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The Journal of Neuroscience, October 22, 2008, 28(43):10864-10874; doi:10.1523/JNEUROSCI.1340-08.2008

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

Brigitte van Zundert,^1,2 Marieke H. Peuscher,¹ Meri Hynynen,² Adam Chen,² Rachael L. Neve,³ Robert H. Brown Jr,² Martha Constantine-Paton,¹ and Mark C. Bellingham^1,4

¹McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, ²Day Laboratory for Neuromuscular Research, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02429, ³Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02178, and ⁴School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia

Correspondence should be addressed to Mark C. Bellingham, School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia. Email: mark.bellingham{at}uq.edu.au

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 (hSOD1^G93A 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 hSOD1^G93A mice were made to characterize functional changes in neuronal activity. Hypoglossal motoneurons (HMs) in postnatal day 4 (P4)–P10 hSOD1^G93A mice displayed hyperexcitability, increased persistent Na⁺ current (PC_Na), 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 hSOD1^G93A 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 hSOD1^G93A 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 PC_Na and hyperexcitability early in life might be one way to mitigate or prevent cell death in the adult CNS.

Key words: action potential; brainstem; dendrite; EPSP; IPSP; motor neuron; interneuron; locomotor activity; sodium channel; synaptic transmission; superior colliculus

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Received March 28, 2008; revised Aug. 7, 2008; accepted Sept. 2, 2008.

Correspondence should be addressed to Mark C. Bellingham, School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia. Email: mark.bellingham{at}uq.edu.au

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