An opposing function of paralogs in balancing developmental synapse maturation.

Area of Science:

• Neuroscience
• Molecular Biology
• Developmental Biology

Background:

• The disc-large (DLG)-membrane-associated guanylate kinase (MAGUK) protein family, including PSD-95 and PSD-93, are key components of the glutamate receptor complex.
• These proteins regulate glutamatergic synapse maturation, a process critical for normal brain development and vulnerable to disruptions leading to neurodevelopmental disorders.
• PSD-95 and PSD-93, paralogs within the DLG-MAGUK family, share similar domains and were previously assumed to have similar functions in synapse regulation.

Purpose of the Study:

• To investigate the distinct roles of PSD-95 and PSD-93 in the developmental maturation of glutamatergic synapses.
• To elucidate the opposing functions of PSD-95 and PSD-93 in regulating α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPAR)-silent synapse maturation.
• To determine the contribution of PSD-95 and PSD-93 to experience-dependent synaptic plasticity and visual development.

Main Methods:

• Analysis of PSD-95 and PSD-93 expression and function during mouse cortical development.
• Investigation of their roles in the maturation of AMPAR-silent synapses.
• Examination of experience-dependent regulation of PSD-93 and its impact on PSD-95 activity in the visual cortex.

Main Results:

• PSD-95 was found to promote, while PSD-93 inhibited, the maturation of immature AMPAR-silent synapses in the developing mouse cortex.
• PSD-93, through experience-dependent mechanisms, directly counteracted the promoting effects of PSD-95 on silent synapse maturation in the visual cortex.
• The coordinated actions of PSD-95 and PSD-93 were essential for governing the critical period of juvenile ocular dominance plasticity (jODP) and refining visual perception.

Conclusions:

• PSD-95 and PSD-93 exhibit opposing roles in glutamatergic synapse maturation, challenging previous assumptions of functional similarity.
• The balanced interplay between PSD-95 and PSD-93 is critical for sculpting cortical networks during developmental critical periods, influencing receptive field integration.
• Dysregulation of the PSD-95/PSD-93 balance may contribute to neurodevelopmental disorders, highlighting their importance in precise neural circuit formation.