TY - JOUR T1 - Hippocampal Synaptic Dysfunction in a Mouse Model of Huntington Disease Is Not Alleviated by Ceftriaxone Treatment JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0440-19.2020 VL - 7 IS - 3 SP - ENEURO.0440-19.2020 AU - Crystal M. Wilkie AU - Jocelyn R. Barnes AU - Cherry-Lynn M. Benson AU - Kyle J. Brymer AU - Firoozeh Nafar AU - Matthew P. Parsons Y1 - 2020/05/01 UR - http://www.eneuro.org/content/7/3/ENEURO.0440-19.2020.abstract N2 - Glutamate transporters, particularly glutamate transporter 1 (GLT-1), help to prevent the adverse effects associated with glutamate toxicity by rapidly clearing glutamate from the extracellular space. Since GLT-1 expression and/or function are reduced in many neurodegenerative diseases, upregulation of GLT-1 is a favorable approach to treat the symptoms of these diseases. Ceftriaxone, a β-lactam antibiotic reported to increase GLT-1 expression, can exert neuroprotective effects in a variety of neurodegenerative diseases; however, many of these diseases do not exhibit uniform brain pathology. In contrast, as a drug that readily crosses the blood–brain barrier, ceftriaxone administration is likely to increase GLT-1 levels globally throughout the neuroaxis. In Huntington disease (HD), low GLT-1 expression is observed in the striatum in postmortem tissue and animal models. While ceftriaxone was reported to increase striatal GLT-1 and ameliorate the motor symptoms in a mouse model of HD, the extrastriatal effects of ceftriaxone in HD are unknown. Using electrophysiology and high-speed imaging of the glutamate biosensor iGluSnFR, we quantified real-time glutamate dynamics and synaptic plasticity in the hippocampus of the Q175FDN mouse model of HD, following intraperitoneal injections of either saline or ceftriaxone. We observed an activity-dependent increase in extracellular glutamate accumulation within the HD hippocampus, which was not the result of reduced GLT-1 expression. Surprisingly, ceftriaxone had little effect on glutamate clearance rates and negatively impacted synaptic plasticity. These data provide evidence for glutamate dysregulation in the HD hippocampus but also caution the use of ceftriaxone as a treatment for HD. ER -