J Neurosci. 2024 Aug 20:e1245232024. doi: 10.1523/JNEUROSCI.1245-23.2024. Online ahead of print.
ABSTRACT
Communication in the form of non-verbal, social vocalization, or crying is evolutionary conserved in mammals and is impaired early in human infants that are later diagnosed with autism spectrum disorder (ASD). Defects in infant vocalization have been proposed as an early sign of ASD that may exacerbate ASD development. However, the neural mechanisms associated with early communicative deficits in ASD are not known. Here, we expressed a constitutively active mutant of Rheb (RhebS16H), which is known to upregulate two ASD core pathways, mTOR complex 1 (mTORC1) and ERK1/2, in layer (L) 2/3 pyramidal neurons of the neocortex of mice of either sex. We found that cellular mosaic expression of RhebS16H in L2/3 pyramidal neurons altered the production of isolation calls from neonatal mice. This was accompanied by an expected misplacement of neurons and dendrite overgrowth, along with an unexpected increase in spine density and length, which was associated with increased excitatory synaptic activity. This contrasted with the known decrease in spine density in RhebS16H neurons of one-month-old mice. Reducing the levels of the actin crosslinking and adaptor protein filamin A (FLNA), known to be increased downstream of ERK1/2, attenuated dendrite overgrowth and fully restored spine properties, synaptic connectivity, and the production of pup isolation calls. These findings suggest that upper-layer cortical pyramidal neurons contribute to communicative deficits in a condition known to affect two core ASD pathways and that these mechanisms are regulated by FLNA.Significance Statement An infant’s cry is a form of evolutionarily conserved social communication that is altered in ASD and has been proposed as an early sign of ASD. However, the neural substrate of early communicative deficits is not known. We show that cellular mosaic expression of a constitutively active Rheb, known to upregulate two core ASD pathways, selectively in upper-layer neocortical pyramidal neurons, alters the production of pup isolation calls and synaptic connectivity. These defects were prevented by reducing the expression of the adaptor protein FLNA. This underscores the importance of a specific neuronal substrate responsible for communicative deficits and its regulation by FLNA.
PMID:39164108 | DOI:10.1523/JNEUROSCI.1245-23.2024
