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Doris D.Wang and Arnold R. Kriegstein- Defining the role of GABA in cortical development

Doris D.Wang and Arnold R. Kriegstein- Defining the role of GABA in cortical development

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 J Physiol 
587.9 (2009) pp 1873–1879
1873SYMPOSIUM REPORT
Defining the role of GABA in cortical development
Doris D. Wang
1
,
2
and Arnold R. Kriegstein
1
1
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research and 
Neuroscience Graduate Program, University of California SanFrancisco, San Francisco, CA 94143, USA
Of the many signals in the developing nervous system, GABA (
γ 
-aminobutyric acid) has beenshown to be one of the earliest neurotransmitters present. Unlike in the adult, where thistransmitter acts synaptically to inhibit neurons, during development, GABA can depolarizeprogenitor cells and their progeny due to their high intracellular chloride concentration. Thisearly form of GABA signalling may provide the main excitatory drive for the immature corticalnetwork and play a central role in regulating cortical development. Many features of GABAsignalling are conserved in different species and are recapitulated during neurogenesis inthe adult brain, demonstrating the importance of this versatile molecule in driving corticalformation. Here,wepresent recent evidence supportingthe multiplefunctions of GABA duringembryonic development and adult neurogenesis, from regulating progenitor proliferation toinfluencing the migration and maturation of newborn neurons.
(Received 9 December 2008; accepted after revision 14 January 2009; first published online 19 January 2009)
Corresponding author
D. D. Wang: Eli and Edythe Broad Center of Regeneration Medicine and Stem CellResearch, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.Email: doris.wang@ucsf.edu
The construction of a three-dimensional cerebral cortexfrom a single sheet of neuroepithelium requires multipletightly regulated developmental processes working inconcert. In order to form this complex structure, neuronsmust be generated in the correct numbers, migrate tothe proper position in the cortex, and form intricateconnections with neighbours and targets. Of the many cell-intrinsic and extrinsic signals involved in neocorticaldevelopment, neurotransmitters have been shown to bekey players in building the cortical network, and GABAin particular proves to be an important regulator in thisprocess.GABA is the main inhibitory neurotransmitter in theadult brain and acts primarily by binding to GABA
A
or GABA
B
receptors. The GABA
A
receptor gates a Cl
channel,andin the maturebrain,GABA activation causesCl
influx and membrane hyperpolarization due to thelow intracellular Cl
concentration established by theK
+
–Cl
cotransporter KCC2 (Rivera
et al.
1999; Li
et al.
2002; Wang
et al.
2002). However, during development,GABA exerts a different effect by depolarizing corticalprogenitors (radial glia) and immature neurons. This is
This report was presented at
The Journal of Physiology 
Symposiumon
Mechanisms of neocortical development 
, which took place on 14November 2008 at the annual meeting of the Society for Neurosciencein Washington, DC. It was commissioned by the Editorial Board andreflects the views of the authors.
due to the Cl
gradient established by the Na
+
–K
+
–2Cl
cotransporter NKCC1, expressed from mid-embryonicstages until the first week of postnatal life in rodents(Li
et al.
2002; Wang
et al.
2002). NKCC1 importsCl
into immature cells, thereby causing Cl
effluxand membrane depolarization upon GABA
A
receptoractivation (Plotkin
et al.
1997; Wang
et al.
2002).Interestingly, radial glia and migrating neurons expressGABA
A
receptors early in development, thus providingthem with the mechanism to respond to GABA (LoTurco
et al.
1995; Owens
et al.
1996, 1999). Why is aGABAsignallingsystemestablishedwellbeforefunctionalsynapses are formed? GABA-mediated signalling has beenimplicated in most of the developmental steps from cellproliferationtosynapticintegration.Asitisthefirstneuro-transmitter active in the immature brain and providesthe main excitatory drive, GABA is poised to serve as anideal signal to coordinate corticogenesis. Here, we willdiscuss the developmental roles of GABA in modulatingprogenitor proliferation, neuronal migration, and circuitformation in the cortex. We will focus on recent studiesand address controversial as well as emerging functions of GABA in network construction.
