Identification and characterization of a novel, conserved metallo-β-lactamase regulator of dopamine and glutamate signaling

Abstract

Coordinated neurotransmission of fast acting neurotransmitters like glutamate (GLU) and neuromodulators such as dopamine (DA) is critical for the proper execution of complex behaviors such as cognition, locomotor control, learning, and reward. Across phylogeny, both glia and neurons cooperate to control the length and amplitude of synaptic and extrasynaptic neurotransmission. In this study we report the our attempts to isolate novel regulators of DA neurotransmission using C. elegans and the identification and characterization of a novel, conserved enzymatic regulator of DA and GLU signaling called swip-10. We determined that swip-10 is expressed and functions in worm glia and regulates the excitability of worm DA neurons indirectly through the actions of GLU receptors and transporters. We report the expression pattern of its mammalian homolog, Mblac1, in the mouse brain and its association with glial compartments and GLU-related signaling proteins. We hypothesize that Mblac1 represents a central node for the control of extrasynaptic GLU signaling, an obligate target of β-lactam antibiotic action in the central nervous system, and a novel link to multiple brain disorders including amyotrophic lateral sclerosis, Parkinson’s disease, depression, and addiction.