Limits...
Development and regulation of chloride homeostasis in the central nervous system.

Watanabe M, Fukuda A - Front Cell Neurosci (2015)

Bottom Line: Generally, developmental shifts (decreases) in [Cl(-)]i parallel the maturation of the nervous system, e.g., early in the spinal cord, hypothalamus and thalamus, followed by the limbic system, and last in the neocortex.KCC2 and NKCC1 functions are also regulated by phosphorylation by enzymes such as PKC, Src-family tyrosine kinases, and WNK1-4 and their downstream effectors STE20/SPS1-related proline/alanine-rich kinase (SPAK)-oxidative stress responsive kinase-1 (OSR1).Therefore, regional developmental regulation of these regulators and modulators of Cl(-) transporters may also play a pivotal role in the development of Cl(-) homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurophysiology, Hamamatsu University School of Medicine Hamamatsu, Japan.

ABSTRACT
γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter of the mature central nervous system (CNS). The developmental switch of GABAergic transmission from excitation to inhibition is induced by changes in Cl(-) gradients, which are generated by cation-Cl(-) co-transporters. An accumulation of Cl(-) by the Na(+)-K(+)-2Cl(-) co-transporter (NKCC1) increases the intracellular Cl(-) concentration ([Cl(-)]i) such that GABA depolarizes neuronal precursors and immature neurons. The subsequent ontogenetic switch, i.e., upregulation of the Cl(-)-extruder KCC2, which is a neuron-specific K(+)-Cl(-) co-transporter, with or without downregulation of NKCC1, results in low [Cl(-)]i levels and the hyperpolarizing action of GABA in mature neurons. Development of Cl(-) homeostasis depends on developmental changes in NKCC1 and KCC2 expression. Generally, developmental shifts (decreases) in [Cl(-)]i parallel the maturation of the nervous system, e.g., early in the spinal cord, hypothalamus and thalamus, followed by the limbic system, and last in the neocortex. There are several regulators of KCC2 and/or NKCC1 expression, including brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF), and cystic fibrosis transmembrane conductance regulator (CFTR). Therefore, regionally different expression of these regulators may also contribute to the regional developmental shifts of Cl(-) homeostasis. KCC2 and NKCC1 functions are also regulated by phosphorylation by enzymes such as PKC, Src-family tyrosine kinases, and WNK1-4 and their downstream effectors STE20/SPS1-related proline/alanine-rich kinase (SPAK)-oxidative stress responsive kinase-1 (OSR1). In addition, activation of these kinases is modulated by humoral factors such as estrogen and taurine. Because these transporters use the electrochemical driving force of Na(+) and K(+) ions, topographical interaction with the Na(+)-K(+) ATPase and its modulators such as creatine kinase (CK) should modulate functions of Cl(-) transporters. Therefore, regional developmental regulation of these regulators and modulators of Cl(-) transporters may also play a pivotal role in the development of Cl(-) homeostasis.

No MeSH data available.


Related in: MedlinePlus

Differential development of NKCC1 (red) and KCC2 (blue) expression in the brain. HP, hippocampus; DLG, dorsal lateral geniculate nucleus; VPL, ventral posterior thalamic nucleus (Mikawa et al., 2002; Shimizu-Okabe et al., 2002; Wang et al., 2002, 2005; Ikeda et al., 2003).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4585146&req=5

Figure 2: Differential development of NKCC1 (red) and KCC2 (blue) expression in the brain. HP, hippocampus; DLG, dorsal lateral geniculate nucleus; VPL, ventral posterior thalamic nucleus (Mikawa et al., 2002; Shimizu-Okabe et al., 2002; Wang et al., 2002, 2005; Ikeda et al., 2003).

Mentions: The regional differences in Cl− homeostasis during development are apparent (Figure 2). In general, evolutionarily older brain structures that develop earlier show more advanced maturation of Cl− homeostasis, as described in more detail below. The neurogenesis of the rat brain extends from embryonic day (E)12 to postnatal day (P)19 (Bayer and Altman, 1995). The timetables for neurogenesis in the rat brain show a highly sequential pattern among different neuronal populations (Bayer and Altman, 1995). The oldest neurons exist in the spinal cord and medulla and are born mainly on E12–E13. Neurons in the thalamus, hypothalamus and amygdala are mainly generated during E13–E16. In the neocortex, most neurons originate during E16–E18. In the hippocampus, pyramidal neurons arise during E17–E19 and dentate granule cells are born after birth. KCC2 mRNA expression follows this same sequence. On E18, strong KCC2 mRNA expression was observed to be already present in the thalamus, hypothalamus, and amygdala. In contrast, in the neocortex and hippocampus, the earliest strong KCC2 mRNA expression is observed on P15. Thus, the expression profile of KCC2 mRNA in the developing rat brain is well correlated with the sequential maturation of neurons (Li et al., 2002; Wang et al., 2002; Stein et al., 2004). Generally, the ontogeny of KCC2 mRNA in mouse brain is similar to that in rat brain, but the timing includes delays of 2 days in rat embryos (Li et al., 2002).


