Cabp2-KO Mouse

Cabp2, or Calcium-binding protein 2, is a potent modulator of inner hair cell (IHC) voltage-gated calcium channels CaV1.3 [1]. It is part of the Ca2+ binding proteins family related to calmodulin, and is highly expressed in the cochlea [2]. In the cochlea, it plays a crucial role in auditory function by influencing the availability of CaV1.3 Ca2+ channels for synaptic sound encoding [3].

In Cabp2 -/- mice, enhanced steady-state inactivation of IHC CaV1.3 channels was observed, effectively limiting their ability to trigger synaptic transmission, which led to hearing impairment similar to the human DFNB93 non-syndromic autosomal recessive hearing impairment [1,3]. Gene therapy using AAV2/1 and AAV-PHP.eB viral vectors to deliver the Cabp2 coding sequence into IHCs of early postnatal Cabp2 -/- mice restored hair cell function and improved hearing, demonstrating the feasibility of DFNB93 gene therapy [1]. Additionally, CaBP2 KO mice showed significant ABR threshold elevations at 4 weeks of age, which became more severe in the mid-frequency range by 9 weeks, and DPOAEs were significantly reduced in the mid-frequency range by 9 weeks, revealing its requirement in the peripheral auditory system [2].

In conclusion, Cabp2 is essential for normal auditory function, mainly by modulating the inactivation of CaV1.3 channels in inner hair cells. Studies on Cabp2 KO mouse models have provided valuable insights into the pathogenesis of DFNB93 non-syndromic autosomal recessive hearing impairment and the potential for gene therapy in treating this form of hearing loss [1,2,3].

References:

1. Oestreicher, David, Picher, Maria Magdalena, Rankovic, Vladan, Moser, Tobias, Pangrsic, Tina. 2021. Cabp2-Gene Therapy Restores Inner Hair Cell Calcium Currents and Improves Hearing in a DFNB93 Mouse Model. In Frontiers in molecular neuroscience, 14, 689415. doi:10.3389/fnmol.2021.689415. https://pubmed.ncbi.nlm.nih.gov/34489639/

2. Yang, Tian, Hu, Ning, Pangršič, Tina, Hansen, Marlan, Lee, Amy. 2018. Functions of CaBP1 and CaBP2 in the peripheral auditory system. In Hearing research, 364, 48-58. doi:10.1016/j.heares.2018.04.001. https://pubmed.ncbi.nlm.nih.gov/29661613/

3. Picher, Maria Magdalena, Gehrt, Anna, Meese, Sandra, Strenzke, Nicola, Moser, Tobias. 2017. Ca2+-binding protein 2 inhibits Ca2+-channel inactivation in mouse inner hair cells. In Proceedings of the National Academy of Sciences of the United States of America, 114, E1717-E1726. doi:10.1073/pnas.1617533114. https://pubmed.ncbi.nlm.nih.gov/28183797/