Dissecting primary motor cortex circuit dysfunction in a mouse model of MeCP2 duplication syndrome

  • Awarded: 2016
  • Award Type: Research
  • Award #: 402047

Motor dysfunction is common in autism. The primary motor cortex (area M1) has been implicated in the manifestation of these symptoms. Stelios Smirnakis proposes to study M1 circuit function, particularly during motor skill learning, to elucidate mechanisms that underlie motor deficits in autism.

Several autism mouse models (MeCP2 duplication, 15q11-q13 duplication, PTEN, neuroligin-3, CNTNAP2 and others) exhibit enhanced motor learning associated with behavioral inflexibility. MeCP2 duplication syndrome is a 100 percent penetrant cause of autism that leads to progressive intellectual disability, motor dysfunction, spasticity and epilepsy in affected males. The MeCP2 duplication syndrome mouse model (Tg1) shows similar deficits, with pre-symptomatic Tg1 mice initially exhibiting enhanced motor-skill learning and memory. The enhanced-learning phenotype is followed by motor regression, spasticity and lack of coordination. This makes the Tg1 mouse model ideal for elucidating motor cortex circuit dysfunction and for studying the progression of this disease phenotype in autism.

Preliminary studies from the Smirnakis laboratory have shown that dendritic spine consolidation is abnormally high in corticospinal area M1 neurons of the pre-symptomatic Tg1 mouse during motor learning. Further, the degree of consolidation correlates with the animal’s enhanced performance, suggesting that changes in M1 circuitry are important for the behavioral phenotype. The researchers also observed that this enhanced learning plasticity involves the Ras-MAPK signaling pathway; deficits in this pathway have previously been implicated in autism. Both the abnormal M1 synaptic consolidation and the behavioral motor learning were restored to wild-type levels with a specific inhibitor of Ras-MAPK signaling.

For the current project, Smirnakis’ team aims to use state-of-the-art, in vivo two-photon imaging with the chronic calcium indicator GCaMP6 to study the progression of disease pathology and motor symptoms in area M1 of Tg1 mice. The team will follow Tg1 mice from the pre-symptomatic stage, through a period of motor-skill training, to the onset of motor regression. M1 neuron tuning functions will be measured and compared between Tg1 mice and wild-type littermates at different time points. Neuronal synchrony, the reliability of neuronal activity, and changes in the level of synchrony of identified M1 neurons will be monitored over time and correlated with behavior. Measurements both within and across cortical laminae will capture potential malfunction in tangential and vertical M1 microcircuits. In vivo patch-clamp recordings will directly assess how subthreshold inhibitory versus excitatory M1 inputs are modulated during locomotion in Tg1 versus control mice. Finally, the team will study the role that different types of neurons play in M1 dysfunction by overexpressing MeCP2 in specific neuronal subtypes.

Results from this project are expected to provide valuable insights into how changes in M1 neuronal properties and circuit function lead to the development of motor deficits in autism.


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