Developmental overproduction of cortical superficial neurons impairs adult auditory cortical processing

Abstract

SummaryWhile evolutionary cortical expansion is thought to underlie the evolution of human cognitive capabilities, developmental expansion can lead to megalencephaly, often found in neurodevelopmental disorders such as autism spectrum disorder. Still, little is known about how the overproduction of cortical neurons during development affects cortical processing and behavior in later life. Here we show that the overproduction of cortical superficial neurons leads to hyposensitivity to auditory stimuli in mice. We took advantage of a WNT/β-catenin signaling inhibitor, XAV939, to overproduce cortical superficial excitatory neurons during development. XAV939-treated adult mice exhibited a higher threshold to detect acoustic stimuli behaviorally. This behavioral deficit is associated with abnormal auditory cortical processing, such as higher delta power as well as lower spontaneous and auditory-evoked activity in putative excitatory cells. On the other hand, the auditory thalamus did not show any significant difference in neural firing between XAV939-treated and control groups. Within auditory cortical populations, functional monosynaptic connections were reduced across cell classes. A computational model predicts that the weakened excitatory-inhibitory connections lead to reduced spontaneous and evoked activity. Altogether, our results suggest that atypical auditory processing in XAV939-treated animals originates from weakened synaptic connections among cortical neurons. Although the expansion of cortical size is evolutionarily advantageous, an abnormal expansion during development can cause detrimental effects on cortical processing and perceptual behavior in adulthood.