranes.” It has been viewed in this respect as the hallmark of epileptic discharge .…”

Isoflurane, but Not the Nonimmobilizers F6 and F8, Inhibits Rat Spinal Cord Motor Neuron CaV1 Calcium Currents

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