Neonatal Neuronal Circuitry Shows Hyperexcitable Disturbance in a Mouse Model of the Adult-Onset Neurodegenerative Disease Amyotrophic Lateral Sclerosis

Distinguishing the primary from secondary effects and compensatory mechanisms is of crucial importance in understanding adult-onset neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Transgenic mice that overexpress the G93A mutation of the human Cu-Zn superoxide dismutase 1 gene (hSOD1G93A mice) are a commonly used animal model of ALS. Whole-cell patch-clamp recordings from neurons in acute slice preparations from neonatal wild-type and hSOD1G93A mice were made to characterize functional changes in neuronal activity. Hypoglossal motoneurons (HMs) in postnatal day 4 (P4)–P10 hSOD1G93A mice displayed hyperexcitability, increased persistent Na+ current (PCNa), and enhanced frequency of spontaneous excitatory and inhibitory transmission, compared with wild-type mice. These functional changes in neuronal activity are the earliest yet reported for the hSOD1G93A mouse, and are present 2–3 months before motoneuron degeneration and clinical symptoms appear in these mice. Changes in neuronal activity were not restricted to motoneurons: superior colliculus interneurons also displayed hyperexcitability and synaptic changes (P10–P12). Furthermore, in vivo viral-mediated GFP (green fluorescent protein) overexpression in hSOD1G93A HMs revealed precocious dendritic remodeling, and behavioral assays revealed transient neonatal neuromotor deficits compared with controls. These findings underscore the widespread and early onset of abnormal neural activity in this mouse model of the adult neurodegenerative disease ALS, and suggest that suppression of PCNa and hyperexcitability early in life might be one way to mitigate or prevent cell death in the adult CNS.

[1]  M. Kiernan,et al.  Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis. , 2008, Brain : a journal of neurology.

[2]  B. Kampa,et al.  Action potential generation requires a high sodium channel density in the axon initial segment , 2008, Nature Neuroscience.

[3]  S. Smittkamp,et al.  Time-course and characterization of orolingual motor deficits in B6SJL-Tg(SOD1-G93A)1Gur/J mice , 2008, Neuroscience.

[4]  Hynek Wichterle,et al.  Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons , 2007, Nature Neuroscience.

[5]  Kevin Eggan,et al.  Non–cell autonomous effect of glia on motor neurons in an embryonic stem cell–based ALS model , 2007, Nature Neuroscience.

[6]  R. Kalb,et al.  Embryonic motor neuron dendrite growth is stunted by inhibition of nitric oxide‐dependent activation of soluble guanylyl cyclase and protein kinase G , 2007, The European journal of neuroscience.

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

[8]  Robert H. Brown,et al.  Molecular biology of amyotrophic lateral sclerosis: insights from genetics , 2006, Nature Reviews Neuroscience.

[9]  M. Kiernan,et al.  Novel threshold tracking techniques suggest that cortical hyperexcitability is an early feature of motor neuron disease. , 2006, Brain : a journal of neurology.

[10]  G. Kollias,et al.  Onset and Progression in Inherited ALS Determined by Motor Neurons and Microglia , 2006, Science.

[11]  R. Guiloff,et al.  Widespread loss of neuronal populations in the spinal ventral horn in sporadic motor neuron disease. A morphometric study , 2006, Journal of the Neurological Sciences.

[12]  B. Keller,et al.  Ca2+, mitochondria and selective motoneuron vulnerability: implications for ALS , 2005, Trends in Neurosciences.

[13]  E. Nestler,et al.  Use of herpes virus amplicon vectors to study brain disorders. , 2005, BioTechniques.

[14]  M. Barrot,et al.  Regulation of Drug Reward by cAMP Response Element-Binding Protein: Evidence for Two Functionally Distinct Subregions of the Ventral Tegmental Area , 2005, The Journal of Neuroscience.

[15]  C. Heckman,et al.  Increased persistent Na+ current and its effect on excitability in motoneurones cultured from mutant SOD1 mice , 2005, The Journal of physiology.

[16]  M. Bellingham,et al.  Glycinergic and GABAergic Synaptic Activity Differentially Regulate Motoneuron Survival and Skeletal Muscle Innervation , 2005, The Journal of Neuroscience.

[17]  M. Bellingham,et al.  P2X7-like receptor subunits enhance excitatory synaptic transmission at central synapses by presynaptic mechanisms , 2004, Neuroscience.

