Visual Experience-Dependent Oscillations and Underlying Circuit Connectivity Changes Are Impaired in Fmr1 KO Mice.

Fragile X syndrome (FX), the most common inherited form of autism and intellectual disability, is a condition associated with visual perceptual learning deficits. We recently discovered that perceptual experience can encode visual familiarity via persistent low-frequency oscillations in the mouse primary visual cortex (V1). Here, we combine this paradigm with a multifaceted experimental approach to identify neurophysiological impairments of these oscillations in FX mice. Extracellular recordings reveal shorter durations, lower power, and lower frequencies of peak oscillatory activity in FX mice. Directed information analysis of extracellularly recorded spikes reveals differences in functional connectivity from multiple layers in FX mice after the perceptual experience. Channelrhodopsin-2 assisted circuit mapping (CRACM) reveals increased synaptic strength from L5 pyramidal onto L4 fast-spiking cells after experience in wild-type (WT), but not FX, mice. These results suggest differential encoding of visual stimulus familiarity in FX via persistent oscillations and identify circuit connections that may underlie these changes.

[1]  M. Stryker,et al.  Modulation of Visual Responses by Behavioral State in Mouse Visual Cortex , 2010, Neuron.

[2]  E. Berry-Kravis.  Mechanism-based treatments in neurodevelopmental disorders: fragile X syndrome. , 2014, Pediatric neurology.

[3]  J. Wilding,et al.  Nature of the Working Memory Deficit in Fragile-X Syndrome , 2000, Brain and Cognition.

[4]  George H. Denfield,et al.  Pupil Fluctuations Track Fast Switching of Cortical States during Quiet Wakefulness , 2014, Neuron.

[5]  Sotiris C Masmanidis,et al.  Brain activity mapping at multiple scales with silicon microprobes containing 1,024 electrodes. , 2015, Journal of neurophysiology.

[6]  Carlos Portera-Cailliau,et al.  Impaired perceptual learning in a mouse model of Fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible. , 2018, Nature Neuroscience.

[7]  C. Granger.  Investigating Causal Relations by Econometric Models and Cross-Spectral Methods , 1969 .

[8]  V. Crunelli,et al.  Childhood absence epilepsy: Genes, channels, neurons and networks , 2002, Nature Reviews Neuroscience.

[9]  Martin Vinck,et al.  Arousal and Locomotion Make Distinct Contributions to Cortical Activity Patterns and Visual Encoding , 2014, Neuron.

[10]  R. Meredith,et al.  Hyperactivity, perseveration and increased responding during attentional rule acquisition in the Fragile X mouse model , 2013, Front. Behav. Neurosci..

[11]  G. Buzsáki,et al.  Inhibition-Induced Theta Resonance in Cortical Circuits , 2013, Neuron.

[12]  Jozsef Csicsvari,et al.  Dynamic Reconfiguration of Hippocampal Interneuron Circuits during Spatial Learning , 2013, Neuron.

[13]  J. Gibson,et al.  Altered Neocortical Rhythmic Activity States in Fmr1 KO Mice Are Due to Enhanced mGluR5 Signaling and Involve Changes in Excitatory Circuitry , 2011, The Journal of Neuroscience.

[14]  C. Portera-Cailliau.  Which Comes First in Fragile X Syndrome, Dendritic Spine Dysgenesis or Defects in Circuit Plasticity? , 2012, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[15]  Benjamin W. Avants,et al.  NeuroPG: open source software for optical pattern generation and data acquisition , 2015, Front. Neuroeng..

[16]  Michael X Cohen,et al.  Analyzing Neural Time Series Data: Theory and Practice , 2014 .

[17]  D. Feldman,et al.  Increased Excitation-Inhibition Ratio Stabilizes Synapse and Circuit Excitability in Four Autism Mouse Models , 2018, Neuron.

[18]  Rishikesh Narayanan,et al.  Long-Term Potentiation in Rat Hippocampal Neurons Is Accompanied by Spatially Widespread Changes in Intrinsic Oscillatory Dynamics and Excitability , 2007, Neuron.

[19]  H. Kennedy,et al.  Alpha-Beta and Gamma Rhythms Subserve Feedback and Feedforward Influences among Human Visual Cortical Areas , 2016, Neuron.

[20]  Sid Visser,et al.  Lumping Izhikevich neurons , 2014 .

[21]  S. Rivera,et al.  Contrast detection in infants with fragile X syndrome , 2008, Vision Research.

[22]  C. Schroeder,et al.  Neuronal Mechanisms and Attentional Modulation of Corticothalamic Alpha Oscillations , 2011, The Journal of Neuroscience.

[23]  Todd P. Coleman,et al.  Estimating the directed information to infer causal relationships in ensemble neural spike train recordings , 2010, Journal of Computational Neuroscience.

