NKCC1 controls GABAergic signaling and neuroblast migration in the postnatal forebrain

Abstract

From an early postnatal period and throughout life there is a continuous production of olfactory bulb (OB) interneurons originating from neuronal precursors in the subventricular zone. To reach the OB circuits, immature neuroblasts migrate along the rostral migratory stream (RMS). In the present study, we employed cultured postnatal mouse forebrain slices and used lentiviral vectors to label neuronal precursors with GFP and to manipulate the expression levels of the Na-K-2Cl cotransporter NKCC1. We investigated the role of this Cl- transporter in different stages of postnatal neurogenesis, including neuroblast migration and integration in the OB networks once they have reached the granule cell layer (GCL). We report that NKCC1 activity is necessary for maintaining normal migratory speed. Both pharmacological and genetic manipulations revealed that NKCC1 maintains high [Cl-]i and regulates the resting membrane potential of migratory neuroblasts whilst its functional expression is strongly reduced at the time cells reach the GCL. As in other developing systems, NKCC1 shapes GABAA-dependent signaling in the RMS neuroblasts. Also, we show that NKCC1 controls the migration of neuroblasts in the RMS. The present study indeed indicates that the latter effect results from a novel action of NKCC1 on the resting membrane potential, which is independent of GABAA-dependent signaling. All in all, our findings show that early stages of the postnatal recruitment of OB interneurons rely on precise, orchestrated mechanisms that depend on multiple actions of NKCC1.

Neural stem cells: mechanisms and modeling

“…Functionally, the GABA-induced excitatory transmission acts as a developmental compensation for the largely absent glutamatergic transmission, especially AMPAR-mediated responses, in young neurons. GABAR activation promotes neuronal differentiation in the SGZ and neuroblast migration in the SVZ (Tozuka et al, 2005;Ge et al, 2006;Mejia-Gervacio et al, 2011). On the other hand, in the SVZ, the GABAergic transmission can delay the proliferation of NSCs (Liu et al, 2005).…”

Glycine is able to induce both a motility speed in- and decrease during zebrafish neuronal migration

“…In this speculative model, newly emerging THNs inherit NKCC1 from precursor cells and therefore exhibit higher intracellular Cl − levels (Figure 3(a)). The opening of the glycine receptor facilitates an efflux of Cl − and membrane depolarization ([7,23], Figure 3(b)), increasing THN speed. In early migrating THNs in young embryos, the presence of NKCC1 persists into phase 2 migration at the MHB, still promoting THN speed (Figure 3(c)).…”

From progenitors to integrated neurons: Role of neurotransmitters in adult olfactory neurogenesis

“…The intracellular Cl (Yamada et al, 2004). Since the NKCCl transporter is express in migrating neuroblasts along the RMS and associated to depolarizing effect of GABA, it has been recently proposed to play a role in shaping the action of GABA in neuroblast migration (Mejia-Gervacio et al, 2011). However, although impairment of NKCC1 activity decreases cell migration along the RMS, this effect is independent of the modulation exerted by GABA A receptors (Mejia-Gervacio et al, 2011).…”

“…Since the NKCCl transporter is express in migrating neuroblasts along the RMS and associated to depolarizing effect of GABA, it has been recently proposed to play a role in shaping the action of GABA in neuroblast migration (Mejia-Gervacio et al, 2011). However, although impairment of NKCC1 activity decreases cell migration along the RMS, this effect is independent of the modulation exerted by GABA A receptors (Mejia-Gervacio et al, 2011). Rather, decreased neuroblast migration could depend on the depolarization of the resting membrane potential in cells with impaired NKCC1 function (Mejia-Gervacio et al, 2011).…”

“…This highlights the role of astrocytes, that uniquely express the GABA transporter GAT4, in the homeostatic balance that regulates ambient GABA levels and consequently controls the migration rate of neuroblasts (Bolteus and Bordey, 2004). GABA A receptor activity produces depolarizing or hyperpolarizing effects depending on Cl -gradient across cell consequently affecting cell membrane potential (Mejia-Gervacio et al, 2011;Misgeld et al, 1986;Mueller et al, 1984). The intracellular Cl (Yamada et al, 2004).…”