[18]  M. Constantine‐Paton,et al.  Retina-Driven Dephosphorylation of the NR2A Subunit Correlates with Faster NMDA Receptor Kinetics at Developing Retinocollicular Synapses , 2004, The Journal of Neuroscience.

[19]  C. Winters,et al.  Strong Calcium Entry Activates Mitochondrial Superoxide Generation, Upregulating Kinase Signaling in Hippocampal Neurons , 2004, The Journal of Neuroscience.

[20]  P. Roubertoux,et al.  Altered sensorimotor development in a transgenic mouse model of amyotrophic lateral sclerosis , 2004, The European journal of neuroscience.

[21]  Wei Lu,et al.  Eye Opening Rapidly Induces Synaptic Potentiation and Refinement , 2004, Neuron.

[22]  M. Constantine‐Paton,et al.  Receptor compartmentalization and trafficking at glutamate synapses: a developmental proposal , 2004, Trends in Neurosciences.

[23]  B. Moreno-López,et al.  Nerve injury reduces responses of hypoglossal motoneurones to baseline and chemoreceptor‐modulated inspiratory drive in the adult rat , 2004, The Journal of physiology.

[24]  S. Landau,et al.  Cortical selective vulnerability in motor neuron disease: a morphometric study. , 2004, Brain : a journal of neurology.

[25]  L. Moran,et al.  The facial nerve axotomy model , 2004, Brain Research Reviews.

[26]  S. Nelson,et al.  Homeostatic plasticity in the developing nervous system , 2004, Nature Reviews Neuroscience.

[27]  T. Tiraihi,et al.  Synaptic lesions and synaptophysin distribution change in spinal motoneurons at early stages following sciatic nerve transection in neonatal rats. , 2004, Brain research. Developmental brain research.

[28]  P. Morris,et al.  In Vitro and In Vivo Effects of Genistein on Murine Alveolar Macrophage TNFα Production , 1999, Inflammation.

[29]  T. Dawson,et al.  Free Radicals as Mediators of Neuronal Injury , 1998, Cellular and Molecular Neurobiology.

[30]  C. Heckman,et al.  Hyperexcitability of cultured spinal motoneurons from presymptomatic ALS mice. , 2004, Journal of neurophysiology.

[31]  S. DeKosky,et al.  Looking Backward to Move Forward: Early Detection of Neurodegenerative Disorders , 2003, Science.

[32]  Minh N. H. Nguyen,et al.  Wild-Type Nonneuronal Cells Extend Survival of SOD1 Mutant Motor Neurons in ALS Mice , 2003, Science.

[33]  S. Hansson,et al.  Differential neurochemical properties of central serotonergic transmission in Roman high‐ and low‐avoidance rats , 2003, Journal of neurochemistry.

[34]  S. Pelech,et al.  Protein kinase and protein phosphatase expression in amyotrophic lateral sclerosis spinal cord , 2003, Journal of neurochemistry.

[35]  S. Pelech,et al.  Protein kinase and protein phosphatase expression in the central nervous system of G93A mSOD over‐expressing mice , 2003, Journal of neurochemistry.

[36]  M. Mishina,et al.  Developmental loss of miniature N-methyl-d-aspartate receptor currents in NR2A knockout mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[37]  Marc D Binder,et al.  Persistent sodium and calcium currents in rat hypoglossal motoneurons. , 2003, Journal of neurophysiology.

[38]  M. Colonnese,et al.  Chronic NMDA receptor blockade from birth delays the maturation of NMDA currents, but does not affect AMPA/kainate currents. , 2003, Journal of neurophysiology.

[39]  W. Abraham,et al.  The AMPA Receptor Subunit GluR1 Regulates Dendritic Architecture of Motor Neurons , 2002, The Journal of Neuroscience.

[40]  G. Alcaraz,et al.  Molecular determinants of emerging excitability in rat embryonic motoneurons , 2002, The Journal of physiology.

[41]  Hiroshi Mitsumoto,et al.  Differential Susceptibility of the Ocular Motor System to Disease , 2002, Annals of the New York Academy of Sciences.

[42]  Jeffrey D. Rothstein,et al.  From charcot to lou gehrig: deciphering selective motor neuron death in als , 2001, Nature Reviews Neuroscience.

[43]  V. Silani,et al.  Early vacuolization and mitochondrial damage in motor neurons of FALS mice are not associated with apoptosis or with changes in cytochrome oxidase histochemical reactivity , 2001, Journal of the Neurological Sciences.

