A cell-type-specific alternative splicing regulator shapes synapse properties in a trans-synaptic manner.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Synaptic property specification is crucial for neuronal circuit function.
• Terminal selector transcription factors and pan-neuronal splicing regulators are known to influence neuronal differentiation and properties.
• The precise mechanisms by which splicing regulators control specific synaptic properties are not fully understood.

Purpose of the Study:

• To investigate the role of the RNA-binding protein SLM2 in hippocampal synapse specification.
• To uncover how SLM2 contributes to cell-type-specific synaptic properties through alternative splicing.

Main Methods:

• Genome-wide mapping of messenger RNA (mRNA) targets for SLM2.
• Cell-type-specific loss-of-function studies in pyramidal cells and somatostatin (SST)-positive GABAergic interneurons.
• Analysis of intrinsic neuronal properties, synaptic phenotypes, and hippocampus-dependent memory tasks.

Main Results:

• SLM2 preferentially binds and regulates alternative splicing of transcripts encoding synaptic proteins.
• Neuronal populations lacking SLM2 show normal intrinsic properties but exhibit non-cell-autonomous synaptic phenotypes.
• Defects in hippocampus-dependent memory tasks were observed in the absence of SLM2.

Conclusions:

• Alternative splicing, regulated by proteins like SLM2, is a critical mechanism for specifying neuronal connectivity.
• SLM2 plays a significant role in instructing synaptic properties in a trans-synaptic manner.
• Dysregulation of SLM2-mediated splicing impacts synaptic function and cognitive behavior.