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

Abstract

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 γ-aminobutyric acid A (GABAA) 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 GABAA receptor α1 and β2,3 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.

Bumetanide Prevents Brain Trauma-Induced Depressive-Like Behavior

“…Parvalbumin-containing interneurons are the principal source of GABA release within the dentate gyrus and thus potential candidates to explain controlled-cortical impact (CCI)-induced dysregulations through their role in the synchronicity of hippocampal networks (Curia et al, 2008; Drexel et al, 2011; Shiri et al, 2014). Moreover, it is accepted that the activity of this class of interneurons could act on secondary neurogenesis by providing a source of ambient GABA (Song et al, 2012; Butler et al, 2016; Hu D. et al, 2017; Pérez-Domínguez et al, 2017), but little is known about the relationship that exists between parvalbumin-containing interneurons and the establishment of post-traumatic depression (Earnheart et al, 2007; Luscher et al, 2011; Fenton, 2015). Moreover, in human depression, their action is far from being established (Khundakar et al, 2011; Pehrson and Sanchez, 2015; Smiley et al, 2016).…”

Environmental regulation of the chloride transporter KCC2: switching inflammation off to switch the GABA on?

“…Stressful conditions occurring at early post-developmental stages also impact GABAergic signaling. Indeed, animal models of maternal separation, based on daily rounds of pup separation from the mother lasting from the first postnatal day up to 2 weeks, display longer latency to play and decreased social play behavior 107 , and anxiety-like states 108 , associated with KCC2 deregulation delayed GABA developmental switch and excitatory GABA action 109 , 110 . However, it should be noted that in a different experimental setting based on 6 h daily separation from the dam at P4 for just 3 days, KCC2 immunoreactivity was found to be increased only in males and not females, indicating a gender-specific effect of early post-natal stress on KCC2 expression 111 .…”

“… Age Environmental challenge Duration Effect Brain region Species Sex Reference Prenatal GD9 Maternal immune activation (PolyI:C) Acute ↓KCC2 (PND20-90), ↑ NKCC1 (E17) Cortex Mouse Mix [ 64 ] GD14-21 Maternal restraint stress Chronic (7 days) ↓KCC2 (PND22-40),↑KCC2 transient (PND21), ↓NKCCl transient (PND14) Hippocampus Rat NS [ 104 ] GD15 Maternal restraint stress or betamethasone i.p. (2x0,4mg/kg) Acute ↓KCC2 (PND7-15) Cortex Rat Mix [ 105 ] GD16-PND14 Environmental enrichment Chronic (20days) ↑KCC2 (PND2) Forebrain and hippocampus Mouse Both [ 148 ] Postnatal PND1-21 Maternal separation Chronic (21days) ↓KCC2 (PND35–38), = NKCC1 Hippocampus Mouse Male [ 109 ] PND2-14 Maternal separation Chronic (13days) ↑KCC2 (PND40), ↑NKCCl (PND14) Hippocampus Rat Mix [ 110 ] PND4-6 Maternal separation plus saline injection Chronic (3 days) ↑KCC2 (PND10 - males only) Hippocampus Rat Both [ 111 ] PND21-28 Restraint stress Acute ↓KCC2 activity Paraventricular nucleus Rat …”

Maternal cannabinoid exposure during lactation alters the developmental trajectory of prefrontal cortex GABA-currents in offspring

“…The delayed GABA "switch" in perinatally cannabinoid-exposed pups is prevented by bumetanide treatment Inhibition of NKCC1 has been studied as a potential pharmacotherapeutic means of correcting problems in GABAergic development in such conditions as neonatal seizures (Löscher et al 2013) and maternal separation-induced stress (Hu et al 2017), amongst others in which GABA maintains an excitatory role. Thus, to confirm the role of the KCC2/NKCC1 imbalance in the effects of perinatal WIN exposure, we treated pups with the NKCC1 inhibitor bumetanide from P01 to P15 during concomitant exposure to WIN via lactation.…”