Specification of neural circuit architecture shaped by context-dependent patterned LAR-RPTP microexons

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Leucine-rich repeat receptor protein tyrosine phosphatases (LAR-RPTPs) are crucial presynaptic cell-adhesion molecules involved in synaptic pathways.
• Alternative splicing of LAR-RPTP mRNAs may generate diverse isoforms that regulate synapse identity and signaling strength.
• Direct evidence for the functional role of these isoforms in vivo was lacking.

Purpose of the Study:

• To investigate the cell-type- and circuit-specific expression patterns of LAR-RPTPs, particularly focusing on microexons.
• To determine the physiological function of specific LAR-RPTP variants in synaptic transmission and memory formation.
• To explore the dynamic regulation of these microexon codes in response to neuronal activity.

Main Methods:

• Targeted RNA sequencing was employed to detect LAR-RPTP mRNAs in various adult male mouse brain regions and cell types.
• Analysis focused on the inclusion patterns of two microexons, meA and meB, within Ptprd mRNAs.
• Conditional ablation of specific Ptprd variants was performed in hippocampal circuits to assess functional consequences.

Main Results:

• Pronounced cell-type-specific expression patterns of Ptprd microexons (meA and meB) were identified across different brain areas.
• Distinct neural circuits targeting the same neuronal populations exhibited different Ptprd variants with varying microexon inclusion.
• Conditional ablation of presynaptic Ptprd meA+ variants impaired specific synaptic transmission modes and objection-location memory.
• Activity-triggered changes in the presynaptic Ptprd meA code in subicular neurons modulated NMDA receptor-mediated postsynaptic responses and memory.

Conclusions:

• This study provides the first in vivo evidence for cell-type- and circuit-specific expression of LAR-RPTP microexons.
• Dynamic regulation of these microexon codes plays a critical role in modulating synaptic transmission and cognitive functions like objection-location memory.
• These findings highlight the importance of alternative splicing in generating functional diversity within the LAR-RPTP family for precise neural circuit operation.