This is a resubmission (A1) of application 1R15 NS120154-01, “The neuropathology of cerebellum in spinal
muscular atrophy”, which was reviewed in June 2020 at the ZRG1 MDCN-R (86) section.
Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. It arises from the mutation of the
survival motor neuron one (SMN1) gene. Despite decades of research, its mechanisms of neuropathology are far from clear.
The recent US FDA approved SMN restoration therapies (Nusinersen, Zolgensma, and Risdiplam) are effective in rescuing
the motor dysfunction but not cure for SMA. It is not clear how long the effect will last, nor whether patients will suffer
problems due to dysfunction of SMN deficient neurons in other parts of the nervous system. Accumulating evidence
suggests that low levels of SMN not only alter the function of spinal motor neurons, but also of neurons and neural circuits
in other parts of the motor network. However, currently there is little understanding of neuronal pathology in SMA beyond
the spinal cord motor neuron (MN) circuit. As new treatments allow patients to live longer, knowledge of the role of central
motor network in the neuropathology of SMA will be key for developing long-term prognoses and treatment strategies for
The objective of this application is to investigate cerebellar pathology and neural circuit dysfunction in SMA mouse
models using magnetic resonance imaging (MRI) and electrophysiological techniques. The rational for this project is based
on the important role of cerebellum in motor control, the reports of cerebellar pathology in human SMA patients, as well as
our preliminary data showing alterations in the structure and function of cerebellar neural network in mouse models of SMA.
Our central hypothesis is that in SMA, alterations in the neurons and neural circuits of the cerebellum decrease
cerebellar output and alter descending motor commands from the motor cortex and brainstem to the spinal cord,
contributing to neuropathology and motor system dysfunction. This central hypothesis will be tested by three specific aims:
1) Identify changes in the morphology and fiber connections of the cerebellum in SMN¿7 and MN rescue mice by magnetic
resonance imaging techniques; 2) Elucidate the functional alteration of cerebellar neurons and neural circuits related to
SMA pathophysiology using electrophysiological techniques; 3) Relate changes in cerebellar structure and neural circuit
function to SMA disease progression in MN rescue mouse model. To determine the contribution of structural and functional
pathology in the cerebellum to the phenotype of SMA, we will use MRI and electrophysiology to investigate the
development of neuropathology in the cerebellum at pre-symptomatic (postnatal day 3–4, P3–P4), early- (P7–P8), and end-symptomatic (P12–P13) stage of SMA.
The comparison studies between SMN¿7 and motor neuron MN mouse models will confirm and elucidate the
correlation of cerebellar neuropathology with spinal motor neuron dysfunction in SMA mice. Identifying the start and
progression of cerebellar neuropathology will indicate how cerebellar structural or functional pathology or both contribute
to the SMA phenotype. The proposed research is innovative because it will be the first thorough study of the dysfunction
and its mechanisms of the cerebellar neural network in SMA mice with a unique combination of electrophysiological, MRI
and immunohistochemical techniques. This kind of study is required to develop a complete systematic understanding of the
pathophysiology of SMA, and almost no studies so far have investigated the critical issue of dysfunction in the brain network
and its contribution to motor dysfunction. The proposed research is significant because understanding specific abnormalities
cerebellar network can lead to new targets for potential therapeutics aimed at preserving motor function in SMA patients.