Early motor and electrophysiological changes in transgenic mouse model of amyotrophic lateral sclerosis and gender differences on clinical outcome

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disorder affecting motoneurons and the SOD1(G93A) transgenic mice are widely employed to study disease physiopathology and therapeutic strategies. Despite the cellular and biochemical evidences of an early motor system dysfunction, the conventional behavioral tests do not detect early motor impairments in SOD1 mouse model. We evaluated early changes in motor behavior of ALS mice by doing the analyses of tail elevation, footprint, automatic recording of motor activities by means of an infrared motion sensor activity system and electrophysiological measurements in male and female wild-type (WT) and SOD1(G93A) mice from postnatal day (P) 20 up to endpoint. The classical evaluations of mortality, weight loss, tremor, rotometer, hanging wire and inclined plane were also employed. There was a late onset (after P90) of the impairments of classical parameters and the outcome varied between genders of ALS mice, being tremor, cumulative survival, weight loss and neurological score about 10 days earlier in male than female ALS mice and also about 20 days earlier in ALS males regarding rotarod and hanging wire performances. While diminution of hindpaw base was 10 days earlier in ALS males (P110) compared to females, the steep length decreased 40 days earlier in ALS females (P60) than ALS males. The automatic analysis of motor impairments showed substantial late changes (after P90) of motility and locomotion in the ALS females, but not in the ALS males. It was surprising that the scores of tail elevation were already decreased in ALS males and females by P40, reaching the minimal values at the endpoint. The electrophysiological analyses showed early changes of measures in the ALS mouse sciatic nerve, i.e., decreased values of amplitude (P40) and nerve conduction velocity (P20), and also an increased latency (P20) reaching maximal level of impairments at the late disease phase. The early changes were not accompanied by reductions of neuronal protein markers of neurofilament 200 and ChAT in the ventral part of the lumbar spinal cord of P20 and P60 ALS mice by means of Western blot technique, despite remarkable decreases of those protein levels in P120 ALS mice. In conclusion, early changes of motor behavior and electrophysiological parameters in ALS mouse model must be taken into attention in the analyses of disease mechanisms and therapeutic effects.

Granulocyte Colony-Stimulating Factor Ameliorates Skeletal Muscle Dysfunction in Amyotrophic Lateral Sclerosis Mice and Improves Proliferation of SOD1-G93A Myoblasts in vitro

“…All animals performed these tests following a previously established methodology in this model [29,30]. For the footprint data, the stride length was normalized for each individual mouse to the initial stride length before the start of the treatment to eliminate sex and size variability.…”

Progressive Degeneration and Inhibition of Peripheral Nerve Regeneration in the SOD1-G93A Mouse Model of Amyotrophic Lateral Sclerosis

“…Degeneration of motor axons in the PNS is a crucial and significant pathological feature in patients and in animal models of ALS, and it is linked to defects in axonal transport and message transmission [16]. At a late stage, the expression of the SOD1-G93A mutant coincides with the occurrence of axon degeneration and behavioral deficits that are linked to the peripheral nerves.…”

Chronic Proximal Axonopathy in Rats is Associated With Long-Standing Neurofilament Depletion in Neuromuscular Junctions and Behavioral Deficits

“…For example, holding times in an inverted grid test, which probably involved similar motor requirements to those in our vertical ladder test in rats, were considerably reduced in Tardbp +/j mice despite normal walking stride parameters (36). In addition, reduced tail elevation was found as an early motor effect in SOD1 G93A mice, well before changes in stride parameters were recorded (37). Further work is necessary to ascertain whether the alterations in behavior recorded in this study do in fact reflect deficits in neuromuscular function.…”