No abstract

The coactivation of prefrontal and hippocampal networks in oscillatory rhythms is critical for precise information flow in mnemonic and executive tasks, yet the mechanisms governing its development are still unknown. Here, we demonstrate that already in neonatal rats, patterns of discontinuous oscillatory activity precisely entrain the firing of prefrontal neurons and have distinct spatial and temporal organization over cingulate and prelimbic cortices. Moreover, we show that hippocampal theta bursts drive the generation of neonatal prefrontal oscillations by phase-locking the neuronal firing via axonal pathways. Consequently, functional impairment of the hippocampus reduces the prefrontal activity. With ongoing maturation continuous theta-gamma oscillations emerge and mutually entrain the prejuvenile prefrontal-hippocampal networks. Thus, theta-modulated communication within developing prefrontal-hippocampal networks may be relevant for circuitry refinement and maturation of functional units underlying information storage at adulthood.

Atypical brain connectivity is a major contributor to the pathophysiology of neurodevelopmental disorders (NDDs) including autism spectrum disorders (ASDs). TAOK2 is one of several genes in the 16p11.2 microdeletion region, but whether it contributes to NDDs is unknown. We performed behavioral analysis on Taok2 heterozygous (Het) and knockout (KO) mice and found gene dosage-dependent impairments in cognition, anxiety, and social interaction. Taok2 Het and KO mice also have dosage-dependent abnormalities in brain size and neural connectivity in multiple regions, deficits in cortical layering, dendrite and synapse formation, and reduced excitatory neurotransmission. Whole-genome and -exome sequencing of ASD families identified three de novo mutations in TAOK2 and functional analysis in mice and human cells revealed that all the mutations impair protein stability, but they differentially impact kinase activity, dendrite growth, and spine/synapse development. Mechanistically, loss of Taok2 activity causes a reduction in RhoA activation, and pharmacological enhancement of RhoA activity rescues synaptic phenotypes. Together, these data provide evidence that TAOK2 is a neurodevelopmental disorder risk gene and identify RhoA signaling as a mediator of TAOK2-dependent synaptic development.