Pyramidal neurons form active, transient, multilayered circuits perturbed by autism-associated mutations at the inception of neocortex.

Cortical circuits are composed predominantly of pyramidal-to-pyramidal neuron connections, yet their assembly during embryonic development is not well understood. We show that mouse embryonic Rbp4-Cre cortical neurons, transcriptomically closest to layer 5 pyramidal neurons, display two phases of circuit assembly in vivo. At E14.5, they form a multi-layered circuit motif, composed of only embryonic near-projecting-type neurons. By E17.5, this transitions to a second motif involving all three embryonic types, analogous to the three adult layer 5 types. In vivo patch clamp recordings and two-photon calcium imaging of embryonic Rbp4-Cre neurons reveal active somas and neurites, tetrodotoxin-sensitive voltage-gated conductances, and functional glutamatergic synapses, from E14.5 onwards. Embryonic Rbp4-Cre neurons strongly express autism-associated genes and perturbing these genes interferes with the switch between the two motifs. Hence, pyramidal neurons form active, transient, multi-layered pyramidal-to-pyramidal circuits at the inception of neocortex, and studying these circuits could yield insights into the etiology of autism.

Divergent recruitment of developmentally defined neuronal ensembles supports memory dynamics.

Memories are dynamic constructs whose properties change with time and experience. The biological mechanisms underpinning these dynamics remain elusive, particularly concerning how shifts in the composition of memory-encoding neuronal ensembles influence the evolution of a memory over time. By targeting developmentally distinct subpopulations of principal neurons, we discovered that memory encoding resulted in the concurrent establishment of multiple memory traces in the mouse hippocampus. Two of these traces were instantiated in subpopulations of early- and late-born neurons and followed distinct reactivation trajectories after encoding. The divergent recruitment of these subpopulations underpinned gradual reorganization of memory ensembles and modulated memory persistence and plasticity across multiple learning episodes. Thus, our findings reveal profound and intricate relationships between ensemble dynamics and the progression of memories over time.