Development and regulation of chloride homeostasis in the central nervous system.

Watanabe M, Fukuda A - Front Cell Neurosci (2015)

Differential development of NKCC1 (red) and KCC2 (blue) expression in the brain. HP, hippocampus; DLG, dorsal lateral geniculate nucleus; VPL, ventral posterior thalamic nucleus (Mikawa et al., 2002; Shimizu-Okabe et al., 2002; Wang et al., 2002, 2005; Ikeda et al., 2003).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585146&req=5

Figure 2: Differential development of NKCC1 (red) and KCC2 (blue) expression in the brain. HP, hippocampus; DLG, dorsal lateral geniculate nucleus; VPL, ventral posterior thalamic nucleus (Mikawa et al., 2002; Shimizu-Okabe et al., 2002; Wang et al., 2002, 2005; Ikeda et al., 2003).
Mentions: The regional differences in Cl− homeostasis during development are apparent (Figure 2). In general, evolutionarily older brain structures that develop earlier show more advanced maturation of Cl− homeostasis, as described in more detail below. The neurogenesis of the rat brain extends from embryonic day (E)12 to postnatal day (P)19 (Bayer and Altman, 1995). The timetables for neurogenesis in the rat brain show a highly sequential pattern among different neuronal populations (Bayer and Altman, 1995). The oldest neurons exist in the spinal cord and medulla and are born mainly on E12–E13. Neurons in the thalamus, hypothalamus and amygdala are mainly generated during E13–E16. In the neocortex, most neurons originate during E16–E18. In the hippocampus, pyramidal neurons arise during E17–E19 and dentate granule cells are born after birth. KCC2 mRNA expression follows this same sequence. On E18, strong KCC2 mRNA expression was observed to be already present in the thalamus, hypothalamus, and amygdala. In contrast, in the neocortex and hippocampus, the earliest strong KCC2 mRNA expression is observed on P15. Thus, the expression profile of KCC2 mRNA in the developing rat brain is well correlated with the sequential maturation of neurons (Li et al., 2002; Wang et al., 2002; Stein et al., 2004). Generally, the ontogeny of KCC2 mRNA in mouse brain is similar to that in rat brain, but the timing includes delays of 2 days in rat embryos (Li et al., 2002).

Bottom Line: Generally, developmental shifts (decreases) in [Cl(-)]i parallel the maturation of the nervous system, e.g., early in the spinal cord, hypothalamus and thalamus, followed by the limbic system, and last in the neocortex.KCC2 and NKCC1 functions are also regulated by phosphorylation by enzymes such as PKC, Src-family tyrosine kinases, and WNK1-4 and their downstream effectors STE20/SPS1-related proline/alanine-rich kinase (SPAK)-oxidative stress responsive kinase-1 (OSR1).Therefore, regional developmental regulation of these regulators and modulators of Cl(-) transporters may also play a pivotal role in the development of Cl(-) homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurophysiology, Hamamatsu University School of Medicine Hamamatsu, Japan.

ABSTRACT
γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter of the mature central nervous system (CNS). The developmental switch of GABAergic transmission from excitation to inhibition is induced by changes in Cl(-) gradients, which are generated by cation-Cl(-) co-transporters. An accumulation of Cl(-) by the Na(+)-K(+)-2Cl(-) co-transporter (NKCC1) increases the intracellular Cl(-) concentration ([Cl(-)]i) such that GABA depolarizes neuronal precursors and immature neurons. The subsequent ontogenetic switch, i.e., upregulation of the Cl(-)-extruder KCC2, which is a neuron-specific K(+)-Cl(-) co-transporter, with or without downregulation of NKCC1, results in low [Cl(-)]i levels and the hyperpolarizing action of GABA in mature neurons. Development of Cl(-) homeostasis depends on developmental changes in NKCC1 and KCC2 expression. Generally, developmental shifts (decreases) in [Cl(-)]i parallel the maturation of the nervous system, e.g., early in the spinal cord, hypothalamus and thalamus, followed by the limbic system, and last in the neocortex. There are several regulators of KCC2 and/or NKCC1 expression, including brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF), and cystic fibrosis transmembrane conductance regulator (CFTR). Therefore, regionally different expression of these regulators may also contribute to the regional developmental shifts of Cl(-) homeostasis. KCC2 and NKCC1 functions are also regulated by phosphorylation by enzymes such as PKC, Src-family tyrosine kinases, and WNK1-4 and their downstream effectors STE20/SPS1-related proline/alanine-rich kinase (SPAK)-oxidative stress responsive kinase-1 (OSR1). In addition, activation of these kinases is modulated by humoral factors such as estrogen and taurine. Because these transporters use the electrochemical driving force of Na(+) and K(+) ions, topographical interaction with the Na(+)-K(+) ATPase and its modulators such as creatine kinase (CK) should modulate functions of Cl(-) transporters. Therefore, regional developmental regulation of these regulators and modulators of Cl(-) transporters may also play a pivotal role in the development of Cl(-) homeostasis.

No MeSH data available.


Related in: MedlinePlus