Abstract
Young neurons in the adult brain are key to some types of learning and memory. They integrate in the dentate gyrus (DG) of the hippocampus contributing to such cognitive processes following timely developmental events. While experimentally impairing GABAergic transmission through the blockade or elimination of the ionic cotransporter NKCC1 leads to alterations in the proper maturation of young neurons, it is still unknown if the in vivo administration of common use diuretic drugs that block the cotransporter, alters the development of young hippocampal neurons and affects DG-related functions. In this study, we delivered chronically and intracerebroventricularly the NKCC1 blocker bumetanide to young-adult rats. We analyzed doublecortin density and development parameters (apical dendrite length and angle and dendritic arbor length) in doublecortin positive neurons from different subregions in the DG and evaluated the performance of animals in contextual fear learning and memory. Our results show that in bumetanide-treated subjects, doublecortin density is diminished in the infra and suprapyramidal blades of the DG; the length of primary dendrites is shortened in the infrapyramidal blade and; the growth angle of primary dendrites in the infrapyramidal blade is different from control animals. Behaviorally, treated animals showed the typical learning curve in a contextual fear task, and freezing-time displayed during contextual fear memory was not different from controls. Thus, in vivo icv delivery of bumetanide negatively alters DCX density associated to young neurons and its proper development but not to the extent of affecting a DG dependent task as aversive context learning and memory.
Highlights
The subgranular zone of the rodent dentate gyrus harbors neural progenitors that divide symmetrically or generate intermediate neural progenitors, which in turn can self-renovate or differentiate as neuroblasts
GABAergic stimulation is important to neuronal maturation (Rivera et al, 1999; Ben-Ari, 2002); as neural progenitors mature, the expression of the NKCC1 cotransporter fades and at the same time there is an increase in the expression of the ionic cotransporter KCC2, which transports K+ and Cl− ions outside the cell (Yamada et al, 2004; for a review see Blaesse et al, 2009)
The dentate gyrus of the hippocampus processes information that leads to the formation of episodic memories, while specific functions such as contextual memory and pattern separation are highly dependent on the participation of young neurons (Squire, 1992; Nilsson et al, 1999; Clelland et al, 2009; Huckleberry et al, 2018)
Summary
The subgranular zone of the rodent dentate gyrus harbors neural progenitors that divide symmetrically or generate intermediate neural progenitors, which in turn can self-renovate or differentiate as neuroblasts. The change of the depolarizing effect of GABA to a hyperpolarizing one in young neurons through the silencing of the gene for NKCC1 produces synaptic impairment and halts dendritic development (Ge et al, 2006) These findings pose GABAergic activity as an essential stimulus for the maturation and functionality of young neurons (Ge et al, 2006; Palloto and Deprez, 2014). These observations are of clinical relevance given that the NKCC1 cotransporter is a pharmacological target of furosemide and bumetanide (Walcott et al, 2012; for a review see Ben-Ari and Tyzio, 2011). Given the interest that poses the clinical use of bumetanide, in the present study we analyzed the long-term effect of the intracerebral delivery of bumetanide on the structural maturation of young hippocampal dentate gyrus neurons and evaluated its impact on contextual fear conditioning and memory in rats
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