The Cell-Intrinsic Requirement of Sox6 for Cortical Interneuron Development

We describe the role of Sox6 in cortical interneuron development, from a cellular to a behavioral level. We identify Sox6 as a protein expressed continuously within MGE-derived cortical interneurons from postmitotic progenitor stages into adulthood. Both its expression pattern and null phenotype suggests that Sox6 gene function is closely linked to that of Lhx6. In both Lhx6 and Sox6 null animals, the expression of PV and SST and the position of both basket and Martinotti neurons are abnormal. We find that Sox6 functions downstream of Lhx6. Electrophysiological analysis of Sox6 mutant cortical interneurons revealed that basket cells, even when mispositioned, retain characteristic but immature fast-spiking physiological features. Our data suggest that Sox6 is not required for the specification of MGE-derived cortical interneurons. It is, however, necessary for their normal positioning and maturation. As a consequence, the specific removal of Sox6 from this population results in a severe epileptic encephalopathy.

[1]  G. Fishell,et al.  Cerebral Cortex doi:10.1093/cercor/bhm258 Gene Expression in Cortical Interneuron Precursors is Prescient of their Mature Function , 2008 .

[2]  G. Fishell,et al.  The caudal ganglionic eminence is a source of distinct cortical and subcortical cell populations , 2002, Nature Neuroscience.

[3]  O. Marín,et al.  Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular respecification within the basal telencephalon: evidence for a transformation of the pallidum into the striatum. , 1999, Development.

[4]  I. Tetko,et al.  Parvalbumin deficiency affects network properties resulting in increased susceptibility to epileptic seizures , 2004, Molecular and Cellular Neuroscience.

[5]  Jessica A. Cardin,et al.  Driving fast-spiking cells induces gamma rhythm and controls sensory responses , 2009, Nature.

[6]  S. Anderson,et al.  Fate mapping Nkx2.1‐lineage cells in the mouse telencephalon , 2008, The Journal of comparative neurology.

[7]  O. Britanova,et al.  Satb2 Is a Postmitotic Determinant for Upper-Layer Neuron Specification in the Neocortex , 2008, Neuron.

[8]  H. Tabata,et al.  COUP-TFII Is Preferentially Expressed in the Caudal Ganglionic Eminence and Is Involved in the Caudal Migratory Stream , 2008, The Journal of Neuroscience.

[9]  G. Fishell,et al.  The Temporal and Spatial Origins of Cortical Interneurons Predict Their Physiological Subtype , 2005, Neuron.

[10]  V. Lefebvre,et al.  The transcription factors L-Sox5 and Sox6 are essential for cartilage formation. , 2001, Developmental cell.

[11]  L. Maffei,et al.  Reactivation of Ocular Dominance Plasticity in the Adult Visual Cortex , 2002, Science.

[12]  Y. Yanagawa,et al.  Lhx6 Activity Is Required for the Normal Migration and Specification of Cortical Interneuron Subtypes , 2007, The Journal of Neuroscience.

[13]  D. Paré,et al.  Contrasting Activity Profile of Two Distributed Cortical Networks as a Function of Attentional Demands , 2009, The Journal of Neuroscience.

[14]  J. Willoughby,et al.  Kainic acid induces distinct types of epileptiform discharge with differential involvement of hippocampus and neocortex , 2000, Brain Research Bulletin.

[15]  M. Calcagnotto,et al.  Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy , 2005, Nature Neuroscience.

[16]  F. Kimura,et al.  Brain-Derived Neurotrophic Factor Regulates the Maturation of Layer 4 Fast-Spiking Cells after the Second Postnatal Week in the Developing Barrel Cortex , 2007, The Journal of Neuroscience.

[17]  Y. Ben-Ari.  Basic developmental rules and their implications for epilepsy in the immature brain. , 2006, Epileptic disorders : international epilepsy journal with videotape.

[18]  Ken Sugino,et al.  Transcriptional and Electrophysiological Maturation of Neocortical Fast-Spiking GABAergic Interneurons , 2009, The Journal of Neuroscience.

[19]  S. Anderson,et al.  Distinct cortical migrations from the medial and lateral ganglionic eminences. , 2001, Development.

[20]  Shankar Srinivas,et al.  Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus , 2001, BMC Developmental Biology.

[21]  S. Mcconnell,et al.  Faculty Opinions recommendation of Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo. , 2005 .

[22]  O. Dulac,et al.  Epileptic Encephalopathies: A Brief Overview , 2003, Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society.

[23]  Y. Kubota,et al.  Three distinct subpopulations of GABAergic neurons in rat frontal agranular cortex , 1994, Brain Research.

[24]  S. Nelson,et al.  The Fezf2–Ctip2 genetic pathway regulates the fate choice of subcortical projection neurons in the developing cerebral cortex , 2008, Proceedings of the National Academy of Sciences.

[25]  A. Prochiantz,et al.  Experience-Dependent Transfer of Otx2 Homeoprotein into the Visual Cortex Activates Postnatal Plasticity , 2008, Cell.

