Perturbation of Cortical Excitability in a Conditional Model of PCDH19 Disorder

PCDH19 epilepsy (DEE9) is an X-linked syndrome associated with cognitive and behavioral disturbances. Since heterozygous females are affected, while mutant males are spared, it is likely that DEE9 pathogenesis is related to disturbed cell-to-cell communication associated with mosaicism. However, the effects of mosaic PCDH19 expression on cortical networks are unknown. We mimicked the pathology of DEE9 by introducing a patch of mosaic protein expression in one hemisphere of the cortex of conditional PCDH19 knockout mice one day after birth. In the contralateral area, PCDH19 expression was unaffected, thus providing an internal control. In this model, we characterized the physiology of the disrupted network using local field recordings and two photon Ca2+ imaging in urethane anesthetized mice. We found transient episodes of hyperexcitability in the form of brief hypersynchronous spikes or bursts of field potential oscillations in the 9–25 Hz range. Furthermore, we observed a strong disruption of slow wave activity, a crucial component of NREM sleep. This phenotype was present also when PCDH19 loss occurred in adult mice, demonstrating that PCDH19 exerts a function on cortical circuitry outside of early development. Our results indicate that a focal mosaic mutation of PCDH19 disrupts cortical networks and broaden our understanding of DEE9.

[1]  M. Passafaro,et al.  A rat model of a focal mosaic expression of PCDH19 replicates human brain developmental abnormalities and behaviours , 2022, Brain Communications.

[2]  Lishuo Liu,et al.  Decreased expression of the clock gene Bmal1 is involved in the pathogenesis of temporal lobe epilepsy , 2021, Molecular brain.

[3]  N. Hoshina,et al.  Female-specific synaptic dysfunction and cognitive impairment in a mouse model of PCDH19 disorder , 2021, Science.

[4]  S. Landi,et al.  Modelling genetic mosaicism of neurodevelopmental disorders in vivo by a Cre-amplifying fluorescent reporter , 2020, Nature Communications.

[5]  Richard Gao,et al.  Parameterizing neural power spectra into periodic and aperiodic components , 2020, Nature Neuroscience.

[6]  M. Passafaro,et al.  The Epilepsy-Related Protein PCDH19 Regulates Tonic Inhibition, GABAAR Kinetics, and the Intrinsic Excitability of Hippocampal Neurons , 2020, Molecular Neurobiology.

[7]  I. Scheffer,et al.  PCDH19 Pathogenic Variants in Males: Expanding the Phenotypic Spectrum. , 2020, Advances in experimental medicine and biology.

[8]  I. Arnulf,et al.  N3 sleep with rapid eye movements in a PCDH19 mutation: a new dissociate state between N3 and REM sleep. , 2020, Sleep medicine.

[9]  G. Cioni,et al.  Novel translational phenotypes and biomarkers for creatine transporter deficiency , 2020, Brain communications.

[10]  C. Barba,et al.  Quantitative MRI-Based Analysis Identifies Developmental Limbic Abnormalities in PCDH19 Encephalopathy. , 2020, Cerebral cortex.

[11]  G. Ratto,et al.  Evolution of Epileptiform Activity in Zebrafish by Statistical-Based Integration of Electrophysiology and 2-Photon Ca2+ Imaging , 2020, Cells.

[12]  N. Mercuri,et al.  The striatal-enriched protein Rhes is a critical modulator of cocaine-induced molecular and behavioral responses , 2019, Scientific Reports.

[13]  S. Landi,et al.  A Cre-amplifier to generate and detect genetic mosaics in vivo , 2019, bioRxiv.

[14]  I. Scheffer,et al.  Schizophrenia is a later‐onset feature of PCDH19 Girls Clustering Epilepsy , 2019, Epilepsia.

[15]  C. Portera-Cailliau,et al.  Autism in the Balance: Elevated E-I Ratio as a Homeostatic Stabilization of Synaptic Drive , 2019, Neuron.

[16]  I. Scheffer,et al.  A systematic review and meta-analysis of 271 PCDH19-variant individuals identifies psychiatric comorbidities, and association of seizure onset and disease severity , 2018, Molecular Psychiatry.

