Behavior-Dependent Activity and Synaptic Organization of Septo-hippocampal GABAergic Neurons Selectively Targeting the Hippocampal CA3 Area

Summary Rhythmic medial septal (MS) GABAergic input coordinates cortical theta oscillations. However, the rules of innervation of cortical cells and regions by diverse septal neurons are unknown. We report a specialized population of septal GABAergic neurons, the Teevra cells, selectively innervating the hippocampal CA3 area bypassing CA1, CA2, and the dentate gyrus. Parvalbumin-immunopositive Teevra cells show the highest rhythmicity among MS neurons and fire with short burst duration (median, 38 ms) preferentially at the trough of both CA1 theta and slow irregular oscillations, coincident with highest hippocampal excitability. Teevra cells synaptically target GABAergic axo-axonic and some CCK interneurons in restricted septo-temporal CA3 segments. The rhythmicity of their firing decreases from septal to temporal termination of individual axons. We hypothesize that Teevra neurons coordinate oscillatory activity across the septo-temporal axis, phasing the firing of specific CA3 interneurons, thereby contributing to the selection of pyramidal cell assemblies at the theta trough via disinhibition. Video Abstract

[1]  P. Somogyi,et al.  Immunolocalization of metabotropic glutamate receptor 1α (mGluR1α) in distinct classes of interneuron in the CA1 region of the rat hippocampus , 2004, Hippocampus.

[2]  P. Somogyi,et al.  Network state-dependent inhibition of identified hippocampal CA3 axo-axonic cells in vivo , 2013, Nature Neuroscience.

[3]  T. Freund,et al.  GABA-containing neurons in the septum control inhibitory interneurons in the hippocampus , 1988, Nature.

[4]  D. Pinault,et al.  A novel single-cell staining procedure performed in vivo under electrophysiological control: morpho-functional features of juxtacellularly labeled thalamic cells and other central neurons with biocytin or Neurobiotin , 1996, Journal of Neuroscience Methods.

[5]  Lauren L. Long,et al.  Theta variation and spatiotemporal scaling along the septotemporal axis of the hippocampus , 2015, Front. Syst. Neurosci..

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

[7]  Menno P. Witter,et al.  Entorhinal projections to the hippocampal CA1 region in the rat: An underestimated pathway , 1988, Neuroscience Letters.

[8]  S. D. Berry,et al.  Medial septal lesions retard classical conditioning of the nicitating membrane response in rabbits. , 1979, Science.

[9]  G. Buzsáki,et al.  Distinct Representations and Theta Dynamics in Dorsal and Ventral Hippocampus , 2010, The Journal of Neuroscience.

[10]  Michael E. Hasselmo,et al.  A Proposed Function for Hippocampal Theta Rhythm: Separate Phases of Encoding and Retrieval Enhance Reversal of Prior Learning , 2002, Neural Computation.

[11]  Gray Eg.  Axo-somatic and axo-dendritic synapses of the cerebral cortex: An electron microscope study , 1959 .

[12]  Adriano B. L. Tort,et al.  OLM interneurons differentially modulate CA3 and entorhinal inputs to hippocampal CA1 neurons , 2012, Nature Neuroscience.

[13]  W Buño,et al.  Septo-hippocampal relationships during EEG theta rhythm. , 1982, Electroencephalography and clinical neurophysiology.

[14]  R. S. Sloviter,et al.  Immunocytochemical localization of GABA‐, cholecystokinin‐, vasoactive intestinal polypeptide‐, and somatostatin‐like immunoreactivity in the area dentata and hippocampus of the rat , 1987, The Journal of comparative neurology.

[15]  Martin Fuhrmann,et al.  Locomotion, Theta Oscillations, and the Speed-Correlated Firing of Hippocampal Neurons Are Controlled by a Medial Septal Glutamatergic Circuit , 2015, Neuron.

[16]  M. Moser,et al.  Impaired Spatial Representation in CA1 after Lesion of Direct Input from Entorhinal Cortex , 2008, Neuron.

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

[18]  Z. Henderson,et al.  Conduction velocities and membrane properties of different classes of rat septohippocampal neurons recorded in vitro , 1999, The Journal of physiology.

[19]  Z. Borhegyi,et al.  Phase Segregation of Medial Septal GABAergic Neurons during Hippocampal Theta Activity , 2004, The Journal of Neuroscience.

[20]  James J. Knierim,et al.  CA3 Retrieves Coherent Representations from Degraded Input: Direct Evidence for CA3 Pattern Completion and Dentate Gyrus Pattern Separation , 2014, Neuron.

