Protective effects of long-term lithium administration in a slowly progressive SMA mouse model

Abstract

In the present study we evaluated the long-term effects of lithium administration to a knockout double transgenic mouse model (Smn -/-; SMN1A2G +/-; SMN2 +/+ ) of Spinal Muscle Atrophy type III (SMA-III). This model is characterized by very low levels of the survival motor neuron protein, slow disease progression and motor neuron loss, which enables to detect disease-modifying effects at delayed time intervals. Lithium administration attenuates the decrease in motor activity and provides full protection from motor neuron loss occurring in SMA-III mice, throughout the disease course. In addition, lithium prevents motor neuron enlargement and motor neuron heterotopy and suppresses the occurrence of radial-like glial fibrillary acidic protein immunostaining in the ventral white matter of SMA-III mice. In SMA-III mice long-term lithium administration determines a dramatic increase of survival motor neuron protein levels in the spinal cord.These data demonstrate that long-term lithium administration during a long-lasting motor neuron disorder attenuates behavioural deficit and neuropathology. Since low level of survival motor neuron protein is bound to disease severity in SMA, the robust increase in protein level produced by lithium provides solid evidence which calls for further investigations considering lithium in the longterm treatment of spinal muscle atrophy.

Ultrastructural characterization of peripheral denervation in a mouse model of Type III spinal muscular atrophy

“…This contrasts dramatically with the impressive loss of muscle structure and distal axon architectural disruption, including mitochondrial damage, which was observed in these SMA mice. These findings were quite unexpected since the gross morphology of MNs in these same mice, as assessed in our previous studies, appeared largely heterotypic, often enlarged and hyperchromatic, with intensely basophilic cytoplasm and nucleus (Fulceri et al 2012;Biagioni et al 2017). Instead, the well-preserved ultrastructure observed here seems to rule out overt pathological changes in spared MNs and proximal axons, contrasting markedly with the dramatic ultrastructural alterations which characterize the muscle, muscle spindle, and distal axons.…”

“…To our knowledge, this is the first report comprehensively documenting ultrastructural alterations within the muscle, muscle spindles, and distal axons in SMA III mice models. Remarkably, despite a 40% MNs loss and motor alterations characterizing these very same SMA mice, as assessed in our previous studies (Fulceri et al 2012;Biagioni et al 2017), the ultrastructure of surviving MNs and proximal axons is largely preserved. Instead, subcellular pathology within the muscle, distal axons, and muscle spindles appears mostly severe, with SMA muscles featuring a markedly disarranged sarcomere architecture, which is recapitulated by the severe alterations of intrafusal fibers occurring within the muscle spindle.…”

“…This consisted of a reduction in hind limb extension reflex and paw grip endurance, which started at 200 and 85 days, respectively, and reached a plateau at nearly 300 days of disease progression. Instead, the rota-rod and stride-length test outcomes were not altered at any time points (Fulceri et al 2012;Biagioni et al 2017). Such a dissociation in time and severity concerning MN loss and motor impairment suggests that other biological phenomena are involved in SMA pathogenesis, among which peripheral changes are taking center stage.…”

“…In fact, these experiments require an average of 2 years, making it difficult to replicate motor tests if the mice number is reduced. Motor tests and stereological motor neuron counts in these mice were previously performed and published by our group (Fulceri et al 2012;Biagioni et al 2017). For the present analysis, stored replicates from these previous studies (N = 10 mice per group) were selected.…”

“…In our previous studies, we used this knockout double transgenic (SMN2+/+; Smn−/− ; SMN1A2G+/−) SMA III mouse model to characterize the spinal cord pathology along with motor deficit at prolonged survival times (up to 535 days) (Fulceri et al 2012;Biagioni et al 2017). In particular, MN loss was quantified along with size variations of spared MNs, as well the occurrence of heterotopic MNs and radial glia within the white matter.…”