Contributions of Metallo-Beta-Lactamase Domain Containing Protein 1 (MBLAC1) to the Neurobiological Actions of Ceftriaxone

Abstract

Contributions of Metallo-Beta-Lactamase Domain Containing Protein 1 (MBLAC1) to the Neurobiological Actions of Ceftriaxone Cassandra Lynn Retzlaff

Dissertation under the direction of Professor Randy Blakely, PhD

Recently identified glial-expressed C. elegans gene, swip-10, encodes a metallo-beta-lactamase domain-containing protein, which limits glutamate-dependent changes in dopamine neuron excitability. Bioinformatic analyses identified MBLAC1 as the likely mammalian orthologue of swip-10. Ceftriaxone, a beta-lactam antibiotic, has been reported to act independently of its antimicrobial actions to normalize perturbed central nervous system glutamate levels, principally by elevating expression of glial glutamate transporters. Housing a canonical beta-lactam binding domain, MBLAC1, stood out as a possible molecular target for ceftriaxone, of which one is currently unknown. Using multiple approaches, evidence presented asserts the specific, high affinity binding of ceftriaxone to MBLAC1. Furthermore, the creation of a novel knockout mouse model was utilized in order to test these hypotheses in vivo, and to establish a role for MBLAC1 in the brain.