[26]  Leyuan Shi,et al.  Interneuron migration from basal forebrain to neocortex: dependence on Dlx genes. , 1997, Science.

[27]  O. Marín,et al.  Cell migration in the forebrain. , 2003, Annual review of neuroscience.

[28]  Torsten Werner,et al.  SoxD proteins influence multiple stages of oligodendrocyte development and modulate SoxE protein function. , 2006, Developmental cell.

[29]  Roger D. Traub,et al.  Simulation of Gamma Rhythms in Networks of Interneurons and Pyramidal Cells , 1997, Journal of Computational Neuroscience.

[30]  I. Kill.  Localisation of the Ki-67 antigen within the nucleolus. Evidence for a fibrillarin-deficient region of the dense fibrillar component. , 1996, Journal of cell science.

[31]  J. Rubenstein,et al.  Distinct molecular pathways for development of telencephalic interneuron subtypes revealed through analysis of Lhx6 mutants , 2008, The Journal of comparative neurology.

[32]  I. Cobos,et al.  Cellular patterns of transcription factor expression in developing cortical interneurons. , 2006, Cerebral cortex.

[33]  J. Rubenstein,et al.  Tbr1 Regulates Differentiation of the Preplate and Layer 6 , 2001, Neuron.

[34]  Kenneth D Harris,et al.  Selective Impairment of Hippocampal Gamma Oscillations in Connexin-36 Knock-Out Mouse In Vivo , 2003, The Journal of Neuroscience.

[35]  M. Ekker,et al.  Generation of Cre-transgenic mice using Dlx1/Dlx2 enhancers and their characterization in GABAergic interneurons , 2009, Molecular and Cellular Neuroscience.

[36]  Kristin L. Whitford,et al.  Control of cortical interneuron migration by neurotrophins and PI3-kinase signaling. , 2002, Development.

[37]  V. Lefebvre,et al.  Generation of mice harboring a Sox6 conditional null allele , 2006, Genesis.

[38]  S. Anderson,et al.  NKX2.1 specifies cortical interneuron fate by activating Lhx6 , 2008, Development.

[39]  Kenneth Campbell,et al.  Identification of Two Distinct Progenitor Populations in the Lateral Ganglionic Eminence: Implications for Striatal and Olfactory Bulb Neurogenesis , 2003, The Journal of Neuroscience.

[40]  S. Mcconnell,et al.  Satb2 Regulates Callosal Projection Neuron Identity in the Developing Cerebral Cortex , 2008, Neuron.

[41]  Matthew Grist,et al.  Spatial Genetic Patterning of the Embryonic Neuroepithelium Generates GABAergic Interneuron Diversity in the Adult Cortex , 2007, The Journal of Neuroscience.

[42]  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.

[43]  G. Tamás,et al.  Excitatory Effect of GABAergic Axo-Axonic Cells in Cortical Microcircuits , 2006, Science.

[44]  G G Turrigiano,et al.  Brain-Derived Neurotrophic Factor Mediates the Activity-Dependent Regulation of Inhibition in Neocortical Cultures , 1997, The Journal of Neuroscience.

[45]  G. Miyoshi,et al.  Cerebral Cortex doi:10.1093/cercor/bhp038 Characterization of Nkx6-2-Derived , 2009 .

[46]  Alessandro Filosa,et al.  The COUP-TF nuclear receptors regulate cell migration in the mammalian basal forebrain , 2004, Development.

[47]  O. Marín,et al.  The Embryonic Preoptic Area Is a Novel Source of Cortical GABAergic Interneurons , 2009, The Journal of Neuroscience.

[48]  R. Traub,et al.  A mechanism for generation of long-range synchronous fast oscillations in the cortex , 1996, Nature.

[49]  E. Welker,et al.  K+ Channel Expression Distinguishes Subpopulations of Parvalbumin- and Somatostatin-Containing Neocortical Interneurons , 1999, The Journal of Neuroscience.

[50]  C. Gall,et al.  BDNF Protein Measured by a Novel Enzyme Immunoassay in Normal Brain and after Seizure: Partial Disagreement with mRNA Levels , 1995, The European journal of neuroscience.

[51]  Demian Battaglia,et al.  Classification of NPY-Expressing Neocortical Interneurons , 2009, The Journal of Neuroscience.

[52]  A. Lavdas,et al.  The Medial Ganglionic Eminence Gives Rise to a Population of Early Neurons in the Developing Cerebral Cortex , 1999, The Journal of Neuroscience.

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

[54]  J. Parnavelas,et al.  Lhx6 Regulates the Migration of Cortical Interneurons from the Ventral Telencephalon But Does Not Specify their GABA Phenotype , 2004, The Journal of Neuroscience.

[55]  G. Miyoshi,et al.  Physiologically Distinct Temporal Cohorts of Cortical Interneurons Arise from Telencephalic Olig2-Expressing Precursors , 2007, The Journal of Neuroscience.