GABA and stem cell proliferation
During development, radial glia, which are the corticalneural stem cells, express functional GABA
A
receptors
C
2009 The Authors. Journal compilation
C
2009 The Physiological Society DOI: 10.1113/jphysiol.2008.167635
)by guest on October 31, 2010 jp.physoc.orgDownloaded from J Physiol (
 
1874 D. D. Wang and A. R. Kriegstein
J Physiol 
587.9
(LoTurco
et al.
1995; Owens
et al.
1996). This findinghas led to the hypothesis that GABA supports a trophicfunction besides its normal role in synaptic transmission.A study from our lab demonstrated that GABA andglutamate decreased net DNA synthesis and the numberof progenitor cells that incorporate BrdU in acute corticalslices (LoTurco
et al.
1995). Interestingly, incubating theslices with the GABA
A
receptor antagonist bicucullineincreased DNA synthesis, suggesting that there is tonicreleaseofendogenousGABAtoregulatetherateofneuro-genesis.GABA’seffectoncorticalprogenitorproliferationis likely to be due to its ability to depolarize the cellandactivatevoltage-gatedCa
2
+
channels(VGCCs)thatinturn regulate DNA synthesis (LoTurco
et al.
1995; Owens& Kriegstein, 2002; Represa & Ben-Ari, 2005). AnotherstudycomparedtheproliferativeeffectsofGABAbetweenthe two proliferative zones in the embryonic cortex, theventricular(VZ)andsubventricular(SVZ)zones(Haydar
et al.
2000). Using organotypic slices of mouse embryoniccortex and BrdU labelling, the authors found that GABAappeared to have different effects: promoting VZ celldivision while inhibiting SVZ cell divisions (Haydar
et al.
2000).Withmolecularmarkersnowavailabletoselectively label neurogenic and gliogenic precursors, it would beinteresting to explore GABA’s effects on the proliferationof these two cell types and the mechanism for potentialdifferences.Likewise, studies have shown that GABA can inhibitcell cycle progression in other systems, such as the neuralprecursors in neurospheres and organotypic brain slices(Nguyen
etal.
2003)andintheadultneurogenicSVZ(Liu
etal.
2005).IntheadultSVZ,immatureneuronssynthesizeand release GABA (Stewart
et al.
2002; Bolteus & Bordey,2004; Liu
et al.
2005), which in turn activates GABA
A
receptors in stem cells and immature neurons. TonicGABA
A
activation depolarizes stem cells, causes transientintracellular Ca
2
+
increases, and reduces the number of proliferative stem cells (Liu
et al.
2005). This provides anintriguing mechanism in which the generation of youngGABAergic neurons would increase ambient GABA levelsand serve as a negative feedback loop to reduce theirgeneration by slowing down stem cell proliferation (Platel
et al.
2008). Apparently, the theme of GABA inhibitingstemcellproliferationisdevelopmentallyconservedasthisoccurs even before the formation of the nervous system.Recent evidence suggests that in mice, embryonic stemcellsaswellasneuralcreststemcellsexpressglutamicaciddecarboxylase (GAD) and functional GABA
A
receptors,and just like in the developing cortex, GABA
A
activationdecreasedcellproliferation(Andang
etal.
2008).However,here GABA hyperpolarizes the stem cells and activatesthe S/G
2
DNA-damage checkpoint pathway to inhibit cellcycle progression. This novel mode of neurotransmitterinvolvement in S-phase checkpoint control may operatein other areas of the nervous system, and disruptionsin this pathway may contribute to various congenitalCNS malformations (Andang & Lendahl, 2009). It seemsthat even though GABA can activate different signallingpathways depending on cell-intrinsic factors or extrinsicenvironmental cues, it generally functions to decreaseprogenitor or stem cell proliferation.
GABA and migration
Chemotropic actions of GABA were first identified usingchemotaxis chambers, where dissociated cortical cellswere allowed to undergo gradient-dependent migration,and it was found that extremely low concentrationsof GABA induced cell migration by activating GABA
A
receptors (Behar
et al.
