White Matter Microstructure in Bipolar Disorder Is Influenced by the Interaction between a Glutamate Transporter EAAT1 Gene Variant and Early Stress

Glutamate is the principal excitatory neurotransmitter in the central nervous system. In mature brains, it is critically involved in neuroplasticity and, at high levels, neurotoxicity. The concentrations of glutamate in the extracellular space are maintained at low physiological levels by molecular glutamate transporters (excitatory amino acid transporters-EAATs). Adverse childhood experiences (ACEs) are highly reported in bipolar disorder (BD) and interact with the glutamatergic system in the brain. The aim of the study is to investigate the effect of a glutamate transporter polymorphism EAAT2-181A > C (rs4354668) and exposure to ACE on white matter microstructure in patients with BD. We assessed 175 bipolar subjects using diffusion tensor imaging, Risky Families Questionnaire, and EEAT2 rs4354668 variants. We observed an interaction between ACE and rs4354668: carriers of the G allele showed lower axial diffusivity compared to T/T homozygotes when exposed to high stress and higher axial diffusivity than T/T when exposed to low stress. Since the mutant G allele has been associated with a reduced transcriptional activity and expression of the transporter protein, and early stress is associated with a reduced expression of the EAAT2, we could hypothesize that after exposure to high levels of ACE G/G homozygotes are more vulnerable to stress reporting the highest damage as a consequence of an excess of free glutamate.