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

Multi-modal actions of tonic modulation of the GABAA receptor during corticogenesis. In the ventricular zone (VZ) and subventricular zone (SVZ), ambient GABA affects neurogenesis. Post-mitotic neurons migrating to the cortical plate are tonically depolarized by non-synaptic and non-vesicular ambient GABA, released from tangentially migrating GABA neurons prior to forming synapses, and changing their migratory pace. GABA also acts in an autocrine manner to accelerate tangential migration. Vesicular release of GABA, which remains depolarizing, may contribute to synapse formation. Immediately after establishment of GABAergic synapses (and prior to hyperpolarization), GABA acts as an excitatory neurotransmitter due to high [Cl−]i, predominantly resulting from high NKCC1 expression, while the KCC2 expression level remains low. Green circle: ambient GABA. Brown circle: ambient taurine. Adapted from Egawa and Fukuda (2013).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Multi-modal actions of tonic modulation of the GABAA receptor during corticogenesis. In the ventricular zone (VZ) and subventricular zone (SVZ), ambient GABA affects neurogenesis. Post-mitotic neurons migrating to the cortical plate are tonically depolarized by non-synaptic and non-vesicular ambient GABA, released from tangentially migrating GABA neurons prior to forming synapses, and changing their migratory pace. GABA also acts in an autocrine manner to accelerate tangential migration. Vesicular release of GABA, which remains depolarizing, may contribute to synapse formation. Immediately after establishment of GABAergic synapses (and prior to hyperpolarization), GABA acts as an excitatory neurotransmitter due to high [Cl−]i, predominantly resulting from high NKCC1 expression, while the KCC2 expression level remains low. Green circle: ambient GABA. Brown circle: ambient taurine. Adapted from Egawa and Fukuda (2013).

Mentions: Altered GABAergic functions that occur during early brain development are induced by changes in Cl− homeostasis (Shimizu-Okabe et al., 2002; Yamada et al., 2004) and play important roles in neocortical development by modulating several events of corticogenesis (Egawa and Fukuda, 2013; Luhmann et al., 2015; Figure 1). KCC2 mRNA is not detectable in neuronal precursors or in migrating cells but is observed in differentiated neurons (Li et al., 2002; Wang et al., 2002; Stein et al., 2004). In contrast, NKCC1 is expressed strongly throughout the neuroepithelium, where KCC2 is never observed (Li et al., 2002; Wang et al., 2002). This demonstrates the striking contrast in the natures of these co-transporters.


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

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

Multi-modal actions of tonic modulation of the GABAA receptor during corticogenesis. In the ventricular zone (VZ) and subventricular zone (SVZ), ambient GABA affects neurogenesis. Post-mitotic neurons migrating to the cortical plate are tonically depolarized by non-synaptic and non-vesicular ambient GABA, released from tangentially migrating GABA neurons prior to forming synapses, and changing their migratory pace. GABA also acts in an autocrine manner to accelerate tangential migration. Vesicular release of GABA, which remains depolarizing, may contribute to synapse formation. Immediately after establishment of GABAergic synapses (and prior to hyperpolarization), GABA acts as an excitatory neurotransmitter due to high [Cl−]i, predominantly resulting from high NKCC1 expression, while the KCC2 expression level remains low. Green circle: ambient GABA. Brown circle: ambient taurine. Adapted from Egawa and Fukuda (2013).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Multi-modal actions of tonic modulation of the GABAA receptor during corticogenesis. In the ventricular zone (VZ) and subventricular zone (SVZ), ambient GABA affects neurogenesis. Post-mitotic neurons migrating to the cortical plate are tonically depolarized by non-synaptic and non-vesicular ambient GABA, released from tangentially migrating GABA neurons prior to forming synapses, and changing their migratory pace. GABA also acts in an autocrine manner to accelerate tangential migration. Vesicular release of GABA, which remains depolarizing, may contribute to synapse formation. Immediately after establishment of GABAergic synapses (and prior to hyperpolarization), GABA acts as an excitatory neurotransmitter due to high [Cl−]i, predominantly resulting from high NKCC1 expression, while the KCC2 expression level remains low. Green circle: ambient GABA. Brown circle: ambient taurine. Adapted from Egawa and Fukuda (2013).
Mentions: Altered GABAergic functions that occur during early brain development are induced by changes in Cl− homeostasis (Shimizu-Okabe et al., 2002; Yamada et al., 2004) and play important roles in neocortical development by modulating several events of corticogenesis (Egawa and Fukuda, 2013; Luhmann et al., 2015; Figure 1). KCC2 mRNA is not detectable in neuronal precursors or in migrating cells but is observed in differentiated neurons (Li et al., 2002; Wang et al., 2002; Stein et al., 2004). In contrast, NKCC1 is expressed strongly throughout the neuroepithelium, where KCC2 is never observed (Li et al., 2002; Wang et al., 2002). This demonstrates the striking contrast in the natures of these co-transporters.

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