Deficit of neuronal EAAT2 impairs hippocampus CA3 neuron’s activity and may induce depressive like behaviors

INTRODUCTION: Major depressive disorder (MDD) is a severe neuropsychiatric disease that is accompanied by hippocampal dysfunction. Currently, the complex neuronal types and molecules involved in the various hippocampal subfields in patients with depression remain unclear. OBJECTIVES: We focused on the role of hippocampal excitatory amino acid transporter 2 (EAAT2) in chronic stress. METHODS: We studied two chronic stress models, the chronic unpredictable mild stress (CUMS) and the chronic social defeat stress (CSDS) models, and performed pharmacological inhibition, genetic manipulations to examine overexpression of neuron-specific solute carrier family 1 member 2 (SLC1A2), the gene encoding EAAT2, in the dorsal CA3 and conditional Slc1a2 knockout in CA3, whole-cell recording, and behavioral tests. RESULTS: Our results indicated that decreased EAAT2 expression and specific inhibition were associated with depression-like behavior and enhanced CA3 pyramidal neuron activity. In addition, neuron-specific EAAT2 overexpression in the CA3 yielded antidepressant-like effects and inhibited CA3 pyramidal neuron hyperactivity, whereas conditional CA3 EAAT2 knockout showed opposite effects at both behavioral and functional levels. We also found that the single-nucleotide polymorphism, rs77619780, in the SLCA1A2 gene was associated with lower MDD risk. CONCLUSION: Our findings revealed that EAAT2 deficit in the CA3 induces depression-like behavior, which offers novel insight into MDD pathophysiology.