Progressive Changes in Synaptic Inputs to Motoneurons in Adult Sacral Spinal Cord of a Mouse Model of Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of motoneurons. One potential mechanism is excitotoxicity. We studied the behaviors of spinal neurons using an in vitro preparation of the sacral cord from the G93A SOD1 mouse model of ALS. Measurements were conducted at presymptomatic [approximately postnatal day 50 (ϳP50)], early (ϳP90), and late (ϾP120) stages of the disease. Short-latency reflexes (SRs) in ventral roots, presumably monosynaptic, were evoked by electrical stimulation of a dorsal root. The fraction of motoneurons capable of responding to this activation was evaluated by measuring the compound action potential [total motor activity (TMA)] evoked by antidromic stimulation of the distal ventral root. In mutant SOD1 (mSOD1) mice, both the SR and the TMA decreased with age compared with nontransgenic littermates, ruling out the SR as a source of increasing excitotoxicity. Spinal interneuron activity was assessed using the synchronized ventral root bursts generated by both bath application of blockers of inhibitory neurotransmitters (glycine, GABA A ) and agonists of glutamate receptors (especially NMDA receptors). After symptom onset, a higher percentage of preparations from mSOD1 mice exhibited bursting, and these bursts exhibited more sub-bursts and a more disorganized pattern. In mSOD1 mice with clear muscle tremor, the ventral roots exhibited spontaneous synchronized bursts, which were highly sensitive to the blockade of NMDA receptors. These data suggest that although short-latency sensory input does not increase as symptoms develop, interneuron activity does increase and may contribute to excitotoxicity.

Selective degeneration of a physiological subtype of spinal motor neuron in mice with SOD1-linked ALS

“…In addition, several anatomical studies have noted an increase in the ratio of excitatory to inhibitory synapses onto MNs in the context of overall synapse loss over the course of disease (32)(33)(34). Additionally, some studies have suggested broad changes in synaptic and network function that lead to abnormal MN output in the form of irregular bursting patterns (35); however, the specific nature and ultimate consequence of such network abnormalities is not understood.…”

NO Orchestrates the Loss of Synaptic Boutons from Adult “Sick” Motoneurons: Modeling a Molecular Mechanism

“…This strain overexpresses the human mutant cytosolic Cu/Zn SOD1 possessing a glycine to alanine substitution at the 93rd position (G93A) [85]. These mice, expressing ∼20 copies of the transgene, develop an ALS-like disease with initial symptoms that include fine tremor or shaking and weakness in the hind limbs at 90 days postnatal (P90), leading to severe hindlimb paralysis at ∼120 days of age [85][86][87][88][89][90][91][92][93][94].…”

TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies

“…8 TRPV4 is a transmembrane Ca 2ϩ -permeable, nonselective cation channel and responsive to mechanical force, osmotic concentration, and increased temperature. 9 The potential for calcium neurotoxicity is emphasized by earlier reviews in neurodegeneration 10 with suggested roles in AD, 11 motor neuron disease, 12 and PTEN-induced putative kinase (PINK1)-associated PD. 13 Additionally, L-type calcium channel blockers have recently been shown as neuroprotective in development of idiopathic PD.…”