The vulnerability of spinal motoneurons and soma size plasticity in a mouse model of amyotrophic lateral sclerosis

Abstract

α-Motoneuron soma size is correlated with the cell's excitability and function, and has been posited as a plastic property that changes during cellular maturation, injury and disease. This study examined whether α-motoneuron somas change in size over disease progression in the G93A mouse model of amyotrophic lateral sclerosis (ALS), a disease characterized by progressive motoneuron death. We used 2D- and 3D-morphometric analysis of motoneuron size and measures of cell density at four key disease stages: neonatal (P10 - with earliest known disease changes); young adult (P30 - presymptomatic with early motoneuron death); symptom onset (P90 - with death of 70-80% of motoneurons); and end-stage (P120+ - with full paralysis of hindlimbs). We additionally examined differences in lumbar vs. sacral vs. cervical motoneurons; in motoneurons from male vs. female mice; and in fast vs. slow motoneurons. We present the first evidence of plastic changes in the soma size of spinal α-motoneurons occurring throughout different stages of ALS with profound effects on motoneuron excitability. Somatic changes are time dependent and are characterized by early-stage enlargement (P10 and P30); no change around symptom onset; and shrinkage at end-stage. A key finding in the study indicates that disease-vulnerable motoneurons exhibit increased soma sizes (P10 and P30). This pattern was confirmed across spinal cord regions, genders and motoneuron types. This extends the theory of motoneuron size-based vulnerability in ALS: not only are larger motoneurons more vulnerable to death in ALS, but are also enlarged further in the disease. Such information is valuable for identifying ALS pathogenesis mechanisms.

Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology

“…Like corticospinal motor neurons, VENs and fork cells are large Layer 5 projection neurons with likely subcerebral targets [15]. In a mutant SOD1 mouse model of ALS, vulnerable populations of spinal motor neurons showed an initial increase in soma cross-sectional area, followed by atrophy later in disease [21]. This alteration in cell size was predicted to result in altered neuronal excitability [21].…”

“…In a mutant SOD1 mouse model of ALS, vulnerable populations of spinal motor neurons showed an initial increase in soma cross-sectional area, followed by atrophy later in disease [21]. This alteration in cell size was predicted to result in altered neuronal excitability [21]. Hyperexcitability is an established early feature of ALS, seen across humans [22, 80], mouse models [55] and induced pluripotent stem cell-derived neurons studies [19, 81], including motor neurons from patients with C9orf72 -ALS [19].…”

Circuit-Specific Early Impairment of Proprioceptive Sensory Neurons in the SOD1G93AMouse Model for ALS

“…Specifically, α-MNs forming the fast-fatigable motor units preferentially die followed by fast fatigue-resistant MNs, while the neighboring slow α-MNs and γ-MNs remain resistant to degeneration (Hegedus et al, 2007; Hegedus et al, 2008; Lalancette-Hebert et al, 2016). Although multiple intrinsic factors such as cell size (Dukkipati et al, 2018), Ca 2+ buffering capacities (von Lewinski and Keller, 2005), synaptic organization (Nimchinsky et al, 2000; Lorenzo and Barbe, 2006), gene and protein expression patterns (Brockington et al, 2013; Comley et al, 2015) could govern selective vulnerability, the underlying network architecture can be a crucial determinant. For instance, a lack of muscle spindle afferent terminals on γ- and ocular MNs has been suggested as a mechanism of disease resistance (Keller and Robinson, 1971; Lalancette-Hebert et al, 2016).…”

Strong links in a weak chain: skeletal muscle fibres in amyotrophic lateral sclerosis

“…, Dukkipati et al . ). Slow and fast fatigue‐resistant motor units (S and FR, respectively) are relatively resilient.…”

“…Although the authors did not report the sizes of the remaining MNs, recent work in the SOD1 G93A mouse suggests that the larger MNs from type FInt and FF units are vulnerable, and the remaining surviving MNs are from S and FR units (Dukkipati et al . ).…”