Morpho-physiological Criteria Divide Dentatecc Gyrus Interneurons into Classes

GABAergic inhibitory interneurons control fundamental aspects of neuronal network function. Their functional roles are assumed to be defined by the identity of their input synapses, the architecture of their dendritic tree, the passive and active membrane properties and finally the nature of their postsynaptic targets. Indeed, interneurons display a high degree of morphological and physiological heterogeneity. However, whether their morphological and physiological characteristics are correlated and whether interneuron diversity can be described by a continuum of GABAergic cell types or by distinct classes has remained unclear. Here we perform a detailed morphological and physiological characterization of GABAergic cells in the dentate gyrus, the input region of the hippocampus. To achieve an unbiased and efficient sampling and classification we used knock‐in mice expressing the enhanced green fluorescent protein (eGFP) in glutamate decarboxylase 67 (GAD67)‐positive neurons and performed cluster analysis. We identified five interneuron classes, each of them characterized by a distinct set of anatomical and physiological parameters. Cross‐correlation analysis further revealed a direct relation between morphological and physiological properties indicating that dentate gyrus interneurons fall into functionally distinct classes which may differentially control neuronal network activity. © 2013 The Authors. Hippocampus Published by Wiley Periodicals, Inc.

[1]  Y. Ben-Ari,et al.  Ongoing Epileptiform Activity in the Post-Ischemic Hippocampus Is Associated with a Permanent Shift of the Excitatory–Inhibitory Synaptic Balance in CA3 Pyramidal Neurons , 2006, The Journal of Neuroscience.

[2]  Axel Schleicher,et al.  The innervation of parvalbumin‐containing interneurons by VIP‐immunopositive interneurons in the primary somatosensory cortex of the adult rat , 2007, The European journal of neuroscience.

[3]  P. Somogyi,et al.  Spike timing of dendrite-targeting bistratified cells during hippocampal network oscillations in vivo , 2004, Nature Neuroscience.

[4]  Hannah Monyer,et al.  Differential involvement of oriens/pyramidale interneurones in hippocampal network oscillations in vitro , 2005, The Journal of physiology.

[5]  H. Markram,et al.  Anatomical, physiological, molecular and circuit properties of nest basket cells in the developing somatosensory cortex. , 2002, Cerebral cortex.

[6]  P. Somogyi,et al.  A High Degree of Spatial Selectivity in the Axonal and Dendritic Domains of Physiologically Identified Local‐circuit Neurons in the Dentate Gyms of the Rat Hippocampus , 1993, The European journal of neuroscience.

[7]  P. Jonas,et al.  Postnatal Differentiation of Basket Cells from Slow to Fast Signaling Devices , 2008, The Journal of Neuroscience.

[8]  Y. Kubota,et al.  GABAergic cell subtypes and their synaptic connections in rat frontal cortex. , 1997, Cerebral cortex.

[9]  P. Somogyi,et al.  Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons , 1995, Nature.

[10]  G. Buzsáki,et al.  Gamma Oscillation by Synaptic Inhibition in a Hippocampal Interneuronal Network Model , 1996, The Journal of Neuroscience.

[11]  M. Frotscher,et al.  Rapid Signaling at Inhibitory Synapses in a Dentate Gyrus Interneuron Network , 2001, The Journal of Neuroscience.

[12]  T. Kaneko,et al.  Green fluorescent protein expression and colocalization with calretinin, parvalbumin, and somatostatin in the GAD67‐GFP knock‐in mouse , 2003, The Journal of comparative neurology.

[13]  D. Amaral A golgi study of cell types in the hilar region of the hippocampus in the rat , 1978, The Journal of comparative neurology.

[14]  J. Lacaille,et al.  Interneuron Diversity series: Hippocampal interneuron classifications – making things as simple as possible, not simpler , 2003, Trends in Neurosciences.

[15]  Attila Losonczy,et al.  Persistently active cannabinoid receptors mute a subpopulation of hippocampal interneurons. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[16]  C. Nicholson Electric current flow in excitable cells J. J. B. Jack, D. Noble &R. W. Tsien Clarendon Press, Oxford (1975). 502 pp., £18.00 , 1976, Neuroscience.

[17]  H. Monyer,et al.  Differential Expression of Group I Metabotropic Glutamate Receptors in Functionally Distinct Hippocampal Interneurons , 2000, The Journal of Neuroscience.

[18]  P. Somogyi,et al.  Neuronal Diversity and Temporal Dynamics: The Unity of Hippocampal Circuit Operations , 2008, Science.

[19]  P. Somogyi,et al.  Subdivisions in the Multiple GABAergic Innervation of Granule Cells in the Dentate Gyrus of the Rat Hippocampus , 1993, The European journal of neuroscience.

[20]  C. Houser,et al.  Localization of mRNAs encoding two forms of glutamic acid decarboxylase in the rat hippocampal formation , 1994, Hippocampus.