1996). However, these studiesremain controversial as GABA produces half-maximalresponses in the developing neocortex in the micromolarrangeandGABA
A
receptorsarenotsensitiveinthefemto-molar range (Owens
et al.
1999). Another study showedthat blocking GABA
A
receptors in hippocampal slicecultures reduced the migration of neuroblasts (Manent
et al.
2005). Following these experiments, Behar andcolleagues incubated organotypic neocortical explantswith specific GABA receptor antagonists to show thatactivation of different GABA receptor subtypes regulatedvarious parts of neural migration to the cortical plate.Activation of GABA
A
/
C
receptor promoted migration of neuroblasts from the VZ/SVZ to the intermediate zone(IZ), GABA
B
receptor the entry of migrating neuroblastsfrom the IZ to the cortical plate, and finally GABA
A
receptor to provide a stop signal to end migration (Behar
et al.
2000).Morerecently,
invivo
and
invitro
studiesdemonstratedthatGABA
A
receptordesensitizationbyagonistactivationor blockade with antagonists caused heterotopias inthe most superficial cortical layers, likely to be dueto an overmigration from the loss of a stop signal(Heck
et al.
2007). Heck and colleagues demonstratedthat GABA
A
receptor activation leads to transient Ca
2
+
channel oscillations that may be important for promotingneuronal migration. These studies suggest that the effectof GABA on migration is highly concentration- andlocation-dependent. GABA
A
receptors confer a highdegree of variability due to their subunit composition.Interestingly, different GABA
A
receptor subunits areexpressed in a time- and location-specific manner duringcortical development (Laurie
et al.
1992). Because thesediverse receptor subunits have different sensitivities toGABA, their interactions with extrinsic environmentalcues may differentially regulate the migration of newbornneurons. Recently, a study questioned the necessitof GABA-mediated depolarization in cortical neuronmigration. The authors used
in utero
electroporation tooverexpress KCC2 in proliferating neuronal progenitorsto render immature neurons devoid of depolarizing
C
2009 The Authors. Journal compilation
C
2009 The Physiological Society
)by guest on October 31, 2010 jp.physoc.orgDownloaded from J Physiol (
 
 J Physiol 
587.9
Dening the role of GABA in cortical development 1875
GABAergic responses (Cancedda
et al.
2007). Whilemorphological maturation was markedly impaired inKCC2-expressing immature neurons, neuronal migrationwas not affected. It is unknown whether GABA-mediateddepolarization regulates the migration of deeper-layer,earlier-born neurons, as the study only manipulatedneurons born at E18–19. Future studies targeting theearlier-born neurons would help address the currentdiscrepancy.A GABAergic signalling system influencing neuronalmigration is recapitulated in the adult neurogenic regionsas well. In the adult SVZ, several studies have identifiedthe contribution of GABA in regulating the migration of immature neurons from the SVZ to the olfactory bulb(Nguyen
et al.
2003; Bolteus & Bordey, 2004; Liu
et al.
2005; Ge
et al.
2006). Bolteus and Bordey studied youngneuronmigrationinacutesagittalbrainslicestodetermineif GABA signalling between stem cells and immatureneurons regulates the speed of neuronal migration in therostralmigratorystream(RMS).ItwasfoundthatambientGABA slowed down the migration of young neurons by causing an increase in intracellular Ca
2
+
, independent of membrane depolarization (Bolteus & Bordey, 2004).Interestingly, stem cells ensheathing migrating neuronsexpress the high-affinity GABA transporter GAT4. Thissuggests a model wherein neural precursors can fine-tunethe speed of neuronal migration within the chains by regulatingambientGABAlevels(Bolteus&Bordey,2004).
