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Cacna1b alternative splicing is linked to associative learning.

Simrat Kaur Dhillon1,2, Ava Cardarelli1,2, Ashton Brennecke3

  • 1Robert J & Nancy D Carney Institute for Brain Science, Brown University. 164 Angell St. Providence, RI. 02906.

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|February 27, 2026
PubMed
Summary

Alternative splicing of exon 18a in the Cacna1b gene influences associative learning. Mice with specific splice variants showed altered freezing behavior in a fear conditioning task, highlighting exon 18a

Keywords:
Calcium channelsalternative splicingassociative learningcognitive function

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Voltage-gated calcium channels (CaV 2.2) are crucial for neurotransmitter release and cognitive functions, including learning and memory.
  • The Cacna1b gene, encoding CaV 2.2 channels, undergoes extensive cell-specific alternative splicing, but its link to cognitive processes remains unclear.
  • Alternative splicing of exon 18a generates two variants (+18a-Cacna1b and Δ18a-Cacna1b) affecting the synprint site and channel function.

Purpose of the Study:

  • To investigate the role of alternative splicing of Cacna1b exon 18a in associative learning.
  • To determine if specific splice variants of Cacna1b influence learning and memory-related behaviors.

Main Methods:

  • Generated genetically engineered mice constitutively expressing either +18a-Cacna1b or Δ18a-Cacna1b splice variants.
  • Validated splicing patterns and CaV 2.2 protein levels in engineered mice.
  • Conducted comprehensive behavioral analyses, including trace fear conditioning, spatial working memory, and nociception tests.

Main Results:

  • Mice expressing +18a-Cacna1b showed reduced freezing in trace fear conditioning, while Δ18a-Cacna1b mice exhibited enhanced freezing compared to wild-type controls.
  • These bidirectional effects indicate that exon 18a splicing significantly shapes aversive associative learning.
  • Exon 18a splicing did not impact spatial working memory, locomotion, or nociception, suggesting a selective behavioral role.

Conclusions:

  • Alternative splicing of Cacna1b exon 18a is a key molecular determinant of aversive associative learning.
  • The functional specialization of CaV 2.2 splice variants contributes selectively to specific cognitive processes.
  • These findings identify a novel link between pre-mRNA splicing and complex behaviors like associative learning.