p21-Activated kinases 1 and 3 control brain size through coordinating neuronal complexity and synaptic properties

Area of Science:

• Neuroscience
• Molecular Biology
• Developmental Biology

Background:

• The molecular basis of postnatal brain development, including brain enlargement and synaptic maturation, is not fully understood.
• Neuronal complexity is crucial for brain function, but the mechanisms controlling it are largely unknown.

Purpose of the Study:

• To investigate the role of p21-activated kinases (PAKs) in regulating postnatal brain growth, neuronal complexity, and synaptic properties.
• To elucidate the molecular mechanisms underlying PAK-mediated control of brain development.

Main Methods:

• Generation and analysis of double-knockout (DK) mice lacking both PAK1 and PAK3.
• Assessment of brain size, neuronal morphology (soma size, dendritic arbors, axons), cell density, and synapse density.
• Electrophysiological recordings to evaluate basal synaptic responses and synaptic plasticity.
• Analysis of cofilin activity and actin filament properties.

Main Results:

• DK mice exhibited significantly reduced postnatal brain growth and brain volume despite normal initial size.
• DK neurons showed smaller soma, simplified dendritic and axonal structures, and reduced synapse density.
• DK mice displayed enhanced basal synaptic responses but severe deficits in bidirectional synaptic plasticity.
• Alterations in cofilin activity and actin filament properties were observed in DK mice.

Conclusions:

• PAK1 and PAK3 are essential in vivo regulators of neuronal complexity, coordinating postnatal brain enlargement and synaptic properties.
• Dendrite and axon growth, controlled by PAKs, are critical for achieving normal brain size and function.
• PAK-mediated regulation of cofilin and actin dynamics is implicated in these developmental processes.