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

[18]  A. Poduri,et al.  PCDH19‐related epilepsy is associated with a broad neurodevelopmental spectrum , 2018, Epilepsia.

[19]  Y. Bozzi,et al.  Neurobiological bases of autism–epilepsy comorbidity: a focus on excitation/inhibition imbalance , 2018, The European journal of neuroscience.

[20]  Yuguo Yu,et al.  Synaptic E-I Balance Underlies Efficient Neural Coding , 2018, Front. Neurosci..

[21]  M. Passafaro,et al.  The female epilepsy protein PCDH19 is a new GABAAR-binding partner that regulates GABAergic transmission as well as migration and morphological maturation of hippocampal neurons , 2018, Human molecular genetics.

[22]  C. Korff,et al.  Focal cortical malformations in children with early infantile epilepsy and PCDH19 mutations: case report , 2018, Developmental medicine and child neurology.

[23]  James N. Hughes,et al.  Abnormal Cell Sorting Underlies the Unique X-Linked Inheritance of PCDH19 Epilepsy , 2018, Neuron.

[24]  T. Miyakawa,et al.  Loss of X-linked Protocadherin-19 differentially affects the behavior of heterozygous female and hemizygous male mice , 2017, Scientific Reports.

[25]  G. Mancini,et al.  Male patients affected by mosaic PCDH19 mutations: five new cases , 2017, neurogenetics.

[26]  Giulio Tononi,et al.  Ultrastructural evidence for synaptic scaling across the wake/sleep cycle , 2017, Science.

[27]  B. Bacskai,et al.  Optogenetic Restoration of Disrupted Slow Oscillations Halts Amyloid Deposition and Restores Calcium Homeostasis in an Animal Model of Alzheimer’s Disease , 2017, PloS one.

[28]  S. Landi,et al.  Epileptiform activity in the mouse visual cortex interferes with cortical processing in connected areas , 2017, Scientific Reports.

[29]  Richard Gao,et al.  Inferring synaptic excitation/inhibition balance from field potentials , 2016, NeuroImage.

[30]  Laurie D. Smith,et al.  PCDH19‐related epileptic encephalopathy in a male mosaic for a truncating variant , 2016, American journal of medical genetics. Part A.

[31]  James N. Hughes,et al.  Pcdh19 Loss-of-Function Increases Neuronal Migration In Vitro but is Dispensable for Brain Development in Mice , 2016, Scientific Reports.

[32]  Daniel Levenstein,et al.  Network Homeostasis and State Dynamics of Neocortical Sleep , 2016, Neuron.

[33]  H. Ikeda,et al.  Characteristic phasic evolution of convulsive seizure in PCDH19-related epilepsy. , 2016, Epileptic disorders : international epilepsy journal with videotape.

[34]  A. Gordus,et al.  Sensitive red protein calcium indicators for imaging neural activity , 2016, bioRxiv.

[35]  Garrett Neske,et al.  The Slow Oscillation in Cortical and Thalamic Networks: Mechanisms and Functions , 2016, Front. Neural Circuits.

[36]  L. Lewejohann,et al.  Lifetime development of behavioural phenotype in the house mouse (Mus musculus) , 2015, Frontiers in Zoology.

[37]  J. Gotman,et al.  Facilitation of epileptic activity during sleep is mediated by high amplitude slow waves , 2015, Brain : a journal of neurology.

[38]  D. Hoffman-Zacharska,et al.  Epilepsy and mental retardation restricted to females: X-linked epileptic infantile encephalopathy of unusual inheritance , 2015, Journal of Applied Genetics.

[39]  B. Connors,et al.  Contributions of Diverse Excitatory and Inhibitory Neurons to Recurrent Network Activity in Cerebral Cortex , 2015, The Journal of Neuroscience.

[40]  A. Gabrielli,et al.  SCOPRISM: A new algorithm for automatic sleep scoring in mice , 2014, Journal of Neuroscience Methods.

[41]  G. Tononi,et al.  Sleep and the Price of Plasticity: From Synaptic and Cellular Homeostasis to Memory Consolidation and Integration , 2014, Neuron.

[42]  J. Born,et al.  About sleep's role in memory. , 2013, Physiological reviews.

