Cytomatrix proteins CAST and ELKS regulate retinal photoreceptor development and maintenance

Area of Science:

• Neuroscience
• Cell Biology
• Ophthalmology

Background:

• The presynaptic active zone (AZ) relies on cytomatrix proteins CAST and ELKS for organizing neurotransmitter release machinery.
• While CAST's role in AZ size and neurotransmitter release is known, the function of ELKS and the combined CAST/ELKS system remains unclear.

Purpose of the Study:

• To investigate the individual and cooperative roles of CAST and ELKS in the development, function, and maintenance of retinal photoreceptor ribbon synapses.
• To elucidate the molecular mechanisms underlying synaptic organization and neuroprotection mediated by CAST and ELKS.

Main Methods:

• Generation and analysis of CAST/ELKS double knockout (dKO) mice and conditional knockouts.
• Electrophysiological recordings to assess visual responses and presynaptic calcium influx.
• Three-dimensional scanning electron microscopy (SEM) for ultrastructural analysis of synaptic organization.
• Adeno-associated virus (AAV)-mediated gene deletion to study acute ELKS function.

Main Results:

• CAST and ELKS exhibit both redundant and unique functions in retinal synapse development and maintenance.
• CAST/ELKS dKO mice displayed increased ectopic synapses, reduced visual responses, and impaired presynaptic calcium influx.
• CAST deficiency led to age-dependent ectopic synapse formation, while acute ELKS deletion induced neurodegeneration and synapse loss.

Conclusions:

• CAST and ELKS act synergistically to promote the formation, transmission, and structural integrity of retinal ribbon synapses.
• These proteins are essential for maintaining synaptic function and preventing age-related synaptic degeneration in the retina.