Taurine as an Essential Neuromodulator during Perinatal Cortical Development

Abstract

A variety of experimental studies demonstrated that neurotransmitters are an important factor for the development of the central nervous system, affecting neurodevelopmental events like neurogenesis, neuronal migration, programmed cell death, and differentiation. While the role of the classical neurotransmitters glutamate and gamma-aminobutyric acid (GABA) on neuronal development is well established, the aminosulfonic acid taurine has also been considered as possible neuromodulator during early neuronal development. The purpose of the present review article is to summarize the properties of taurine as neuromodulator in detail, focusing on the direct involvement of taurine on various neurodevelopmental events and the regulation of neuronal activity during early developmental epochs. The current knowledge is that taurine lacks a synaptic release mechanism but is released by volume-sensitive organic anion channels and/or a reversal of the taurine transporter. Extracellular taurine affects neurons and neuronal progenitor cells mainly via glycine, GABA(A), and GABA(B) receptors with considerable receptor and subtype-specific affinities. Taurine has been shown to directly influence neurogenesis in vitro as well as neuronal migration in vitro and in vivo. It provides a depolarizing signal for a variety of neuronal population in the immature central nervous system, thereby directly influencing neuronal activity. While in the neocortex, taurine probably enhance neuronal activity, in the immature hippocampus, a tonic taurinergic tone might be necessary to attenuate activity. In summary, taurine must be considered as an essential modulator of neurodevelopmental events, and possible adverse consequences on fetal and/or early postnatal development should be evaluated for pharmacological therapies affecting taurinergic functions.

Keywords: Cajal–Retzius cells; GABA receptors; cerebral cortex; glycine receptors; migration; review; rodent; subplate.

FIGURE 1

Taurine release pathways. (A) The taurine release from HeLa cells after hypoosmotic stimulation was massively attenuated if expression of the volume-regulated anion channel SWELL1 was suppressed (with permission from Qiu et al., 2014). (B) The taurine release from embryonic neocortical slices loaded with 10 mM taurine was not affected by the TauT inhibitor GES, could be blocked the unspecific anion channel blocker DIDS or by DCPIB, a selective blocker of volume-regulated anion channels, and was stimulated by hypoosmotic stimulation (hypo), suggesting that taurine efflux was mainly mediated by volume-regulated anion channels (^∗ and ^$ represent P < 0.05, ^$$ indicate P < 0.01, with permission from Furukawa et al., 2014). (C) Suppression of electrical activity attenuated the spontaneous taurine release from tangential slices of early postnatal rat neocortex, suggesting the existence of a constitutive, activity-dependent taurine release (modified with permission from Qian et al., 2014).

FIGURE 2

Properties of taurine receptors. (A) Taurine affinities and maximal taurine currents critically depend on the subunit composition of GABA_A receptors (modified with permission from Kletke et al., 2013). (B) Typical membrane currents and dose–response curves of taurine on glycine receptors for different neuron populations in the immature neocortex revealed that taurine is a low-affinity agonist with comparable affinities in CRc (blue), SP neurons (SPn, red), and neurons from the CP and developing layers (CPn, green) (modified with permission from Kilb et al., 2002, 2008).

FIGURE 3

Effect of taurine on proliferation and migration. (A) Taurine (10 mM) enhances the fraction of BrdU positive neurons in mouse neurospheres after 4–5 days in culture, indicating that taurine promotes proliferation (^∗ indicate P < 0.05, with permission from Hernandez-Benitez et al., 2010). (B) Radial migration of RFP-labeled neurons in the substantially GABA-depleted GAD67-GFP mice can be enhanced by inhibition of GABA_A receptors with gabazine (middle image) and by inhibition of maternal taurine synthesis with D-cysteinate (D-CSA, lower image), indicating that taurine acting of GABA_A receptors modulate radial migration in vivo (modified with permission from Furukawa et al., 2014).

FIGURE 4

Effect of taurine on GABAergic networks in early postnatal mouse neocortex. (A) In pyramidal neurons taurine induced a tonic inward current and increased the frequency of GBZ-sensitive GABAergic PSCs. (B) Cell-attached recordings demonstrating that GABAergic PSCs enhance action potential frequency, suggesting that the taurine-induced GABAergic PSCs are excitatory. (C) In GABAergic interneurons taurine induced an inward-current that was relatively insensitive to GBZ, but suppressed by strychnine, indicating that taurine acts mainly via glycine receptors in this cell type. (D) Cell-attached recordings from GABAergic interneurons demonstrate that the taurine-induced inward current enhances action potential frequency, suggesting that the taurine is an excitatory neuromodulator in immature interneurons (with permission from Sava et al., 2014).

FIGURE 5

Schematic diagram summarizing the effects of taurine on the immature neocortex. (A) Taurine release is mediated mainly by volume-regulated anion channels (VRAC). The release of taurine is activated by hypoosmotic conditions, electrical activity and via glutamate (Glu), and adenosine (Ado) receptors. (B) Taurine mediates its effects via low-affinity binding to glycine receptors (green symbols) or GABA_A receptors (blue symbols) with subunit compositions typical for synaptic receptors. While the taurine affinity to putatively extrasynaptic GABA_A receptors is moderate, taurine is a high-affinity ligand for GABA_B receptors. In addition, the intracellular taurine concentration, regulated by the TauT, suppresses the function of the Cl^- extruder KCC2 via activation of the WNK pathway, thus maintaining depolarizing taurinergic membrane responses. (C) Putative effect of taurine on different cell populations in the developing neocortex. Taurine promotes proliferation in the VZ, but attenuates proliferation in the SVZ. It stimulates chemotaxis via GABA_B receptors and suppresses radial migration via GABA_A and glycine receptors. Taurine depolarizes SP neurons, pyramidal cell and GABAergic interneurons in the CP, as well as CRc in the MZ via activation of GABA_A and/or glycine receptors. The taurinergic depolarization of GABAergic interneurons is in vitro sufficient to generate GABAergic network activity transmitted to pyramidal cells. CRc participate to propagating activity in the MZ mediated by activity-dependent taurine release. See text for details.