[43]  M. Avoli,et al.  GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity , 2011, Progress in Neurobiology.

[44]  Lief E. Fenno,et al.  Neocortical excitation/inhibition balance in information processing and social dysfunction , 2011, Nature.

[45]  E. Bertini,et al.  Spectrum of phenotypes in female patients with epilepsy due to protocadherin 19 mutations , 2011, Epilepsia.

[46]  C. Redies,et al.  Cadherin expression in the somatosensory cortex: evidence for a combinatorial molecular code at the single-cell level , 2011, Neuroscience.

[47]  F. Rivier,et al.  Mutations and Deletions in PCDH19 Account for Various Familial or Isolated Epilepsies in Females , 2011, Human mutation.

[48]  C. Dickson,et al.  Short-duration epileptic discharges show a distinct phase preference during ongoing hippocampal slow oscillations. , 2010, Journal of neurophysiology.

[49]  Romina Moavero,et al.  Attention deficit hyperactivity disorder in children with epilepsy , 2010, Brain and Development.

[50]  Bijan Pesaran,et al.  Chronux: a platform for analyzing neural signals , 2009, BMC Neuroscience.

[51]  G. Tononi,et al.  Cortical Firing and Sleep Homeostasis , 2009, Neuron.

[52]  M. Ruberg,et al.  Correction: Sporadic Infantile Epileptic Encephalopathy Caused by Mutations in PCDH19 Resembles Dravet Syndrome but Mainly Affects Females , 2009, PLoS Genetics.

[53]  M. Ruberg,et al.  Sporadic Infantile Epileptic Encephalopathy Caused by Mutations in PCDH19 Resembles Dravet Syndrome but Mainly Affects Females , 2009, PLoS genetics.

[54]  M. de Curtis,et al.  Fast activity at seizure onset is mediated by inhibitory circuits in the entorhinal cortex in vitro , 2008, Annals of neurology.

[55]  Arthur Konnerth,et al.  Clusters of Hyperactive Neurons Near Amyloid Plaques in a Mouse Model of Alzheimer's Disease , 2008, Science.

[56]  Andrew Menzies,et al.  X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment , 2008, Nature Genetics.

[57]  K. Friend,et al.  Epilepsy and mental retardation limited to females: an under-recognized disorder. , 2008, Brain : a journal of neurology.

[58]  G. Tononi,et al.  Molecular and electrophysiological evidence for net synaptic potentiation in wake and depression in sleep , 2008, Nature Neuroscience.

[59]  G. Tononi,et al.  Sleep homeostasis and cortical synchronization: II. A local field potential study of sleep slow waves in the rat. , 2007, Sleep.

[60]  Sean L. Hill,et al.  Sleep homeostasis and cortical synchronization: I. Modeling the effects of synaptic strength on sleep slow waves. , 2007, Sleep.

[61]  J. Born,et al.  The contribution of sleep to hippocampus-dependent memory consolidation , 2007, Trends in Cognitive Sciences.

[62]  Rudolf Jaenisch,et al.  Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[63]  C. Elger,et al.  Epileptic Seizures and Epilepsy: Definitions Proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE) , 2005, Epilepsia.

[64]  R. Quian Quiroga,et al.  Unsupervised Spike Detection and Sorting with Wavelets and Superparamagnetic Clustering , 2004, Neural Computation.

[65]  M. Merzenich,et al.  Model of autism: increased ratio of excitation/inhibition in key neural systems , 2003, Genes, brain, and behavior.

[66]  M. Curtis,et al.  Interictal spikes in focal epileptogenesis , 2001, Progress in Neurobiology.

[67]  Nancy B. Spinner,et al.  Epilepsy and mental retardation limited to females: an X-linked dominant disorder with male sparing , 1997, Nature Genetics.

[68]  M. Steriade,et al.  A novel slow (< 1 Hz) oscillation of neocortical neurons in vivo: depolarizing and hyperpolarizing components , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[69]  M. Terzano,et al.  Activation of partial seizures with motor signs during cyclic alternating pattern in human sleep , 1991, Epilepsy Research.

[70]  J. Gotman,et al.  Interictal spiking during wakefulness and sleep and the localization of foci in temporal lobe epilepsy , 1991, Neurology.