[24]  P. Roelfsema,et al.  Alpha and gamma oscillations characterize feedback and feedforward processing in monkey visual cortex , 2014, Proceedings of the National Academy of Sciences.

[25]  Matthew W. Mosconi,et al.  Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome , 2017, Molecular Autism.

[26]  J. Larson,et al.  Age-Dependent and Selective Impairment of Long-Term Potentiation in the Anterior Piriform Cortex of Mice Lacking the Fragile X Mental Retardation Protein , 2005, The Journal of Neuroscience.

[27]  D. Binder,et al.  Translation-relevant EEG phenotypes in a mouse model of Fragile X Syndrome , 2018, Neurobiology of Disease.

[28]  Todd P. Coleman,et al.  Directed Information Graphs , 2012, IEEE Transactions on Information Theory.

[29]  B. Trommer,et al.  Fragile X mice: Reduced long‐term potentiation and N‐Methyl‐D‐Aspartate receptor‐mediated neurotransmission in dentate gyrus , 2011, Journal of neuroscience research.

[30]  Schreiber,et al.  Measuring information transfer , 2000, Physical review letters.

[31]  J. Tiago Gonçalves,et al.  Circuit level defects in the developing neocortex of fragile X mice , 2013, Nature Neuroscience.

[32]  Richard Paylor,et al.  Dynamic Translational and Proteasomal Regulation of Fragile X Mental Retardation Protein Controls mGluR-Dependent Long-Term Depression , 2006, Neuron.

[33]  Yu Zhang,et al.  Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1−/y mice , 2014, Nature Neuroscience.

[34]  Qiuyu Wu,et al.  Application of Automated Image-guided Patch Clamp for the Study of Neurons in Brain Slices. , 2017, Journal of visualized experiments : JoVE.

[35]  Shawn R. Olsen,et al.  Gain control by layer six in cortical circuits of vision , 2012, Nature.

[36]  Suhasa B Kodandaramaiah,et al.  Integration of autopatching with automated pipette and cell detection in vitro. , 2016, Journal of neurophysiology.

[37]  Karel Svoboda,et al.  Circuit Analysis of Experience-Dependent Plasticity in the Developing Rat Barrel Cortex , 2003, Neuron.

[38]  H. Kennedy,et al.  Visual Areas Exert Feedforward and Feedback Influences through Distinct Frequency Channels , 2014, Neuron.

[39]  K. M. Huber,et al.  Metabotropic receptor-dependent long-term depression persists in the absence of protein synthesis in the mouse model of fragile X syndrome. , 2006, Journal of neurophysiology.

[40]  G. Lynch,et al.  Brain-Derived Neurotrophic Factor Rescues Synaptic Plasticity in a Mouse Model of Fragile X Syndrome , 2007, The Journal of Neuroscience.

[41]  A L Reiss,et al.  Cognitive profiles associated with the fra(X) syndrome in males and females. , 1991, American journal of medical genetics.

[42]  P. Grünwald.  The Minimum Description Length Principle (Adaptive Computation and Machine Learning) , 2007 .

[43]  David Whitney,et al.  Resolution of spatial and temporal visual attention in infants with fragile X syndrome. , 2011, Brain : a journal of neurology.

[44]  E. Klann,et al.  Genetic Removal of p70 S6 Kinase 1 Corrects Molecular, Synaptic, and Behavioral Phenotypes in Fragile X Syndrome Mice , 2012, Neuron.

[45]  D. Johnston,et al.  Cell-Type Specific Channelopathies in the Prefrontal Cortex of the fmr1-/y Mouse Model of Fragile X Syndrome1,2,3 , 2015, eNeuro.

[46]  G. V. Simpson,et al.  Phase Locking of Single Neuron Activity to Theta Oscillations during Working Memory in Monkey Extrastriate Visual Cortex , 2003, Neuron.

[47]  J. Gibson,et al.  Imbalance of neocortical excitation and inhibition and altered UP states reflect network hyperexcitability in the mouse model of fragile X syndrome. , 2008, Journal of neurophysiology.

[48]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[49]  Jonathan T. Brown,et al.  Age-Dependent Long-Term Potentiation Deficits in the Prefrontal Cortex of the Fmr1 Knockout Mouse Model of Fragile X Syndrome. , 2016, Cerebral cortex.

[50]  M. Zhuo,et al.  Impaired Presynaptic Long-Term Potentiation in the Anterior Cingulate Cortex of Fmr1 Knock-out Mice , 2015, The Journal of Neuroscience.

[51]  J. Huguenard,et al.  Tapping the Brakes: Cellular and Synaptic Mechanisms that Regulate Thalamic Oscillations , 2016, Neuron.

[52]  P. Golshani,et al.  Cellular mechanisms of brain-state-dependent gain modulation in visual cortex , 2013, Nature Neuroscience.

