Bumetanide treatment during early development rescues maternal separation-induced susceptibility to stress

Stress is a major risk factor for psychiatric disorders, such as depression, posttraumatic stress disorder, and schizophrenia. Early life stress, such as maternal separation, can have long-term effects on the development of the central nervous system and pathogenesis of psychiatric disorders. In the present study, we found that maternal separation increased the susceptibility to stress in adolescent rats, increased the expression of Na+/K+/2Cl(-) cotransporter 1 (NKCC1) on postnatal day 14, and increased the expression of K+/2Cl(-) cotransporter 2 (KCC2) and gamma-aminobutyric acid A (GABA(A)) receptor subunits on postnatal day 40 in the hippocampus. NKCC1 inhibition by the U.S. Food and Drug Administration-approved drug bumetanide during the first two postnatal weeks rescued the depressive-and anxiety-like behavior that was induced by maternal separation and decreased the expression of NKCC1, KCC2 and GABA(A) receptor alpha 1 and beta 2,3 subunits in the hippocampus. Bumetanide treatment during early development did not adversely affect body weight or normal behaviors in naive rats, or affect serum osmolality in adult rats. These results suggest that bumetanide treatment during early development may prevent the maternal separation-induced susceptibility to stress and impairments in GABAergic transmission in the hippocampus.Natural Science Foundation of China [81225009, U1402226, 31571099, 81521063]; National Basic Research Program of China [2015CB553503, 2015CB856400]; Beijing Municipal Science and Technology Commission [Z161100002616006]SCI(E)ARTICLE