Mechanisms of Central Synaptic Dysfunction in SMA

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Project Summary 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 has led us in uncovering part of the molecular mechanisms responsible for synaptic loss, implicating in part the classical complement cascade. Imbalance of excitatory-inhibitory neurotransmission renders vulnerable motor neurons under tonic inhibition. Importantly, SMA motor neurons die through cell-autonomous mechanisms implicating p53 pathway, Mdm2 & Mdm4 as well as Stasimon, a downstream target of SMN. However, the molecular and cellular mechanisms responsible for postural and locomotor deficits in SMA mice are not known. Unraveling therefore the molecular mechanisms responsible for these two phenotypes would provide key insights into the disease mechanisms. In Aim 1, we will study whether dysfunction of dopaminergic synapses is responsible for the postural impairments 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 ventral spinocerebellar tract neurons causing gait and locomotor deficits in SMA mice. We will also use mouse genetics, viral-mediated Cre expression, combined with morphological, physiological and behavioral assays to complete this part of the project. In Aim 3, we will probe into the molecular mechanisms that are responsible for synaptic loss involving CD47 and SIRPα as well as potential synergy with C1q, the initiating protein in the classical complement pathway, under ubiquitous SMN deficiency in mouse models of the disease.