Transcriptomic disruption and hypoactivity in DYT-SGCE medial ganglionic eminence-patterned inhibitory neurons

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Myoclonus Dystonia is an inherited childhood disorder caused by SGCE gene mutations, affecting motor and psychiatric functions.
• Neuronal network disruption, particularly in the basal ganglia-cerebello-thalamo-cortical circuit, is implicated in dystonia.
• Previous research suggested cortical excitatory neuron hyperexcitability, but human studies pointed to a loss of inhibitory tone.

Purpose of the Study:

• To investigate the impact of SGCE mutations on inhibitory GABAergic neurons.
• To compare SGCE-mutation positive neurons with isogenic wild-type controls using patient-derived stem cells.

Main Methods:

• Generated and differentiated patient-derived induced pluripotent stem cells (iPSCs) and gene-edited embryonic stem cells.
• Utilized single-cell RNA sequencing for transcriptomic analysis.
• Performed dendritic morphology characterization.
• Conducted functional analyses using Ca2+ imaging, multi-electrode arrays (MEAs), and single-cell patch clamp electrophysiology.

Main Results:

• SGCE mutations did not affect early or late-stage inhibitory interneuron developmental markers.
• Transcriptomic analysis revealed dysregulation in genes related to axonal organization, synaptic signaling, and action potential generation.
• SGCE-mutation positive neurons exhibited reduced dendritic complexity and shorter branches.
• Functional studies showed lower GABA-induced calcium responses, reduced spike and burst frequencies, fewer action potential trains, and fewer spontaneous post-synaptic currents compared to controls.

Conclusions:

• SGCE mutations lead to decreased inhibitory neuronal activity and reduced dendritic arbor complexity.
• This contributes to the disruption of neuronal excitatory/inhibitory balance in motor circuits, potentially causing the hyperkinetic phenotype in Myoclonus Dystonia.
• These findings may be relevant to the broader dystonia spectrum and suggest potential therapeutic targets.