The dense core vesicle protein IA-2, but not IA-2β, is required for active avoidance learning

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Islet-antigens IA-2 and IA-2β are transmembrane proteins found in dense core vesicles (DCVs).
• Previous research demonstrated that deleting both IA-2 and IA-2β impacts hormone secretion, neurotransmitter release, behavior, and learning.
• The specific roles of individual IA-2 and IA-2β genes in learning remain to be fully elucidated.

Purpose of the Study:

• To investigate the distinct contributions of IA-2 and IA-2β genes to active avoidance learning.
• To explore the molecular mechanisms underlying learning deficits associated with IA-2 and IA-2β gene deletion.

Main Methods:

• Utilized single knockout (SKO) and double knockout (DKO) mouse models lacking IA-2, IA-2β, or both genes.
• Assessed active avoidance learning using a 5-day training paradigm in an active avoidance test.
• Analyzed the phosphorylation levels of cAMP response element-binding protein (CREB) and Ca(2+)/calmodulin-dependent protein kinase II (CAMKII) in the striatum and hippocampus.
• Administered GBR-12909, a dopamine transporter inhibitor, to evaluate its effect on learning and molecular pathways.

Main Results:

• DKO mice and IA-2 SKO mice exhibited significantly impaired active avoidance learning (10-15% response rate) compared to wild-type (WT) mice (60-70%).
• IA-2β SKO mice showed learning abilities comparable to WT mice.
• A marked decrease in CREB and CAMKII phosphorylation was observed in the striatum and hippocampus of IA-2 SKO and DKO mice, but not in IA-2β SKO mice.
• GBR-12909 treatment restored CREB and CAMKII phosphorylation and significantly improved active avoidance learning in DKO and IA-2 SKO mice.

Conclusions:

• The islet-antigen IA-2 protein plays a critical role in active avoidance learning.
• Impaired learning in IA-2 deficient mice is associated with reduced CREB and CAMKII phosphorylation in key brain regions.
• Targeting the CREB and CAMKII pathways may offer therapeutic potential for cognitive deficits related to IA-2 deficiency.