[21]  G. Buzsáki,et al.  Traveling Theta Waves along the Entire Septotemporal Axis of the Hippocampus , 2012, Neuron.

[22]  P. Dutar,et al.  Firing Properties of Anatomically Identified Neurons in the Medial Septum of Anesthetized and Unanesthetized Restrained Rats , 2006, The Journal of Neuroscience.

[23]  W Buño,et al.  Cross-correlation analysis of septohippocampal neurons during theta-rhythm. , 1987, Brain research.

[24]  E. Gray,et al.  Axo-somatic and axo-dendritic synapses of the cerebral cortex: an electron microscope study. , 1959, Journal of anatomy.

[25]  J. Winson.  Loss of hippocampal theta rhythm results in spatial memory deficit in the rat. , 1978, Science.

[26]  R. Traub,et al.  Spread of synchronous firing in longitudinal slices from the CA3 region of the hippocampus. , 1988, Journal of neurophysiology.

[27]  P. Somogyi,et al.  Neuronal Diversity in GABAergic Long-Range Projections from the Hippocampus , 2007, The Journal of Neuroscience.

[28]  A. Fisahn,et al.  Interconnection and synchronization of neuronal populations in the mouse medial septum/diagonal band of Broca. , 2015, Journal of neurophysiology.

[29]  T. Freund,et al.  Disinhibition of rat hippocampal pyramidal cells by GABAergic afferents from the septum. , 1997, The Journal of physiology.

[30]  G. Buzsáki,et al.  Theta Oscillations Provide Temporal Windows for Local Circuit Computation in the Entorhinal-Hippocampal Loop , 2009, Neuron.

[31]  A. Alonso,et al.  Cross-correlation analysis of septohippocampal neurons during ≡-rhythm , 1987, Brain Research.

[32]  J. O’Keefe,et al.  The rhythmicity of cells of the medial septum/diagonal band of Broca in the awake freely moving rat: relationships with behaviour and hippocampal theta , 1998, The European journal of neuroscience.

[33]  Attila Losonczy,et al.  Septo-hippocampal GABAergic signaling across multiple modalities in awake mice , 2013, Nature Neuroscience.

[34]  Laszlo Zaborszky,et al.  The Input-Output Relationship of the Cholinergic Basal Forebrain. , 2017, Cell reports.

[35]  Thomas Klausberger,et al.  Temporal redistribution of inhibition over neuronal subcellular domains underlies state-dependent rhythmic change of excitability in the hippocampus , 2014, Philosophical Transactions of the Royal Society B: Biological Sciences.

[36]  P. Golshani,et al.  Frequency-invariant temporal ordering of interneuronal discharges during hippocampal oscillations in awake mice , 2012, Proceedings of the National Academy of Sciences.

[37]  G. Buzsáki.  Feed-forward inhibition in the hippocampal formation , 1984, Progress in Neurobiology.

[38]  R. Jaffard,et al.  Dissociated roles for the lateral and medial septum in elemental and contextual fear conditioning. , 2007, Learning & memory.

[39]  M. Witter.  Intrinsic and extrinsic wiring of CA3: indications for connectional heterogeneity. , 2007, Learning & memory.

[40]  P. Somogyi,et al.  Properties of horizontal axo‐axonic cells in stratum oriens of the hippocampal CA1 area of rats in vitro , 2004, Hippocampus.

[41]  M. Ding,et al.  Theta-rhythmic drive between medial septum and hippocampus in slow-wave sleep and microarousal: a Granger causality analysis. , 2015, Journal of neurophysiology.

[42]  D. Amaral,et al.  The three-dimensional organization of the hippocampal formation: A review of anatomical data , 1989, Neuroscience.

[43]  J. Csicsvari,et al.  Accuracy of tetrode spike separation as determined by simultaneous intracellular and extracellular measurements. , 2000, Journal of neurophysiology.

[44]  Christof Koch,et al.  Theta Phase Segregation of Input-Specific Gamma Patterns in Entorhinal-Hippocampal Networks , 2014, Neuron.

[45]  H. Petsche,et al.  The firing pattern of septal neurons and the form of the hippocampal theta wave. , 1968, Brain research.

[46]  H. Petsche,et al.  [The significance of the rabbit's septum as a relay station between the midbrain and the hippocampus. I. The control of hippocampus arousal activity by the septum cells]. , 1962, Electroencephalography and clinical neurophysiology.

[47]  David J. Foster,et al.  Hippocampal theta sequences , 2007, Hippocampus.

[48]  S. Kasicki,et al.  The frequency of rat's hippocampal theta rhythm is related to the speed of locomotion , 1998, Brain Research.

