Developmental pruning of excitatory synaptic inputs to parvalbumin interneurons in monkey prefrontal cortex

Area of Science:

• Neuroscience
• Developmental Biology
• Synaptic Plasticity

Background:

• Working memory relies on excitatory input to parvalbumin-positive (PV) interneurons in the dorsolateral prefrontal cortex (DLPFC).
• Adolescent brain maturation involves synaptic pruning, potentially refining neural circuits for cognitive functions like working memory.

Purpose of the Study:

• To investigate whether excitatory synapses on PV interneurons are pruned during adolescence in primates.
• To explore the role of erb-b2 receptor tyrosine kinase 4 (ErbB4) splicing in regulating this developmental synaptic pruning process.

Main Methods:

• Quantified excitatory synapse density (VGlut1+/PSD95+ puncta) on PV interneurons in prepubertal and postpubertal monkeys.
• Analyzed ErbB4 expression and alternative splicing variants in relation to synapse density and PV interneuron activity.
• Utilized cell culture experiments to assess the functional impact of ErbB4 splice variants on excitatory synapses.

Main Results:

• Excitatory synapse density on PV interneurons decreased with age from prepubertal to postpubertal stages.
• Higher levels of VGlut1 and PSD95 proteins in older monkeys correlated with PV activity, suggesting stronger remaining synapses.
• Increased ratios of minor-to-major ErbB4 splice variants correlated with reduced synapse density, while the major variant enhanced synapse formation in vitro.

Conclusions:

• Excitatory synapses on primate DLPFC PV interneurons undergo pruning during adolescence.
• Alternative splicing of ErbB4 plays a crucial role in regulating the number and strength of these excitatory synapses during development.
• ErbB4 splicing represents a key mechanism controlling synaptic refinement essential for mature working memory function.