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

Abstract

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 ϩ 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.

Collapsin Response Mediator Protein 4a (CRMP4a) Is Upregulated in Motoneurons of Mutant SOD1 Mice and Can Trigger Motoneuron Axonal Degeneration and Cell Death

“…After a neonatal period in which motoneuron excitability is altered (Durand et al, 2006;van Zundert et al, 2008), the first morphological changes to be detected are at the neuromuscular junction where motor axons die back, leading to skeletal muscle paralysis that is only transiently overcome by regenerative axon sprouting (Frey et al, 2000;Fischer et al, 2004;Schaefer et al, 2005). Fast motor units are more vulnerable than slow motor units to axonal dieback, even within the same muscle (Pun et al, 2006).…”

Mutant SOD1 protein increases Nav1.3 channel excitability

“…These studies included investigations of human motor cortex [34], murine cell culture and slice preparations of motor cortex [11,35], spinal cord [5,28,30,[36][37][38][39][40][41], and brainstem [10,42]. .…”

“…Also evident, both in vivo and in vitro, are data implicating altered neuronal excitability as another key component of the pathophysiology of ALS. Neuronal hyperexcitability has been documented in primary spinal motor neuron cultures [5,6], in ALS motor neurons derived from induced pluripotential stem cells [7,8] and in slice preparations from transgenic mice carrying the familial ALS mutation G93A (hSOD1 G93A ) [9,10]. In the latter instance, the ALS mice exhibited augmented neuronal excitability and increased persistent sodium current [11].…”

“…In the latter instance, the ALS mice exhibited augmented neuronal excitability and increased persistent sodium current [11]. The hyperexcitability reflects at least three factors: intrinsic hyperexcitability of the neurons themselves, excessive excitatory inputs from interneurons [10], and pro-excitatory effects of soluble factors secreted by astrocytes [9]. Hypoexcitability has also been observed in iPSC-derived ALS motor neurons [12] and is also proposed to be a critical element in the early vulnerability of selected neuronal populations in ALS [13,14].…”

A repertoire of rhythmic bursting produced by hypoglossal motoneurons in physiological and pathological conditions

“…It is interesting to compare the acute action of H 2 O 2 with the motoneuron phenotype of the mutated SOD1 mice with aberrant handling of reactive oxygen species (van Zundert et al 2008). In either case, hypoglossal motoneurons fire more intensely: however, in the mutant, the persistent Na þ current is enhanced without change in input resistance or afterhyperpolarization.…”