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      Cation-chloride cotransporters in neuronal development, plasticity and disease.

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      Journal: Nature reviews. Neuroscience
      Keywords: Animals, Brain, cytology, growth & development, Central Nervous System Diseases, genetics, metabolism, pathology, Humans, Models, Molecular, Neuronal Plasticity, physiology, Neurons, Sodium-Potassium-Chloride Symporters

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          Abstract

          Electrical activity in neurons requires a seamless functional coupling between plasmalemmal ion channels and ion transporters. Although ion channels have been studied intensively for several decades, research on ion transporters is in its infancy. In recent years, it has become evident that one family of ion transporters, cation-chloride cotransporters (CCCs), and in particular K(+)-Cl(-) cotransporter 2 (KCC2), have seminal roles in shaping GABAergic signalling and neuronal connectivity. Studying the functions of these transporters may lead to major paradigm shifts in our understanding of the mechanisms underlying brain development and plasticity in health and disease.

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          GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations.

          Yehezkel Ben-Ari, Jean-Luc Gaiarsa, Roman Tyzio … (2007)
          Developing networks follow common rules to shift from silent cells to coactive networks that operate via thousands of synapses. This review deals with some of these rules and in particular those concerning the crucial role of the neurotransmitter gamma-aminobuytric acid (GABA), which operates primarily via chloride-permeable GABA(A) receptor channels. In all developing animal species and brain structures investigated, neurons have a higher intracellular chloride concentration at an early stage leading to an efflux of chloride and excitatory actions of GABA in immature neurons. This triggers sodium spikes, activates voltage-gated calcium channels, and acts in synergy with NMDA channels by removing the voltage-dependent magnesium block. GABA signaling is also established before glutamatergic transmission, suggesting that GABA is the principal excitatory transmitter during early development. In fact, even before synapse formation, GABA signaling can modulate the cell cycle and migration. The consequence of these rules is that developing networks generate primitive patterns of network activity, notably the giant depolarizing potentials (GDPs), largely through the excitatory actions of GABA and its synergistic interactions with glutamate signaling. These early types of network activity are likely required for neurons to fire together and thus to "wire together" so that functional units within cortical networks are formed. In addition, depolarizing GABA has a strong impact on synaptic plasticity and pathological insults, notably seizures of the immature brain. In conclusion, it is suggested that an evolutionary preserved role for excitatory GABA in immature cells provides an important mechanism in the formation of synapses and activity in neuronal networks.
          Article 0 comments Cited 337 times – based on 0 reviews     Review now
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            GABA regulates synaptic integration of newly generated neurons in the adult brain.

            Shaoyu Ge, Eyleen L. K. Goh, Kurt Sailor … (2006)
            Adult neurogenesis, the birth and integration of new neurons from adult neural stem cells, is a striking form of structural plasticity and highlights the regenerative capacity of the adult mammalian brain. Accumulating evidence suggests that neuronal activity regulates adult neurogenesis and that new neurons contribute to specific brain functions. The mechanism that regulates the integration of newly generated neurons into the pre-existing functional circuitry in the adult brain is unknown. Here we show that newborn granule cells in the dentate gyrus of the adult hippocampus are tonically activated by ambient GABA (gamma-aminobutyric acid) before being sequentially innervated by GABA- and glutamate-mediated synaptic inputs. GABA, the major inhibitory neurotransmitter in the adult brain, initially exerts an excitatory action on newborn neurons owing to their high cytoplasmic chloride ion content. Conversion of GABA-induced depolarization (excitation) into hyperpolarization (inhibition) in newborn neurons leads to marked defects in their synapse formation and dendritic development in vivo. Our study identifies an essential role for GABA in the synaptic integration of newly generated neurons in the adult brain, and suggests an unexpected mechanism for activity-dependent regulation of adult neurogenesis, in which newborn neurons may sense neuronal network activity through tonic and phasic GABA activation.
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              Enforcement of temporal fidelity in pyramidal cells by somatic feed-forward inhibition.

              F Pouille, M Scanziani (2001)
              The temporal resolution of neuronal integration depends on the time window within which excitatory inputs summate to reach the threshold for spike generation. Here, we show that in rat hippocampal pyramidal cells this window is very narrow (less than 2 milliseconds). This narrowness results from the short delay with which disynaptic feed-forward inhibition follows monosynaptic excitation. Simultaneous somatic and dendritic recordings indicate that feed-forward inhibition is much stronger in the soma than in the dendrites, resulting in a broader integration window in the latter compartment. Thus, the subcellular partitioning of feed-forward inhibition enforces precise coincidence detection in the soma, while allowing dendrites to sum incoming activity over broader time windows.
              Article 0 comments Cited 290 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                PubMed ID:: 25234263
                PMC ID:: 4294553
                DOI:: 10.1038/nrn3819

                ScienceOpen disciplines: Chemistry
                Keywords: Animals,Brain,cytology,growth & development,Central Nervous System Diseases,genetics,metabolism,pathology,Humans,Models, Molecular,Neuronal Plasticity,physiology,Neurons,Sodium-Potassium-Chloride Symporters
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                ScienceOpen disciplines: Chemistry
                Keywords: Animals, Brain, cytology, growth & development, Central Nervous System Diseases, genetics, metabolism, pathology, Humans, Models, Molecular, Neuronal Plasticity, physiology, Neurons, Sodium-Potassium-Chloride Symporters

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