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Dissection of the Transversus Abdominis Muscle for Whole-mount Neuromuscular Junction Analysis
Published on: January 11, 2014
Mechanisms involved in spinal cord central synapse loss in a mouse model of spinal muscular atrophy
Olga Tarabal1, Víctor Caraballo-Miralles, Andrea Cardona-Rossinyol
1From the Unitat de Neurobiologia Cel·lular, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida and Institut de Recerca Biomèdica de Lleida, Lleida, Catalonia (OT, FJC, JEE, JC); and Grup de Neurobiologia Cel·lular, Institut Universitari d'Investigacions en Ciències de la Salut and Departament de Biologia, Universitat de les Illes Balears, Palma de Mallorca (VC-M, AC-R, GO, JL), Spain.
Abstract:
Motoneuron (MN) cell death is the histopathologic hallmark of spinal muscular atrophy (SMA), although MN loss seems to be a late event. Conversely, disruption of afferent synapses on MNs has been shown to occur early in SMA. Using a mouse model of severe SMA (SMNΔ7), we examined the mechanisms involved in impairment of central synapses. We found that MNs underwent progressive degeneration in the course of SMA, with MN loss still occurring at late stages. Loss of afferent inputs to SMA MNs was detected at embryonic stages, long before MN death. Reactive microgliosis and astrogliosis were present in the spinal cord of diseased animals after the onset of MN loss. Ultrastructural observations indicate that dendrites and microglia phagocytose adjacent degenerating presynaptic terminals. Neuronal nitric oxide synthase was upregulated in SMNΔ7 MNs, and there was an increase in phosphorylated myosin light chain expression in synaptic afferents on MNs; these observations implicate nitric oxide in MN deafferentation and suggest that the RhoA/ROCK pathway is activated. Together, our observations suggest that the earliest change occurring in SMNΔ7 mice is the loss of excitatory glutamatergic synaptic inputs to MNs; reduced excitability may enhance their vulnerability to degeneration and death.
Insights
Spinal muscular atrophy (SMA) involves early loss of synaptic connections to motoneurons (MNs), preceding cell death. This synaptic disruption, involving nitric oxide and RhoA/ROCK pathways, may contribute to MN degeneration in SMA.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Spinal muscular atrophy (SMA) is characterized by motoneuron (MN) cell death, but this appears to be a late event.
- Early disruption of afferent synapses on MNs is observed in SMA.
Purpose of the Study:
- To investigate the mechanisms underlying central synapse impairment in a mouse model of severe SMA (SMNΔ7).
- To identify the earliest pathological changes in SMA.
Main Methods:
- Utilized the SMNΔ7 mouse model of severe SMA.
- Examined synaptic integrity, neuronal morphology, and glial responses.
- Performed ultrastructural analysis and assessed molecular markers like neuronal nitric oxide synthase and RhoA/ROCK pathway components.
Main Results:
- Motoneurons (MNs) showed progressive degeneration and loss in SMA mice.
- Loss of afferent inputs to MNs occurred early, during embryonic stages, preceding MN death.
- Reactive microgliosis and astrogliosis were observed post-MN loss onset.
- Ultrastructural analysis revealed phagocytosis of presynaptic terminals by dendrites and microglia.
- Increased neuronal nitric oxide synthase and phosphorylated myosin light chain indicated nitric oxide involvement and RhoA/ROCK pathway activation.
Conclusions:
- The earliest pathological change in SMNΔ7 mice is the loss of excitatory glutamatergic synaptic inputs to MNs.
- This deafferentation and reduced neuronal excitability may increase MN vulnerability to degeneration and death.
- Nitric oxide and the RhoA/ROCK pathway are implicated in the deafferentation process in SMA.