[49]  Thomas Klausberger,et al.  Layer-Specific GABAergic Control of Distinct Gamma Oscillations in the CA1 Hippocampus , 2014, Neuron.

[50]  Robert U Muller,et al.  Theta Phase Classification of Interneurons in the Hippocampal Formation of Freely Moving Rats , 2011, The Journal of Neuroscience.

[51]  T. Kosaka.  The axon initial segment as a synaptic site: Ultrastructure and synaptology of the initial segment of the pyramidal cell in the rat hippocampus (CA3 region) , 1980, Journal of neurocytology.

[52]  Johannes E. Schindelin,et al.  Fiji: an open-source platform for biological-image analysis , 2012, Nature Methods.

[53]  H PETSCHE,et al.  The significance of the rabbit's septum as a relay station between the midbrain and the hippocampus. II. The differential influence of drugs upon both the septal cell firing pattern and the hippocampus theta activity. , 1962, Electroencephalography and clinical neurophysiology.

[54]  B. Alger,et al.  Synaptic Cross Talk between Perisomatic-Targeting Interneuron Classes Expressing Cholecystokinin and Parvalbumin in Hippocampus , 2009, The Journal of Neuroscience.

[55]  G Buzsáki,et al.  Interactions between Hippocampus and Medial Septum during Sharp Waves and Theta Oscillation in the Behaving Rat , 1999, The Journal of Neuroscience.

[56]  S. Remy,et al.  Glutamatergic synaptic integration of locomotion speed via septoentorhinal projections , 2016, Nature Neuroscience.

[57]  Thomas Klausberger,et al.  Terminal Field and Firing Selectivity of Cholecystokinin-Expressing Interneurons in the Hippocampal CA3 Area , 2011, The Journal of Neuroscience.

[58]  P. Somogyi,et al.  Behavior‐dependent activity patterns of GABAergic long‐range projecting neurons in the rat hippocampus , 2017, Hippocampus.

[59]  Steven J. Middleton,et al.  Silencing CA3 disrupts temporal coding in the CA1 ensemble , 2016, Nature Neuroscience.

[60]  G. Buzsáki,et al.  Entorhinal-CA3 Dual-Input Control of Spike Timing in the Hippocampus by Theta-Gamma Coupling , 2017, Neuron.

[61]  Z. Borhegyi,et al.  Postsynaptic targets of GABAergic hippocampal neurons in the medial septum-diagonal band of broca complex , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[62]  Kenneth D. Harris,et al.  High-Dimensional Cluster Analysis with the Masked EM Algorithm , 2013, Neural Computation.

[63]  Evgueniy V. Lubenov,et al.  Hippocampal theta oscillations are travelling waves , 2009, Nature.

[64]  J. Meier,et al.  Vertebrate-specific sequences in the gephyrin E-domain regulate cytosolic aggregation and postsynaptic clustering , 2007, Journal of Cell Science.

[65]  Peyman Golshani,et al.  Functional fission of parvalbumin interneuron classes during fast network events , 2014, eLife.

[66]  Paul H. E. Tiesinga,et al.  The Scalable Brain Atlas: Instant Web-Based Access to Public Brain Atlases and Related Content , 2013, Neuroinformatics.

[67]  R. Vertes,et al.  Brainstem-diencephalo-septohippocampal systems controlling the theta rhythm of the hippocampus. , 1997, Neuroscience.

[68]  Thomas Klausberger,et al.  Distinct Dendritic Arborization and In Vivo Firing Patterns of Parvalbumin-Expressing Basket Cells in the Hippocampal Area CA3 , 2013, The Journal of Neuroscience.

[69]  J. Csicsvari,et al.  Oscillatory Coupling of Hippocampal Pyramidal Cells and Interneurons in the Behaving Rat , 1999, The Journal of Neuroscience.

[70]  T. Hökfelt,et al.  Cholecystokinin in Cortico‐striatal Neurons in the Rat: Immunohistochemical Studies at the Light and Electron Microscopical Level , 1994, The European journal of neuroscience.

[71]  Sylvain Williams,et al.  Optogenetic Activation of Septal Glutamatergic Neurons Drive Hippocampal Theta Rhythms , 2016, The Journal of Neuroscience.

[72]  Peter Somogyi,et al.  Synaptic Targets of Medial Septal Projections in the Hippocampus and Extrahippocampal Cortices of the Mouse , 2015, The Journal of Neuroscience.

[73]  Carey Y. L. Huh,et al.  Glutamatergic Neurons of the Mouse Medial Septum and Diagonal Band of Broca Synaptically Drive Hippocampal Pyramidal Cells: Relevance for Hippocampal Theta Rhythm , 2010, The Journal of Neuroscience.