Dysregulation of coordinated neuronal firing patterns in striatum of freely behaving transgenic rats that model Huntington's disease

Altered neuronal activity in the striatum appears to be a key component of Huntington's disease (HD), a fatal, neurodegenerative condition. To assess this hypothesis in freely behaving transgenic rats that model HD (tgHDs), we used chronically implanted micro-wires to record the spontaneous activity of striatal neurons. We found that relative to wild-type controls, HD rats suffer from population-level deficits in striatal activity characterized by a loss of correlated firing and fewer episodes of coincident spike bursting between simultaneously recorded neuronal pairs. These results are in line with our previous report of marked alterations in the pattern of striatal firing in mouse models of HD that vary in background strain, genetic construct, and symptom severity. Thus, loss of coordinated spike activity in striatum appears to be a common feature of HD pathophysiology, regardless of HD model variability.

[1]  J. Vonsattel,et al.  Huntington disease models and human neuropathology: similarities and differences , 2007, Acta Neuropathologica.

[2]  Olaf Riess,et al.  Cellular and subcellular localization of Huntingtin [corrected] aggregates in the brain of a rat transgenic for Huntington disease. , 2007, The Journal of comparative neurology.

[3]  Ronald Wetzel,et al.  Behavioral abnormalities precede neuropathological markers in rats transgenic for Huntington's disease. , 2006, Human molecular genetics.

[4]  G. Rebec,et al.  Hyperactive striatal neurons in symptomatic Huntington R6/2 mice: Variations with behavioral state and repeated ascorbate treatment , 2006, Neuroscience.

[5]  A. Graybiel,et al.  Synchronous, Focally Modulated β-Band Oscillations Characterize Local Field Potential Activity in the Striatum of Awake Behaving Monkeys , 2003, The Journal of Neuroscience.

[6]  J. Bolam,et al.  Synaptic organisation of the basal ganglia , 2000, Journal of anatomy.

[7]  G. Gerhardt,et al.  Aged F344 rats exhibit altered electrophysiological activity in locomotor-unrelated but not locomotor-related striatal neurons , 2004, Neurobiology of Aging.

[8]  M. Chesselet,et al.  Electrophysiological and morphological changes in striatal spiny neurons in R6/2 Huntington's disease transgenic mice. , 2001, Journal of neurophysiology.

[9]  G. P. Moore,et al.  Neuronal spike trains and stochastic point processes. I. The single spike train. , 1967, Biophysical journal.

[10]  Peter S. Harper,et al.  Huntington's disease , 1991 .

[11]  J. Lisman.  Bursts as a unit of neural information: making unreliable synapses reliable , 1997, Trends in Neurosciences.

[12]  F. Walker.  Huntington's disease , 2007, The Lancet.

[13]  T. Haarmeier,et al.  Time is brain , 2011, Der Nervenarzt.

[14]  E. Vaadia,et al.  Synchronization in neuronal transmission and its importance for information processing. , 1994 .

[15]  S. T. Kitai,et al.  Firing patterns and synaptic potentials of identified giant aspiny interneurons in the rat neostriatum , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[16]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[17]  Carlos Cepeda,et al.  The corticostriatal pathway in Huntington's disease , 2007, Progress in Neurobiology.

[18]  G. Graveland,et al.  The frequency and distribution of medium-sized neurons with indented nuclei in the primate and rodent neostriatum , 1985, Brain Research.

[19]  Yasin Temel,et al.  Progressive deterioration of reaction time performance and choreiform symptoms in a new Huntington's disease transgenic ratmodel , 2006, Behavioural Brain Research.

[20]  C. Blakemore,et al.  Dendritic spine pathology and deficits in experience‐dependent dendritic plasticity in R6/1 Huntington's disease transgenic mice , 2004, The European journal of neuroscience.

[21]  J. Penney,et al.  Differential loss of striatal projection systems in Huntington’s disease: a quantitative immunohistochemical study , 2004, Journal of Chemical Neuroanatomy.

[22]  C. Legéndy,et al.  Bursts and recurrences of bursts in the spike trains of spontaneously active striate cortex neurons. , 1985, Journal of neurophysiology.

[23]  Carlos Cepeda,et al.  Transient and Progressive Electrophysiological Alterations in the Corticostriatal Pathway in a Mouse Model of Huntington's Disease , 2003, The Journal of Neuroscience.

[24]  J. Wayne Aldridge,et al.  The temporal structure of spike trains in the primate basal ganglia: afferent regulation of bursting demonstrated with precentral cerebral cortical ablation , 1991, Brain Research.

[25]  Max Kleiman-Weiner,et al.  Differential electrophysiological properties of dopamine D1 and D2 receptor‐containing striatal medium‐sized spiny neurons , 2008, The European journal of neuroscience.

[26]  Carlos Cepeda,et al.  Genetic mouse models of Huntington's and Parkinson's diseases: illuminating but imperfect , 2004, Trends in Neurosciences.

