GABAergic signaling to newborn neurons in dentate gyrus.

Neurogenesis in the dentate gyrus begins before birth but then continues into adulthood. Consequently, many newborn granule cells must integrate into a preexisting hippocampal network. Little is known about the timing of this process or the characteristics of the first established synapses. We used mice that transiently express enhanced green fluorescent protein in newborn granule cells to examine their synaptic input. Although newborn granule cells had functional glutamate receptors, evoked and spontaneous synaptic currents were exclusively GABAergic with immature characteristics including slow rise and decay phases and depolarized reversal potentials. Synaptic currents in newborn granule cells were relatively insensitive to the GABA(A) receptor modulator zolpidem compared with neighboring mature granule cells. Consistent with the kinetics and pharmacology, newborn granule cells isolated by fluorescent cell sorting lacked the alpha1 GABA(A) receptor subunit. Our results indicate that newborn granule cells initially receive only GABAergic synapses even in the adult.

[1]  Y. Ben-Ari Excitatory actions of gaba during development: the nature of the nurture , 2002, Nature Reviews Neuroscience.

[2]  B. Trommer,et al.  GABAA currents in immature dentate gyrus granule cells. , 1998, Journal of neurophysiology.

[3]  R. Mckernan,et al.  Preferential coassembly of alpha4 and delta subunits of the gamma-aminobutyric acidA receptor in rat thalamus. , 1999, Molecular pharmacology.

[4]  Yehezkel Ben-Ari,et al.  The Establishment of GABAergic and Glutamatergic Synapses on CA1 Pyramidal Neurons is Sequential and Correlates with the Development of the Apical Dendrite , 1999, The Journal of Neuroscience.

[5]  Y. Ben-Ari,et al.  Paracrine Intercellular Communication by a Ca2+- and SNARE-Independent Release of GABA and Glutamate Prior to Synapse Formation , 2002, Neuron.

[6]  M. Farrant,et al.  Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors , 2005, Nature Reviews Neuroscience.

[7]  K. Kaila,et al.  Developmental up‐regulation of KCC2 in the absence of GABAergic and glutamatergic transmission , 2003, The European journal of neuroscience.

[8]  Arnold R. Kriegstein,et al.  Is there more to gaba than synaptic inhibition? , 2002, Nature Reviews Neuroscience.

[9]  Kentaroh Takagaki,et al.  Expression of Distinct α Subunits of GABAA Receptor Regulates Inhibitory Synaptic Strength , 2004 .

[10]  F. Gage,et al.  Functional neurogenesis in the adult hippocampus , 2002, Nature.

[11]  R. Malinow,et al.  Maturation of a Central Glutamatergic Synapse , 1996, Science.

[12]  W. Sieghart,et al.  Distribution of alpha1, alpha4, gamma2, and delta subunits of GABAA receptors in hippocampal granule cells. , 2004, Brain research.

[13]  D. Coulter,et al.  gamma-Aminobutyric acid(A) receptor subunit expression predicts functional changes in hippocampal dentate granule cells during postnatal development. , 2001, Journal of neurochemistry.

[14]  R. Cuppini,et al.  Morpho-functional characterization of neuronal cells at different stages of maturation in granule cell layer of adult rat dentate gyrus , 2004, Brain Research.

[15]  F. Gage,et al.  Neural stem cells from adult hippocampus develop essential properties of functional CNS neurons , 2002, Nature Neuroscience.

[16]  M. Low,et al.  A Transgenic Marker for Newly Born Granule Cells in Dentate Gyrus , 2004, The Journal of Neuroscience.

[17]  W Wisden,et al.  The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[18]  I. Módy,et al.  Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by δ subunit-containing GABAA receptors , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Y. Ben-Ari,et al.  A Noncanonical Release of GABA and Glutamate Modulates Neuronal Migration , 2005, The Journal of Neuroscience.

[20]  I. Soltesz,et al.  GABAA Receptor–Mediated Miniature Postsynaptic Currents and α-Subunit Expression in Developing Cortical Neurons , 1999 .

[21]  U. Kristiansen,et al.  GABAA receptor subunit interactions important for benzodiazepine and zinc modulation: a patch‐clamp and single cell RT‐PCR study , 2001, The European journal of neuroscience.

[22]  J. Kapura,et al.  Distribution of a 1 , a 4 , g 2 , and y subunits of GABAA receptors in hippocampal granule cells , 2004 .

[23]  A. Leslie Morrow,et al.  GABAA Receptor α1 Subunit Deletion Prevents Developmental Changes of Inhibitory Synaptic Currents in Cerebellar Neurons , 2001, The Journal of Neuroscience.

[24]  W. Sieghart,et al.  Distribution of α1, α4, γ2, and δ subunits of GABAA receptors in hippocampal granule cells , 2004, Brain Research.

[25]  I. Soltesz,et al.  Slow Kinetics of Miniature IPSCs during Early Postnatal Development in Granule Cells of the Dentate Gyrus , 1997, The Journal of Neuroscience.

[26]  M. Poo,et al.  GABA Itself Promotes the Developmental Switch of Neuronal GABAergic Responses from Excitation to Inhibition , 2001, Cell.

[27]  K. Gingrich,et al.  Dependence of the GABAA receptor gating kinetics on the alpha‐subunit isoform: implications for structure‐function relations and synaptic transmission. , 1995, The Journal of physiology.

[28]  K. Takagaki,et al.  Expression of distinct alpha subunits of GABAA receptor regulates inhibitory synaptic strength. , 2004, Journal of neurophysiology.

[29]  T. Verdoorn Formation of heteromeric gamma-aminobutyric acid type A receptors containing two different alpha subunits. , 1994, Molecular pharmacology.

[30]  I. Martin,et al.  GABA RECEPTORS , 2002 .

[31]  A. Feigenspan,et al.  Composition of the GABAA Receptors of Retinal Dopaminergic Neurons , 1999, The Journal of Neuroscience.

[32]  D. Coulter,et al.  γ‐Aminobutyric acidA receptor subunit expression predicts functional changes in hippocampal dentate granule cells during postnatal development , 2001 .

[33]  W Wisden,et al.  The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[34]  I. Soltesz,et al.  GABAA Receptor – Mediated Miniature Postsynaptic Currents and a-Subunit Expression in Developing Cortical Neurons , 1999 .

[35]  G M Shepherd,et al.  Electrotonic structure of olfactory sensory neurons analyzed by intracellular and whole cell patch techniques. , 1991, Journal of neurophysiology.

[36]  D. Swandulla,et al.  Hyperpolarizing Inhibition Develops without Trophic support by GABA in Cultured Rat Midbrain Neurons , 2003, The Journal of physiology.

[37]  H. Kettenmann,et al.  A subpopulation of precursor cells in the mouse dentate gyrus receives synaptic GABAergic input , 2005, Molecular and Cellular Neuroscience.

[38]  R. Nicoll,et al.  Adenosine gates synaptic plasticity at hippocampal mossy fiber synapses , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[39]  G. Westbrook,et al.  Paradoxical reduction of synaptic inhibition by vigabatrin. , 2001, Journal of neurophysiology.

[40]  Gerd Kempermann,et al.  Milestones of neuronal development in the adult hippocampus , 2004, Trends in Neurosciences.