Cav2.3 (R-Type) Calcium Channels are Critical for Mediating Anticonvulsive and Neuroprotective Properties of Lamotrigine In Vivo

Abstract

Background/Aims: Lamotrigine (LTG) is a popular modern antiepileptic drug (AED), however, its mechanism of action has yet to be fully understood, as it is known to modulate many members of several ion channel families. In heterologous systems, LTG inhibits Ca_v2.3 (R-type) calcium currents, which contribute to kainic-acid- (KA) induced epilepsy in vivo. To gain insight into the role of R-type currents in LTG drug action in vivo, we compared the effects of LTG to topiramate and lacosamide in Ca_v2.3-deficient mice and controls on KA-induced seizures. Methods: Behavioral seizure rating and quantitative electrocorticography were performed after injection of 20 mg/kg [and 30 mg/kg] KA. One hour before KA injection, mice were pretreated with either 30 mg/kg LTG, 50 mg/kg topiramate (TPM) or 30 mg/kg lacosamide (LSM). Results: Ablation of Ca_v2.3 reduced total seizure scores by 28.6% (p=0.0012) and pretreatment with LTG reduced seizure activity of control mice by 23.2% (p=0.02). In Ca_v2.3-deficient mice LTG pretreatment increased seizure activity by 22.1% (p=0.018) and increased the percentage of degenerated CA1 pyramidal neurons (p=0.02). All three tested AEDs reduced seizure activity in control mice, however only the non-calcium channel modulating AED, LSM had an anticonvulsive effect in Ca_v2.3-deficient mice. Furthermore LTG altered electrocorticographic parameters differently in the two genotypes, decreasing relative power of ictal spikes in control mice compared to Ca_v2.3-defcient mice. Conclusion: These findings give first in vivo evidence for an essential role for Ca_v2.3 in LTG pharmacology and shed light on a paradoxical effect of LTG in their absence. Furthermore, LTG appears to promote ictal activity in Ca_v2.3-deficient mice resulting in increased neurotoxicity in the CA1 region. This paradoxical mechanism, possibly reflecting rebound hyperexcitation of pyramidal CA1 neurons after increased inhibition, may be key in understanding LTG-induced seizure aggravation, observed in clinical practice.

Non-Mendelian inheritance during inbreeding of Cav3.2 and Cav2.3 deficient mice

“…Ten mammalian genes are known to encode different ion conducting Ca v α1 subunits of these VGCCs, which have been subdivided into 7 high- and 3 low-voltage activated Ca 2+ channels (for details, 4 ). In vivo, they are assembled with additional auxiliary subunits 5 , for which the complete setup of components is only partially known. Additional structural variation arises from alternative splicing, which increases structural and functional variability 6 , 7 .…”

Cav2.3 channel function and Zn2+-induced modulation: potential mechanisms and (patho)physiological relevance

“…Ca v 2.3 channels are widely expressed throughout the central and peripheral nervous system [ 37 , 64 , 80 , 81 ] and in endocrine [ 80 , 82 , 83 ], cardiovascular [ 84 ], gastrointestinal [ 80 ] and reproductive tissues [ 85 , 86 ]. Despite this widespread expression, Ca v 2.3-deficient mice display a surprisingly subtle phenotype with no major pathologies but altered nociception [ 87 ], glucose homeostasis [ 49 , 88 , 89 ] and spatial memory [ 90 ], impaired autonomic control [ 84 , 91 ], increased anxiety [ 92 ] and reduced susceptibility to chemically induced seizures [ 93 , 94 ].…”

“…The exact physiological relevance of Ca v 2.3 channels in most other brain regions remains elusive, but they have been implicated in a number of pathophysiological conditions. Most notably, Ca v 2.3 channels are thought to play a pro-ictogenic role in convulsive-generalized tonic-clonic and hippocampal seizures, since their genetic ablation reduces the susceptibility to chemically induced seizures [ 93 , 94 , 108 ] and abrogates the effects of several broad-spectrum antiepileptic drugs known to suppress cloned Ca v 2.3 channels [ 94 , 109 , 110 ]. More recently, de novo gain-of-function mutations in Ca v 2.3 channels have also been linked to developmental and epileptic encephalopathies in human patients, which are associated with epileptiform EEG activity, intractable seizures, and developmental impairments [ 111 , 112 ].…”

Lamotrigine in the Prevention of Migraine With Aura: A Narrative Review

“…LTG also blocks TRESK potassium channels with moderate affinity . Interestingly, LTG has high affinity and can inhibit similarly N‐(Cav2.2), P/Q‐(Cav2.1), and R‐type (Cav2.3) voltage‐gated calcium channels . These presynaptic channels are key players for spreading depolarization and glutamate release during CSD .…”