Bumetanide Prevents Brain Trauma-Induced Depressive-Like Behavior
Brain trauma triggers a cascade of deleterious events leading to enhanced incidence of drug resistant epilepsies, depression, and cognitive dysfunctions. The underlying mechanisms leading to these alterations are poorly understood and treatment that attenuates those sequels are not available. Using controlled-cortical impact as an experimental model of brain trauma in adult mice, we found a strong suppressive effect of the sodium-potassium-chloride importer (NKCC1) specific antagonist bumetanide on the appearance of depressive-like behavior. We demonstrate that this alteration in behavior is associated with an impairment of post-traumatic secondary neurogenesis within the dentate gyrus of the hippocampus. The mechanism mediating the effect of bumetanide involves early transient changes in the expression of chloride regulatory proteins and qualitative changes in GABA(A) mediated transmission from hyperpolarizing to depolarizing after brain trauma. This work opens new perspectives in the early treatment of human post-traumatic induced depression. Our results strongly suggest that bumetanide might constitute an efficient prophylactic treatment to reduce neurological and psychiatric consequences of brain trauma.Bumetanide powder
Introduction
Brain trauma is the main cause of disability all over the world with a very high prevalence in developed countries (Meyer et al., 2008; Bondi et al., 2015). According to the World Health Organization and the Centers for Disease Control and Prevention (Meyer et al., 2008), brain trauma classification is based on multiple factors such as altered neurological functions, brain area of interest and genetic variations. Altogether, these factors lead to highly individualized injuries. Sequels of trauma include low prevalence post-traumatic epilepsies (PTEs), with a severity and occurrence dependent on trauma severity (Kelly et al., 2015; Bragin et al., 2016), and cognitive dysfunctions and depression-like phenotypes are also commonly associated (Peeters et al., 2015; Perry et al., 2015; Stein et al., 2015). Following brain trauma, neuronal cell death occurs and more particularly within the neurons of the dentate gyrus of the hippocampus (Ren et al., 2015; Samuels et al., 2015), leading to hippocampal volume reduction (Samuels et al., 2015; Anacker and Hen, 2017). These observations could be related to changes in post-traumatic neurogenesis in the hippocampus. This has been proposed to be a useful marker of therapeutic treatment efficacy (Brandon and McKay, 2015; Alvarez et al., 2016).
In a wide range of neurological and psychiatric disorders, GABAergic signaling is affected through chloride homeostasis impairment triggered by a down regulation of the main neuronal-specific chloride and potassium extruder, KCC2, and up regulation of the chloride importer NKCC1, respectively (Medina et al., 2014). Similar changes in GABAergic transmission have been reported in a different model of brain trauma (Ben-Ari, 2017). This leads to depolarization and also an excitatory action of GABA that could perturb the generation of behaviorally relevant oscillations and integrative properties of brain networks (Rivera et al., 1999; Luscher et al., 2011; Kahle et al., 2013; Medina et al., 2014; Ben-Ari, 2017). These shifts have been observed notably in developmental disorders including autism spectrum disorders (ASDs) (Tyzio et al., 2014), stroke (Jaenisch et al., 2010; Xu et al., 2016) and epilepsy (Pallud et al., 2014; Tyzio et al., 2014; Kelley et al., 2016). The interaction between major depressive disorders (MDDs) and GABAergic neurotransmission has been suggested in a genetic mice model of GABA(B)-R knock-out (Mombereau et al., 2005) and in studies showing an antidepressant effect of potent and selective blockage of GABA(A) transmission (Rudolph and Knoflach, 2011) at both the hippocampus (Boldrini et al., 2013) and mesolimbic system (Kandratavicius et al., 2014). In addition, several observations link chloride homeostasis to secondary neurogenesis through GABA(A) neurotransmission (Luscher et al., 2011; Ostroumov et al., 2016). The generation of new neurons within the DG requires different steps: first, the transition from quiescent to proliferative progenitors, then their differentiation to immature neurons in a GABAergic-dependent manner (Chell and Frisén, 2012; Moss and Toni, 2013). In that context, it's well-accepted that brain trauma alters neurogenesis (Perry et al., 2015; Stein et al., 2015). In the past decade, the relationship between GABA neurotransmission and neurogenesis has been well-established. Ge and collaborators have shown that GABA receptors are expressed in the progenitor cells and that GABA itself, either ambient or synaptically-released GABA, could act at different steps during neurogenesis from proliferation to cell differentiation and finally synaptic integration (Ge et al., 2006; Anacker and Hen, 2017). In addition, the GABAergic polarity acts on the cell integration (Ge et al., 2006) but also in cell proliferation (Sun et al., 2012), thus establishing a causal link between cell cycling and cell cycle exit on depolarizing GABA condition (Scharfman and Bernstein, 2015; Hu J.J. et al., 2017). Apart from the monoamine hypothesis, a new theory based on the GABA release itself has been proposed to contribute to depression. GABA release has been demonstrated to be impaired in psychiatric disorders and particularly in depression (Luscher et al., 2011; Gabbay et al., 2012). More particularly, the GABAergic receptors have been shown to be decreased in expression and function in the dentate gyrus of depressed patients (Luscher et al., 2011; Lüscher and Fuchs, 2015) and brain tissues collected from suicide patients with a history of depression and anxiety (Merali et al., 2004). One of the first phenomenon linking depression and the hippocampus is the change in hippocampal volume observed both in rodent and in human (Savitz et al., 2010; Schuhmacher et al., 2013; Roddy et al., 2018).