TY - JOUR
T1 - Scn1a and Cacna1a mutations mutually alter their original phenotypes in rats
AU - Ohmori, Iori
AU - Kobayashi, Kiyoka
AU - Ouchida, Mamoru
N1 - Funding Information:
This work was supported by a Grant-in-Aid for Scientific Research (B) from the Japanese Ministry of Education, Culture, Sports, Science and Technology (Grant No. 21390312 to I.O.).
Publisher Copyright:
© 2020 The Author(s)
PY - 2020/12
Y1 - 2020/12
N2 - This study aimed to examine the effects of Cacna1a mutation on the phenotype of Scn1a-associated epilepsy in rats. We used rats with an N1417H missense mutation in the Scn1a gene and others with an M251K mutation in the Cacna1a gene. Scn1a/Cacna1a double mutant rats were generated by mating both Scn1a and Cacna1a mutants. We investigated general health and the epileptic phenotype in all these genotypes. The onset threshold of hyperthermia-induced seizures was examined at 5 weeks and spontaneous seizures were monitored using video-EEG recordings from 6 to 12 weeks of age. Scn1a/Cacna1a double mutants showed significantly reduced threshold for hyperthermia-sensitive seizures onset compared with the Scn1a mutants and had absence seizures having 6–7 c/s spike-wave bursts with changes in the spike-wave pattern, whereas Cacna1a mutants had regular 6–7 c/s spike-wave bursts. In Scn1a/Cacna1a double mutants, 6–7 c/s spike-wave bursts were accompanied with eyelid myoclonia and continuously shifting generalized clonic seizures, which were not observed in either Scn1a or Cacna1a mutants. Although a curvature of the spine was observed in rats of all these genotypes, the degree of curvature was more pronounced in Scn1a/Cacna1a double mutants, followed by Cacna1a and Scn1a mutants. Our results indicate that Cacna1a and Scn1a mutations mutually alter their original phenotypes in rats. The phenotype of absence seizures with eyelid myoclonia, generalized clonic seizures, and of spine curvature in the Scn1a/Cacna1a double mutants were similar to that observed in patients with Dravet syndrome.
AB - This study aimed to examine the effects of Cacna1a mutation on the phenotype of Scn1a-associated epilepsy in rats. We used rats with an N1417H missense mutation in the Scn1a gene and others with an M251K mutation in the Cacna1a gene. Scn1a/Cacna1a double mutant rats were generated by mating both Scn1a and Cacna1a mutants. We investigated general health and the epileptic phenotype in all these genotypes. The onset threshold of hyperthermia-induced seizures was examined at 5 weeks and spontaneous seizures were monitored using video-EEG recordings from 6 to 12 weeks of age. Scn1a/Cacna1a double mutants showed significantly reduced threshold for hyperthermia-sensitive seizures onset compared with the Scn1a mutants and had absence seizures having 6–7 c/s spike-wave bursts with changes in the spike-wave pattern, whereas Cacna1a mutants had regular 6–7 c/s spike-wave bursts. In Scn1a/Cacna1a double mutants, 6–7 c/s spike-wave bursts were accompanied with eyelid myoclonia and continuously shifting generalized clonic seizures, which were not observed in either Scn1a or Cacna1a mutants. Although a curvature of the spine was observed in rats of all these genotypes, the degree of curvature was more pronounced in Scn1a/Cacna1a double mutants, followed by Cacna1a and Scn1a mutants. Our results indicate that Cacna1a and Scn1a mutations mutually alter their original phenotypes in rats. The phenotype of absence seizures with eyelid myoclonia, generalized clonic seizures, and of spine curvature in the Scn1a/Cacna1a double mutants were similar to that observed in patients with Dravet syndrome.
KW - Absence seizure
KW - Cacna1a
KW - Dravet syndrome
KW - GABAergic interneuron
KW - GEFS+
KW - Hyperthermia-sensitive seizure
KW - Parvalbumin-positive cell
KW - Scn1a
KW - Skeletal abnormality
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U2 - 10.1016/j.neuint.2020.104859
DO - 10.1016/j.neuint.2020.104859
M3 - Article
C2 - 33045260
AN - SCOPUS:85093975919
VL - 141
JO - Neurochemistry International
JF - Neurochemistry International
SN - 0197-0186
M1 - 104859
ER -