[27]  M. Nicolelis,et al.  Differential Corticostriatal Plasticity during Fast and Slow Motor Skill Learning in Mice , 2004, Current Biology.

[28]  R. Albin,et al.  Rodent genetic models of Huntington disease , 2008, Neurobiology of Disease.

[29]  Manish S. Shah,et al.  A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes , 1993, Cell.

[30]  M. Chesselet,et al.  Time course of early motor and neuropathological anomalies in a knock‐in mouse model of Huntington's disease with 140 CAG repeats , 2003, The Journal of comparative neurology.

[31]  Andreas Bauer,et al.  Sex differences in a transgenic rat model of Huntington's disease: decreased 17beta-estradiol levels correlate with reduced numbers of DARPP32+ neurons in males. , 2008, Human molecular genetics.

[32]  Yasin Temel,et al.  Selective striatal neuron loss and alterations in behavior correlate with impaired striatal function in Huntington's disease transgenic rats , 2006, Neurobiology of Disease.

[33]  A. Engel,et al.  Different Subtypes of Striatal Neurons Are Selectively Modulated by Cortical Oscillations , 2009, The Journal of Neuroscience.

[34]  Scott J Barton,et al.  Altered Information Processing in the Prefrontal Cortex of Huntington's Disease Mouse Models , 2008, The Journal of Neuroscience.

[35]  Charles J. Wilson,et al.  The origins of two-state spontaneous membrane potential fluctuations of neostriatal spiny neurons , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[36]  Thomas Wichmann,et al.  Neuronal firing before and after burst discharges in the monkey basal ganglia is predictably patterned in the normal state and altered in parkinsonism. , 2006, Journal of neurophysiology.

[37]  Stephen B. Dunnett,et al.  Characterization of Progressive Motor Deficits in Mice Transgenic for the Human Huntington’s Disease Mutation , 1999, The Journal of Neuroscience.

[38]  M. Abeles.  Quantification, smoothing, and confidence limits for single-units' histograms , 1982, Journal of Neuroscience Methods.

[39]  L. Raymond,et al.  Corticostriatal synaptic function in mouse models of Huntington's disease: early effects of huntingtin repeat length and protein load , 2007, The Journal of physiology.

[40]  G. P. Moore,et al.  Neuronal spike trains and stochastic point processes. II. Simultaneous spike trains. , 1967, Biophysical journal.

[41]  Carlos Cepeda,et al.  Age-Dependent Alterations of Corticostriatal Activity in the YAC128 Mouse Model of Huntington Disease , 2009, The Journal of Neuroscience.

[42]  Charles J. Wilson,et al.  Spontaneous firing patterns of identified spiny neurons in the rat neostriatum , 1981, Brain Research.

[43]  Scott J Barton,et al.  Dysregulated information processing by medium spiny neurons in striatum of freely behaving mouse models of Huntington's disease. , 2008, Journal of neurophysiology.

[44]  J. Bullier,et al.  Cross-Correlograms for Neuronal Spike Trains. Different Types of Temporal Correlation in Neocortex, their Origin and Significance , 2000 .

[45]  L. Mucke,et al.  A network dysfunction perspective on neurodegenerative diseases , 2006, Nature.

[46]  Olaf Riess,et al.  Cellular and subcellular localization of Huntington aggregates in the brain of a rat transgenic for Huntington disease , 2007 .

[47]  G. Rebec,et al.  Force-plate quantification of progressive behavioral deficits in the R6/2 mouse model of Huntington's disease , 2009, Behavioural Brain Research.

[48]  T. Sejnowski,et al.  Correlated neuronal activity and the flow of neural information , 2001, Nature Reviews Neuroscience.

[49]  Marian DiFiglia,et al.  Huntington Disease , 1998, Journal of neuropathology and experimental neurology.

[50]  Thomas Walther,et al.  Transgenic rat model of Huntington's disease. , 2003, Human molecular genetics.

[51]  J. Berke.  Uncoordinated Firing Rate Changes of Striatal Fast-Spiking Interneurons during Behavioral Task Performance , 2008, The Journal of Neuroscience.

[52]  C. Cepeda,et al.  Changes in Cortical and Striatal Neurons Predict Behavioral and Electrophysiological Abnormalities in a Transgenic Murine Model of Huntington's Disease , 2001, The Journal of Neuroscience.

[53]  H. Covington,et al.  Stereotyped and complex motor routines expressed during cocaine self-administration: results from a 24-h binge of unlimited cocaine access in rats , 2007, Psychopharmacology.

[54]  S. Fowler,et al.  A force-plate actometer for quantitating rodent behaviors: illustrative data on locomotion, rotation, spatial patterning, stereotypies, and tremor , 2001, Journal of Neuroscience Methods.

[55]  E. Simpson,et al.  Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. , 2003, Human molecular genetics.