Reducing Filamin A Restores Cortical Synaptic Connectivity and Early Social Communication Following Cellular...

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Nonverbal communication, such as vocalizations, is crucial in mammals and impaired in infants with autism spectrum disorder (ASD).
• Early communicative defects may worsen ASD development, but the underlying neural mechanisms remain unclear.
• Constitutively active Rheb (Rheb^S16H) upregulates mTORC1 and ERK1/2 pathways implicated in ASD.

Purpose of the Study:

• To investigate the neural mechanisms of early communicative deficits in ASD using a mouse model.
• To examine the role of upper-layer cortical pyramidal neurons in vocalization and synaptic function related to ASD pathways.

Main Methods:

• Expressed Rheb^S16H in Layer 2/3 pyramidal neurons of the mouse neocortex.
• Analyzed neuronal structure, spine density, synaptic activity, and pup isolation calls.
• Investigated the role of filamin A (FLNA) by reducing its levels.

Main Results:

• Mosaic expression of Rheb^S16H altered neonatal mouse isolation calls, accompanied by neuronal misplacement and dendrite overgrowth.
• Increased spine density and length, and heightened excitatory synaptic activity were observed.
• Reducing FLNA levels attenuated dendrite overgrowth and restored spine properties, synaptic connectivity, and pup isolation calls.

Conclusions:

• Upper-layer cortical pyramidal neurons contribute to communicative deficits in ASD-related pathways.
• FLNA is a key regulator of neuronal structure, synaptic function, and vocalization in this context.
• Targeting FLNA may offer therapeutic potential for communication impairments in ASD.