Motor circuits control fundamental behaviors such as swallowing, breathing and locomotion. Spinal motor neurons are the key mediators translating motor commands generated within the central nervous system to peripheral muscle targets. Motor neurons are activated by a precisely regulated pattern of synaptic activity from sensory neurons, local spinal interneurons and descending pathways from the brain. During early development, synaptic activity received by motor neurons shapes their functional properties. In contrast, gene mutations that induce perturbations in either neuronal wiring or synaptic drive received by motor neurons often result in motor system disorders. A prominent example of this situation is spinal muscular atrophy (SMA)?an inherited neuromuscular disease caused by ubiquitous deficiency in the survival motor neuron (SMN) protein. SMA pathogenesis involves alterations of multiple components of the motor circuit leading to abnormalities in spinal reflexes, motor neuron loss and skeletal muscle atrophy. However, the molecular, cellular and circuit mechanisms underlying SMA remain largely elusive. Our previous work have led us in uncovering synaptic dysfunction of proprioceptive origin as a key determinant event early in the disease process. Impaired function and eventual loss of the sensory-motor excitatory synapses induce changes in the expression of channels on the motor neuron membrane, resulting in reduced motor output. Unraveling therefore the molecular mechanisms responsible for synaptic dysfunction and loss would provide key insights into the disease mechanisms.
In Aim 1, we will study whether complement proteins are responsible for the dysfunction and ultimately the elimination of vulnerable synapses in in SMA mice. To address this, we will employ mouse genetics together with morphological and functional assays.
In Aim 2, we will investigate the role of certain key classical complement proteins in the assembly and refinement of sensory-motor circuits during normal development. We will also use mouse genetics, combined with morphological and functional assays to complete this part of the project.
In Aim 3, we will probe into the molecular mechanisms that may cause the selective attack by aberrant activation of the immune system towards synapses under ubiquitous SMN deficiency in mouse models of the disease.
Neuronal control of movement is extensively studied not only because it underlies fundamental human behaviors but also because neurodegenerative diseases that affect the motor system represent a significant burden for human health. We have identified abnormalities in the way neurons communicated with each by means of abnormal removal of synaptic connections, which result in pathological situations. This proposal describes a multidisciplinary effort aimed to determine the molecular and cellular mechanisms that may contribute to human diseases such as spinal muscular atrophy?the leading genetic cause of death in infancy.