[21]  T. Freund,et al.  Differences between Somatic and Dendritic Inhibition in the Hippocampus , 1996, Neuron.

[22]  Hannah Monyer,et al.  A Novel Type of GABAergic Interneuron Connecting the Input and the Output Regions of the Hippocampus , 1997, The Journal of Neuroscience.

[23]  M. Frotscher,et al.  A hippocampal interneuron associated with the mossy fiber system. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[24]  PA Schwartzkroin,et al.  Interneurons and inhibition in the dentate gyrus of the rat in vivo , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[25]  J. Hyvärinen,et al.  Cortical neuronal mechanisms in flutter-vibration studied in unanesthetized monkeys. Neuronal periodicity and frequency discrimination. , 1969, Journal of neurophysiology.

[26]  M. Frotscher,et al.  Fast synaptic inhibition promotes synchronized gamma oscillations in hippocampal interneuron networks , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[27]  P. Somogyi,et al.  A new type of specific interneuron in the monkey hippocampus forming synapses exclusively with the axon initial segments of pyramidal cells , 1983, Brain Research.

[28]  T. Sejnowski,et al.  LETTERS TO NATURE , 1996 .

[29]  A. Thomson,et al.  IPSPs elicited in CA1 pyramidal cells by putative basket cells in slices of adult rat hippocampus , 1999, The European journal of neuroscience.

[30]  R. Traub,et al.  Synchronized oscillations in interneuron networks driven by metabotropic glutamate receptor activation , 1995, Nature.

[31]  Christophe Bernard,et al.  Interneurons targeting similar layers receive synaptic inputs with similar kinetics , 2006, Hippocampus.

[32]  P. Somogyi,et al.  Immunoreactivity for the GABAA receptor alpha1 subunit, somatostatin and Connexin36 distinguishes axoaxonic, basket, and bistratified interneurons of the rat hippocampus. , 2007, Cerebral cortex.

[33]  Stefan Hefft,et al.  Asynchronous GABA release generates long-lasting inhibition at a hippocampal interneuron–principal neuron synapse , 2005, Nature Neuroscience.

[34]  Ivan Soltesz,et al.  Neurogliaform cells in the molecular layer of the dentate gyrus as feed‐forward γ‐aminobutyric acidergic modulators of entorhinal–hippocampal interplay , 2011, The Journal of comparative neurology.

[35]  G. Buzsáki,et al.  Neuronal Oscillations in Cortical Networks , 2004, Science.

[36]  H. Katsumaru,et al.  GABAergic neurons containing the Ca2+-binding protein parvalbumin in the rat hippocampus and dentate gyrus , 1987, Brain Research.

[37]  N Spruston,et al.  Specialized electrophysiological properties of anatomically identified neurons in the hilar region of the rat fascia dentata. , 1998, Journal of neurophysiology.

[38]  Dennis A. Turner,et al.  Interneurons of the Dentate–Hilus Border of the Rat Dentate Gyrus: Morphological and Electrophysiological Heterogeneity , 1997, The Journal of Neuroscience.

[39]  Dimitri M Kullmann,et al.  Hebbian LTP in feed-forward inhibitory interneurons and the temporal fidelity of input discrimination , 2005, Nature Neuroscience.

[40]  S. Baraban,et al.  Interneuron Diversity series: Interneuronal neuropeptides – endogenous regulators of neuronal excitability , 2004, Trends in Neurosciences.

[41]  P. Jonas,et al.  Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks , 2007, Nature Reviews Neuroscience.

[42]  W. Rall Core Conductor Theory and Cable Properties of Neurons , 2011 .

[43]  Massimo Scanziani,et al.  Routing of spike series by dynamic circuits in the hippocampus , 2004, Nature.

[44]  S. Nelson,et al.  Molecular taxonomy of major neuronal classes in the adult mouse forebrain , 2006, Nature Neuroscience.

[45]  J. Csicsvari,et al.  Mechanisms of Gamma Oscillations in the Hippocampus of the Behaving Rat , 2003, Neuron.

[46]  C. McBain,et al.  Long-Term Potentiation in Distinct Subtypes of Hippocampal Nonpyramidal Neurons , 1996, The Journal of Neuroscience.

[47]  P. Somogyi,et al.  Unitary IPSPs evoked by interneurons at the stratum radiatum‐stratum lacunosum‐moleculare border in the CA1 area of the rat hippocampus in vitro , 1998, The Journal of physiology.

[48]  G. Tamás,et al.  Identified Sources and Targets of Slow Inhibition in the Neocortex , 2003, Science.

[49]  E. P. Gardner,et al.  Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex , 2008, Nature Reviews Neuroscience.

[50]  M. Scanziani,et al.  Enforcement of Temporal Fidelity in Pyramidal Cells by Somatic Feed-Forward Inhibition , 2001, Science.