GABA and synaptogenesis
Neural circuit development is a complicated processwhereby a neuron extends its axon and receives inputsfrom targets. For a young neuron to become a functionalunit of the cortical circuit, it must establish a maturemorphology, make synaptic contacts with other cells, andrefine those connections. Increasing evidence suggeststhat neuronal activity regulates circuit formation. Inmany brain regions examined in rodents and primates,newborn neurons express GABA
A
receptors beforeglutamate receptors. Moreover, young neurons firstreceive GABAergic inputs before forming glutamatergicsynapses in the neocortex (Owens
et al.
1999; Tyzio
et al.
1999; Hennou
et al.
2002; Ben-Ari, 2006). Thesespontaneous GABA depolarizations may provide thefirst excitatory drive necessary for activity-dependentsynapse formation (Ben-Ari, 2006). Why is a GABAsignalling system established before a glutamatergic one?GABA can at least partially substitute for glutamateas an excitatory neurotransmitter by providing enoughmembrane depolarization to activate voltage-gatedcalcium channels (VGCC) (Owens & Kriegstein, 2002;Ben-Ari, 2006). However, unlike glutamate, GABA exertsa shunting effect by clamping the membrane potentialnear the Cl
reversal potential (approximately 
40mVin immature neurons), thereby preventing long-lastingactivation of voltage-gated channels that might engendertoxic amounts of Ca
2
+
influx. This makes GABA anideal regulator for synaptogenesis because this neuro-transmittercanexciteneuronswithoutdirectlyproducingexcitotoxicity.Several recent studies have manipulated the Cl
gradient to study the effect of GABA-depolarizationon synaptogenesis. By prematurely shifting the GABAreversal potential to a more hyperpolarizing potential (by knocking down NKCC1 or overexpressing KCC2), it hasrecently been shown that reversing the excitatory effectof GABA in cortical neurons results in fewer and shorterdendrites(Cancedda
etal.
2007)andlessmaturedendriticspines (decreased density and increased lengths) (Wang &Kriegstein, 2008). Likewise, in the adult hippocampus,disturbing GABA-mediated depolarization altered themorphology of newly generated granule neurons (Ge
etal.
2006).Evidencesuggeststhatmorphologicalchangescould be a result of disrupted glutamatergic signallingin these neurons. Glutamatergic activity, via AMPAreceptor-mediated transmission, has been known topromote dendritic arbor growth by mobilizing intra-cellular signalling cascades that stabilize and maintainbranch formation (Wu
et al.
1996; Rajan & Cline, 1998;Shi
et al.
1999; Haas
et al.
2006).Moreover, increasing evidence shows that GABA-mediated depolarization regulates synaptic developmentof young neurons. Recently, by altering the Cl
gradientof newborn cortical neurons
in vivo
, we showed thatGABA-induced excitation via GABA
A
receptor activationplays a permissive role in the formation of synaptic inputson newborn cortical neurons (Wang & Kriegstein, 2008).Our results complement the findings of a study in newly generated granule neurons in the adult dentate gyrus(Ge
et al.
2006), providing evidence that GABA-mediatedexcitationdrivessynapticintegrationofnewbornneuronsin both embryos and adults. Intriguingly, GABA not only regulates development of synapses in the nervous system,but it also regulates the balance between excitation andinhibition in a developing circuit. A premature hyper-polarizing shift in the Cl
reversal potential has beenshown to increase the ratio of inhibitory to excitatory inputs in
Xenopus 
tectal neurons and rat cortical neuronsin culture (Chudotvorova
et al.
2005; Akerman & Cline,2006). This occurs in the mammalian cortex as well, asGABAregulatestheformationofexcitatorysynapsesintheneocorticalcircuit(Wang&Kriegstein,2008).Inaddition,the mechanism for GABA’s regulation of excitatory synapse formation entails the cooperation betweenGABA
A
and NMDA receptor activation. Cortical neuronsbegin to express functional NMDA receptors when they migrate to the cortical plate, but the initial glutamatergicsynapses are ‘silent’ due to the Mg
2
+
block of NMDAreceptorsattherestingmembranepotential(LoTurco
etal.
C
2009 The Authors. Journal compilation
C
2009 The Physiological Society
)by guest on October 31, 2010 jp.physoc.orgDownloaded from J Physiol (

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