[53]  F. Niere,et al.  Evidence for a Fragile X Mental Retardation Protein-Mediated Translational Switch in Metabotropic Glutamate Receptor-Triggered Arc Translation and Long-Term Depression , 2012, The Journal of Neuroscience.

[54]  Szabolcs Káli,et al.  Differences in subthreshold resonance of hippocampal pyramidal cells and interneurons: the role of h-current and passive membrane characteristics , 2010, The Journal of physiology.

[55]  M. Bear,et al.  A current source density analysis of evoked responses in slices of adult rat visual cortex: implications for the regulation of long-term potentiation. , 1996, Cerebral cortex.

[56]  M. Bear,et al.  Fragile X mental retardation protein and synaptic plasticity , 2013, Molecular Brain.

[57]  Klas H. Pettersen,et al.  Current-source density estimation based on inversion of electrostatic forward solution: Effects of finite extent of neuronal activity and conductivity discontinuities , 2006, Journal of Neuroscience Methods.

[58]  Matteo Carandini,et al.  Kilosort: realtime spike-sorting for extracellular electrophysiology with hundreds of channels , 2016, bioRxiv.

[59]  K. Svoboda,et al.  Channelrhodopsin-2–assisted circuit mapping of long-range callosal projections , 2007, Nature Neuroscience.

[60]  P. Hagerman,et al.  Autism profiles of males with fragile X syndrome. , 2008, American journal of mental retardation : AJMR.

[61]  Mark F. Bear,et al.  Altered synaptic plasticity in a mouse model of fragile X mental retardation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[62]  Craig G. Richter,et al.  Top-Down Beta Enhances Bottom-Up Gamma , 2016, The Journal of Neuroscience.

[63]  Jessica L. Burris,et al.  Visual motion processing deficits in infants with the fragile X premutation , 2014, Journal of Neurodevelopmental Disorders.

[64]  H. Marko,et al.  The Bidirectional Communication Theory - A Generalization of Information Theory , 1973, IEEE Transactions on Communications.

[65]  Dietmar Schmitz,et al.  Cell-specific synaptic plasticity induced by network oscillations , 2016, eLife.

[66]  Y. Yarom,et al.  Resonance, oscillation and the intrinsic frequency preferences of neurons , 2000, Trends in Neurosciences.

[67]  Henry J. Alitto,et al.  Simultaneous Recordings from the Primary Visual Cortex and Lateral Geniculate Nucleus Reveal Rhythmic Interactions and a Cortical Source for Gamma-Band Oscillations , 2014, The Journal of Neuroscience.

[68]  S. Tonegawa,et al.  Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486 , 2013, Proceedings of the National Academy of Sciences.

[69]  D. Licatalosi,et al.  FMRP Stalls Ribosomal Translocation on mRNAs Linked to Synaptic Function and Autism , 2011, Cell.

[70]  D. Heck,et al.  Thalamocortical Communication in the Awake Mouse Visual System Involves Phase Synchronization and Rhythmic Spike Synchrony at High Gamma Frequencies , 2018, Front. Neurosci..

[71]  Bryan M. Hooks,et al.  Organization of Cortical and Thalamic Input to Pyramidal Neurons in Mouse Motor Cortex , 2013, The Journal of Neuroscience.

[72]  A. Reiss,et al.  Compulsive, self-injurious, and autistic behavior in children and adolescents with fragile X syndrome. , 2008, American journal of mental retardation : AJMR.

[73]  Anne Gallagher,et al.  Fragile X-associated disorders: a clinical overview , 2012, Journal of Neurology.

[74]  Alexander A. Chubykin,et al.  Oscillatory Encoding of Visual Stimulus Familiarity , 2018, The Journal of Neuroscience.

[75]  C. Blakemore,et al.  Pyramidal neurons in layer 5 of the rat visual cortex. I. Correlation among cell morphology, intrinsic electrophysiological properties, and axon targets , 1994, The Journal of comparative neurology.

[76]  Kenneth D Harris,et al.  Spike sorting for large, dense electrode arrays , 2015, Nature Neuroscience.

[77]  U. Mitzdorf.  Current source-density method and application in cat cerebral cortex: investigation of evoked potentials and EEG phenomena. , 1985, Physiological reviews.

[78]  J. Fallon,et al.  The FXG: A Presynaptic Fragile X Granule Expressed in a Subset of Developing Brain Circuits , 2009, The Journal of Neuroscience.

[79]  G. Lynch,et al.  Patterned stimulation at the theta frequency is optimal for the induction of hippocampal long-term potentiation , 1986, Brain Research.

[80]  Shawn R. Olsen,et al.  Translaminar Inhibitory Cells Recruited by Layer 6 Corticothalamic Neurons Suppress Visual Cortex , 2014, Neuron.

[81]  Andrzej Wróbel,et al.  Inverse Current-Source Density Method in 3D: Reconstruction Fidelity, Boundary Effects, and Influence of Distant Sources , 2007, Neuroinformatics.