[44]  C J Lumsden,et al.  Inherited neurodegenerative diseases: the one-hit model of neurodegeneration. , 2001, Human molecular genetics.

[45]  K. Williams.  Ifenprodil, a novel NMDA receptor antagonist: site and mechanism of action. , 2001, Current drug targets.

[46]  William A. Catterall,et al.  Neuromodulation of Na+ channels: An unexpected form of cellular platicity , 2001, Nature Reviews Neuroscience.

[47]  W. Robberecht,et al.  Amyotrophic lateral sclerosis: pathogenesis. , 2000, Seminars in neurology.

[48]  A. Urbani,et al.  Riluzole inhibits the persistent sodium current in mammalian CNS neurons , 2000, The European journal of neuroscience.

[49]  M. Constantine‐Paton,et al.  Activity-Dependent Induction of Tonic Calcineurin Activity Mediates a Rapid Developmental Downregulation of NMDA Receptor Currents , 2000, Neuron.

[50]  E. Klann,et al.  Superoxide-induced Stimulation of Protein Kinase C via Thiol Modification and Modulation of Zinc Content* , 2000, The Journal of Biological Chemistry.

[51]  R. Brownstone,et al.  Characterization of calcium currents in functionally mature mouse spinal motoneurons , 2000, The European journal of neuroscience.

[52]  P. Stieg,et al.  Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. , 2000, Science.

[53]  S. Aamodt,et al.  Chronic NMDA exposure accelerates development of GABAergic inhibition in the superior colliculus. , 2000, Journal of neurophysiology.

[54]  J. O’Brien,et al.  Cotransmission of GABA and glycine to brain stem motoneurons. , 1999, Journal of neurophysiology.

[55]  A. Goldin.  Diversity of Mammalian Voltage‐Gated Sodium Channels , 1999, Annals of the New York Academy of Sciences.

[56]  Bruce P. Bean,et al.  Ionic Currents Underlying Spontaneous Action Potentials in Isolated Cerebellar Purkinje Neurons , 1999, The Journal of Neuroscience.

[57]  M. Gutnick,et al.  Activation of protein kinase C increases neuronal excitability by regulating persistent Na+ current in mouse neocortical slices. , 1998, Journal of neurophysiology.

[58]  D. Burke,et al.  Strength-duration properties of sensory and motor axons in amyotrophic lateral sclerosis. , 1998, Brain : a journal of neurology.

[59]  J. Morrison,et al.  Time course of neuropathology in the spinal cord of G86R superoxide dismutase transgenic mice , 1998, The Journal of comparative neurology.

[60]  R. Oppenheim,et al.  Characterization of spinal motoneuron degeneration following different types of peripheral nerve injury in neonatal and adult mice. , 1998, The Journal of comparative neurology.

[61]  S. Aamodt,et al.  Temporal Correlations between Functional and Molecular Changes in NMDA Receptors and GABA Neurotransmission in the Superior Colliculus , 1997, The Journal of Neuroscience.

[62]  M. Bellingham,et al.  Presynaptic depression of excitatory synaptic inputs to rat hypoglossal motoneurons by muscarinic M2 receptors. , 1996, Journal of neurophysiology.

[63]  J. D. Porter,et al.  The Neuronal Voltage-Gated Sodium Channel, Scn8a, Is Essential for Postnatal Maturation of Spinal, but Not Oculomotor, Motor Units , 1996, Experimental Neurology.

[64]  J. Sanes,et al.  Failure of postsynaptic specialization to develop at neuromuscular junctions of rapsyn-deficient mice , 1995, Nature.

[65]  J. Feldman,et al.  Differential innervation of protruder and retractor muscles of the tongue in rat , 1995, The Journal of comparative neurology.

[66]  R. Kalb.  Regulation of motor neuron dendrite growth by NMDA receptor activation. , 1994, Development.

[67]  M. Gurney,et al.  Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. , 1994, Science.

[68]  G. Barrionuevo,et al.  Morphology of developing rat genioglossal motoneurons studied in vitro: Changes in length, branching pattern, and spatial distribution of dendrites , 1994, The Journal of comparative neurology.

[69]  J. Haines,et al.  Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis , 1993, Nature.

[70]  W. Catterall,et al.  Functional modulation of brain sodium channels by protein kinase C phosphorylation. , 1991, Science.

[71]  Mulder Dw.  Clinical limits of amyotrophic lateral sclerosis. , 1982 .

[72]  D. W. Mulder.  Clinical limits of amyotrophic lateral sclerosis. , 1982, Advances in neurology.