Plaza-Briceno, W. | bioRxiv Science

bioRxiv2026

EXECUTIVE DYSFUNCTIONS IN THE EAAT3 OVEREXPRESSING MOUSE MODEL OF COMPULSIVE BEHAVIOR

Executive functions are a set of cognitive processes that regulate behavior and adapt responses to changing demands. Impairments in these processes are common in various neuropsychiatric conditions, including obsessive-compulsive disorder. Mice overexpressing the neuronal glutamate transporter EAAT3 in the forebrain (EAAT3glo/CaMKII) exhibit increased compulsive behaviors and synaptic alterations relevant to OCD. However, whether EAAT3 overexpression affects executive functioning across multiple cognitive domains has not been studied. Using operant conditioning and visuospatial learning tasks, we evaluated the performance of EAAT3glo/CaMKII mice across three behavioral domains commonly associated with executive function: cognitive flexibility, working memory, and inhibitory control. EAAT3glo/CaMKII mice showed impaired cognitive flexibility in both operant extinction and reversal learning. EAAT3glo/CaMKII mice also failed to acquire the Trial-unique, delayed nonmatching-to-location task, suggesting impaired working memory, and showed increased impulsivity in the five-choice serial reaction time task, as evidenced by elevated premature responses. Perseverative responses, response accuracy, and attentional performance were unaffected in EAAT3glo/CaMKII mice. Collectively, these findings suggest that EAAT3 overexpression in forebrain neurons is associated with a cognitive profile characterized by difficulties in flexibility and task acquisition, alongside increased impulsivity, while attentional performance and motivational measures remain intact in a model of compulsive behavior.

animal behavior and cognition↗

bioRxiv2026

Neuronal glutamate transporter EAAT3 regulates hippocampal GABAergic plasticity and reversal learning

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.

neuroscience↗