Hippocampal synaptic dysfunction in a mouse model of Huntington disease is not alleviated by ceftriaxone treatment.

Glutamate transporters, particularly glutamate transporter 1 (GLT-1), help prevent the adverse effects associated with glutamate toxicity by rapidly clearing glutamate from the extracellular space. Since GLT-1 expression and/or function is reduced in many neurodegenerative diseases, upregulation of GLT-1 is a favourable approach to treat the symptoms of these diseases. Ceftriaxone, a beta-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 post-mortem 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 i.p. 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. Huntington disease (HD) is an inherited neurodegenerative disease. In addition to the debilitating motor symptoms, HD is commonly associated with burdensome cognitive impairments. Here, we used a mouse model of HD to show that in a region essential for cognition, the hippocampus, excessive levels of the neurotransmitter glutamate accumulate during neural activity. While required for rapid cellular communication, too much glutamate impairs synapse strengthening and negatively impacts cellular health. Glutamate accumulation in the HD hippocampus appeared not to be due to altered expression of glutamate transporter-1, a highly-expressed protein in the brain that controls glutamate levels. This is the first study to show abnormal glutamate accumulation in the HD hippocampus, which may underlie the devastating cognitive symptoms associated with HD.