[56]  M. Ekker,et al.  Distinct cis-Regulatory Elements from the Dlx1/Dlx2 Locus Mark Different Progenitor Cell Populations in the Ganglionic Eminences and Different Subtypes of Adult Cortical Interneurons , 2007, The Journal of Neuroscience.

[57]  S. Itohara,et al.  Dorsal telencephalon‐specific expression of Cre recombinase in PAC transgenic mice , 2004, Genesis.

[58]  O. Marín,et al.  A long, remarkable journey: Tangential migration in the telencephalon , 2001, Nature Reviews Neuroscience.

[59]  Mark Ellisman,et al.  The potassium channel subunit KV3.1b is localized to somatic and axonal membranes of specific populations of CNS neurons , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[60]  K. Deisseroth,et al.  Parvalbumin neurons and gamma rhythms enhance cortical circuit performance , 2009, Nature.

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

[62]  David J. Anderson,et al.  Lhx6 Delineates a Pathway Mediating Innate Reproductive Behaviors from the Amygdala to the Hypothalamus , 2005, Neuron.

[63]  G. Fishell,et al.  The Gsh2 homeodomain gene controls multiple aspects of telencephalic development. , 2000, Development.

[64]  Miles A. Whittington,et al.  Impaired Electrical Signaling Disrupts Gamma Frequency Oscillations in Connexin 36-Deficient Mice , 2001, Neuron.

[65]  P. Rakic,et al.  Four-Dimensional Migratory Coordinates of GABAergic Interneurons in the Developing Mouse Cortex , 2003, The Journal of Neuroscience.

[66]  Jeffrey A. Golden,et al.  FACS‐array gene expression analysis during early development of mouse telencephalic interneurons , 2008, Developmental neurobiology.

[67]  R. Desimone,et al.  Modulation of Oscillatory Neuronal Synchronization by Selective Visual Attention , 2001, Science.

[68]  S. Anderson,et al.  Mutations of the Homeobox Genes Dlx-1 and Dlx-2 Disrupt the Striatal Subventricular Zone and Differentiation of Late Born Striatal Neurons , 1997, Neuron.

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

[70]  Oscar Marín,et al.  The LIM-homeobox gene Lhx8 is required for the development of many cholinergic neurons in the mouse forebrain , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[71]  Rosa Cossart,et al.  Sequential Generation of Two Distinct Synapse-Driven Network Patterns in Developing Neocortex , 2008, The Journal of Neuroscience.

[72]  Peter Somogyi,et al.  Interneurons hyperpolarize pyramidal cells along their entire somatodendritic axis , 2009, Nature Neuroscience.

[73]  Sean M Montgomery,et al.  Theta and Gamma Coordination of Hippocampal Networks during Waking and Rapid Eye Movement Sleep , 2008, The Journal of Neuroscience.

[74]  Paola Arlotta,et al.  Neuronal Subtype-Specific Genes that Control Corticospinal Motor Neuron Development In Vivo , 2005, Neuron.

[75]  T. Bliss,et al.  Loss of forebrain cholinergic neurons and impairment in spatial learning and memory in LHX7‐deficient mice , 2005, The European journal of neuroscience.

[76]  S. Anderson,et al.  Origins of Cortical Interneuron Subtypes , 2004, The Journal of Neuroscience.

[77]  Arnold R Kriegstein,et al.  Patterns of neuronal migration in the embryonic cortex , 2004, Trends in Neurosciences.

[78]  Adriano B. L. Tort,et al.  Hippocampal theta rhythm and its coupling with gamma oscillations require fast inhibition onto parvalbumin-positive interneurons , 2009, Proceedings of the National Academy of Sciences.

[79]  G. Miyoshi,et al.  The Requirement of Nkx2-1 in the Temporal Specification of Cortical Interneuron Subtypes , 2008, Neuron.

[80]  P. Arlotta,et al.  SOX5 Controls the Sequential Generation of Distinct Corticofugal Neuron Subtypes , 2008, Neuron.

[81]  Y. Kawaguchi.  Physiological subgroups of nonpyramidal cells with specific morphological characteristics in layer II/III of rat frontal cortex , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[82]  O. Caillard,et al.  Role of the calcium-binding protein parvalbumin in short-term synaptic plasticity. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[83]  V. Lefebvre,et al.  Control of cell fate and differentiation by Sry-related high-mobility-group box (Sox) transcription factors. , 2007, The international journal of biochemistry & cell biology.

[84]  P. Levitt,et al.  Hepatocyte Growth Factor/Scatter Factor Is a Motogen for Interneurons Migrating from the Ventral to Dorsal Telencephalon , 2001, Neuron.

[85]  R. Palmiter,et al.  Knock-Out Mice Reveal a Critical Antiepileptic Role for Neuropeptide Y , 1997, The Journal of Neuroscience.

[86]  G. Fishell,et al.  Telencephalic cells take a tangent: non-radial migration in the mammalian forebrain , 2001, Nature Neuroscience.

[87]  S. Anderson,et al.  Postmitotic Nkx2-1 Controls the Migration of Telencephalic Interneurons by Direct Repression of Guidance Receptors , 2008, Neuron.