[51]  P. Somogyi,et al.  Input and frequency‐specific entrainment of postsynaptic firing by IPSPs of perisomatic or dendritic origin , 2004, The European journal of neuroscience.

[52]  R. Miles,et al.  How Many Subtypes of Inhibitory Cells in the Hippocampus? , 1998, Neuron.

[53]  O. Paulsen,et al.  Spike Timing of Distinct Types of GABAergic Interneuron during Hippocampal Gamma Oscillations In Vitro , 2004, The Journal of Neuroscience.

[54]  Tamás F Freund,et al.  Interneuron Diversity series: Rhythm and mood in perisomatic inhibition , 2003, Trends in Neurosciences.

[55]  P. Somogyi,et al.  Brain-state- and cell-type-specific firing of hippocampal interneurons in vivo , 2003, Nature.

[56]  Peter Jonas,et al.  Distinct nonuniform cable properties optimize rapid and efficient activation of fast-spiking GABAergic interneurons , 2009, Proceedings of the National Academy of Sciences.

[57]  Peter Jonas,et al.  Gating, modulation and subunit composition of voltage‐gated K+ channels in dendritic inhibitory interneurones of rat hippocampus , 2002, The Journal of physiology.

[58]  J. Rossier,et al.  Classification of fusiform neocortical interneurons based on unsupervised clustering. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[59]  R. Morris Foundations of cellular neurophysiology , 1996 .

[60]  John M. Bekkers,et al.  Modulation of Excitability by α-Dendrotoxin-Sensitive Potassium Channels in Neocortical Pyramidal Neurons , 2001, The Journal of Neuroscience.

[61]  G. Stuart,et al.  Excitatory Actions of GABA in the Cortex , 2003, Neuron.

[62]  P. Somogyi,et al.  Salient features of synaptic organisation in the cerebral cortex 1 Published on the World Wide Web on 3 March 1998. 1 , 1998, Brain Research Reviews.

[63]  M. Bartos,et al.  Role of microcircuit structure and input integration in hippocampal interneuron recruitment and plasticity , 2011, Neuropharmacology.

[64]  D. Jacobowitz,et al.  Calretinin is present in non-pyramidal cells of the rat hippocampus—II. Co-existence with other calcium binding proteins and gaba , 1992, Neuroscience.

[65]  Idan Segev,et al.  Principles Governing the Operation of Synaptic Inhibition in Dendrites , 2012, Neuron.

[66]  P. Jonas,et al.  Dendritic Mechanisms Underlying Rapid Synaptic Activation of Fast-Spiking Hippocampal Interneurons , 2010, Science.

[67]  M. Frotscher,et al.  GABAergic innervation of the rat fascia dentata: A novel type of interneuron in the granule cell layer with extensive axonal arborization in the molecular layer , 1993, The Journal of comparative neurology.

[68]  P. Somogyi,et al.  Physiological properties of anatomically identified axo-axonic cells in the rat hippocampus. , 1994, Journal of neurophysiology.

[69]  R. Yuste,et al.  Correlation between axonal morphologies and synaptic input kinetics of interneurons from mouse visual cortex. , 2007, Cerebral cortex.

[70]  John Zachary Young,et al.  Quantitative differences among the brains of cephalopods , 1987 .

[71]  C. McBain,et al.  Potassium conductances underlying repolarization and after‐hyperpolarization in rat CA1 hippocampal interneurones. , 1995, The Journal of physiology.

[72]  H. Markram,et al.  Organizing principles for a diversity of GABAergic interneurons and synapses in the neocortex. , 2000, Science.

[73]  T. Freund,et al.  Electrotonic profile and passive propagation of synaptic potentials in three subpopulations of hippocampal CA1 interneurons , 2001, Neuroscience.

[74]  M. Bartos,et al.  Recruitment of Early Postnatal Parvalbumin-Positive Hippocampal Interneurons by GABAergic Excitation , 2010, The Journal of Neuroscience.

[75]  Karen L. Smith,et al.  Novel Hippocampal Interneuronal Subtypes Identified Using Transgenic Mice That Express Green Fluorescent Protein in GABAergic Interneurons , 2000, The Journal of Neuroscience.

[76]  G. Buzsáki,et al.  Temporal structure in spatially organized neuronal ensembles: a role for interneuronal networks , 1995, Current Opinion in Neurobiology.

[77]  H. Scharfman Electrophysiological diversity of pyramidal‐shaped neurons at the granule cell layer/hilus border of the rat dentate gyrus recorded in vitro , 1995, Hippocampus.

[78]  G. Buzsáki,et al.  Interneurons of the hippocampus , 1998, Hippocampus.

[79]  G Buzsáki,et al.  Interneurons in the Hippocampal Dentate Gyrus: an In Vivo intracellular Study , 1997, The European journal of neuroscience.

[80]  P. Somogyi,et al.  Defined types of cortical interneurone structure space and spike timing in the hippocampus , 2005, The Journal of physiology.