Postsynaptic FMRP Regulates Synaptogenesis In Vivo in the Developing Cochlear Nucleus

Area of Science:

• Neuroscience
• Molecular Biology
• Developmental Biology

Background:

• Global loss of fragile X mental retardation protein (FMRP) causes intellectual disabilities and sensory dysfunction, linked to synaptic deficits.
• FMRP's role in postsynaptic development and circuit formation requires elucidation.

Purpose of the Study:

• To determine the autonomous function of postsynaptic FMRP in circuit formation, synaptogenesis, and synaptic maturation.
• To investigate the impact of reduced FMRP on neuronal morphology and excitatory synapse development.

Main Methods:

• Utilized *in ovo* electroporation of drug-inducible Fmr1-shRNA in chicken embryos for mosaic FMRP reduction.
• Performed structural analyses of axosomatic endbulb synapses and dendritic development.
• Conducted patch-clamp recordings to assess functional consequences on neurotransmission.

Main Results:

• Postsynaptic FMRP reduction resulted in smaller, abnormally shaped presynaptic endbulbs.
• FMRP deficiency led to delayed dendritic branch retraction in postsynaptic neurons.
• Functional deficits included smaller amplitudes and slower kinetics of excitatory postsynaptic currents (EPSCs).

Conclusions:

• Postsynaptic FMRP is essential for timely maturation of somatodendritic morphology.
• Delayed morphological maturation impairs synaptogenesis and contributes to lasting deficits in excitatory synapses.
• These findings highlight FMRP's role in developmental processes relevant to fragile X syndrome.