Impairment of hippocampal long-term potentiation by soluble amyloid-β oligomers is mediated by glutamate transporter 1 expressed in neurons.

In Alzheimer’s disease, perturbations of glutamate neurotransmission lead to synaptic dysfunction and synapse loss. Several studies have used glutamate transport inhibitors to demonstrate that soluble oligomers of amyloid-β induce synaptic dysfunction by interrupting glutamate uptake mediated by glutamate transporter 1, the major glutamate transporter in the brain. The cellular targets of the synaptic effects of soluble amyloid-β oligomers, including the nature of any interaction with glutamate transporter 1, remain ill-defined. We have generated a conditional glutamate transporter 1 knockout mouse to investigate cell-type specific functions of glutamate transporter 1. Field excitatory postsynaptic potentials were examined in the CA1 region of mouse hippocampal slices. We confirmed that hippocampal long-term potentiation impairment is induced by both soluble amyloid-β oligomers and glutamate uptake inhibitors. Amyloid-β oligomers, including those isolated directly from the cortex of patients with Alzheimer’s disease, failed to inhibit hippocampal long-term potentiation in neuronal glutamate transporter 1 but not astrocytic glutamate transporter 1 knockout mice. The masking or occlusion of the effect of soluble amyloid-β oligomers by knockout of glutamate transporter 1 in neurons suggests that the metabolic or signaling consequences of knockout of glutamate transporter 1 in neurons and amyloid-β oligomer inhibition of synaptic plasticity show epistasis and thus share a similar molecular pathway. To extend these observations, we tested the effects of other types of manipulation of glutamate homeostasis on synaptic plasticity and the pathophysiology of soluble amyloid-β oligomers. Ceftriaxone, which upregulates glutamate transporter 1 levels, among other effects, prevented the impairment of long-term potentiation by soluble amyloid-β oligomers. Collectively, our findings suggest that the effects of amyloid-β on synaptic function are highly dependent on glutamate reuptake homeostasis and that the disruption of synaptic function by soluble amyloid-β oligomers is mediated by pathways linked to neuronal, not astrocytic, glutamate transporter 1. The findings of this study highlight the translational potential of targeting neuronal glutamate transporter 1 to counteract amyloid-β–induced synaptic dysfunction in Alzheimer’s disease. By showing that glutamate transporter 1 upregulation (e.g., via ceftriaxone) can prevent amyloid-β-related impairments, this research supports developing therapies aimed at modulating glutamate homeostasis to preserve synaptic function and combat cognitive decline in patients with Alzheimer’s disease.