Increased Forebrain Eaat3 Expression Confers Resilience To Chronic Stress

Abstract Depression is a disabling and highly prevalent psychiatric illness. Multiple studies have linked glutamatergic dysfunction with the pathophysiology of depression, but the exact alterations in the glutamatergic system that contribute to depressive‐like behaviors are not fully understood. Recent evidence suggests that a decreased level in neuronal glutamate transporter (EAAT3), known to control glutamate levels and limit the activation of glutamate receptors at synaptic sites, may contribute to the manifestation of a depressive phenotype. Here, we tested the possibility that increased EAAT3 expression at excitatory synapses could reduce the susceptibility of mice to develop depressive‐like behaviors when challenged to a 5‐week unpredictable chronic mild stress (UCMS) protocol. Mice overexpressing EAAT3 in the forebrain (EAAT3 glo /CMKII) and control littermates (EAAT3 glo ) were assessed for depressive‐like behaviors and long‐term memory performance after being subjected to UCMS conditions. We found that, after UCMS, EAAT3 glo /CMKII mice did not exhibit depressive‐like behaviors or memory alterations observed in control mice. Moreover, we found that EAAT3 glo /CMKII mice did not show alterations in phasic dopamine release in the nucleus accumbens neither in long‐term synaptic plasticity in the CA1 region of the hippocampus after UCMS, as observed in control littermates. Altogether these results suggest that forebrain EAAT3 overexpression may be related to a resilient phenotype, both at behavioral and functional level, to the deleterious effect of chronic stress, highlighting the importance of neuronal EAAT3 in the pathophysiology of depressive‐like behaviors. image