Neuronal glutamate transporter EAAT3 regulates hippocampal GABAergic plasticity and reversal learning
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Long-term depression (LTD) is a form of synaptic plasticity implicated in tasks involving the modification or elimination of previously learned information. While glial glutamate transporters can control the strength of synaptic plasticity, much less is known about the contribution of the neuronal glutamate transporter EAAT3 in controlling hippocampal LTD and learning processes. Here, we report that overexpression of EAAT3 in principal neurons, but not in GABAergic interneurons, impairs heterosynaptic GABAergic synaptic plasticity (iLTD) and homosynaptic excitatory LTD in the hippocampus. LTD impairments can be reversed by inhibiting EAAT3 or by a brief exogenous activation of mGluR during LTD induction, suggesting that, by limiting glutamate spillover between neighboring synapses, EAAT3 contributes to setting the strength of different forms of hippocampal LTD. Moreover, mice overexpressing EAAT3 in principal neurons, but not in GABAergic interneurons, display impaired reversal learning, a phenotype that can be rescued by blocking EAAT3 in vivo . Together, these findings reveal that, by controlling the strength of hippocampal LTD, EAAT3 contributes to cognitive flexibility required for processing new information.
Significance statement
Cognitive flexibility, particularly reversal learning, depends critically on the ability to weaken outdated synaptic connections, a cellular process mediated by long-term depression (LTD), that enables new memories to be stored in overlapping circuits. While astrocytic glutamate transporters are known to shape synaptic plasticity, the contribution of neuronal glutamate transporter EAAT3 has remained unclear. Here we identify EAAT3 as a key factor for hippocampal LTD and behavioral flexibility. Overexpression of EAAT3 in principal neurons, but not in GABAergic interneurons, impairs homosynaptic and heterosynaptic forms of LTD, and produces perseverative deficits in hippocampal-mediated reversal learning tasks that are rescued by EAAT3 blockade. These findings reveal that neuronal glutamate uptake, likely by limiting glutamate spillover between neighboring synapses, plays an important role in setting the threshold for multiple forms of hippocampal LTD and establishing a mechanistic link between EAAT3, synaptic depotentiation, and the capacity to update learned information in vivo .
