TARGETED REPAIR OF PRIMARY CILIA DEFECTS RESTORES MEMORY AND SEIZURE SUSCEPTIBILITY UPON ABNORMAL PERSISTENCE OF CAJAL-RETZIUS CELLS

Cajal-Retzius cells (CRs) are transient neurons essential for cortical lamination and circuit formation. In mice, CRs predominantly undergo programmed cell death (PCD) during the second postnatal week, particularly in the neocortex. Using a BaxCKO model, we demonstrated that a subset of CRs evade PCD, leading to increased dendritic complexity in pyramidal neurons, disrupted hippocampal gamma oscillations, memory deficits, and heightened seizure susceptibility. This suggested lack of cicuits maturation in mutant upon CRs aberrant survival. The molecular mechanisms underlying these effects remained unclear. Transcriptomic and proteomic analyses revealed in BaxCKO a significant downregulation of Crocc, which encodes Rootletin, a key structural component essential for the formation and function of primary cilia rootlets. Histological examination showed widespread loss of ciliary rootlets in the somatosensory cortex and hippocampus, along with decreased primary cilia density specifically in the hippocampal CA3 region. Treatment at P75 with a drug, known to promote primary cilia biogenesis and function, rescued both memory deficits and seizure susceptibility in male and female mice when assessed at P90. In contrast, treatment at P10 restored the phenotype in a sex-dependent manner, reflecting differences in circuit maturation between males and females. These results implicate primary cilia dysfunction as a key mediator of neural deficits associated with the abnormal persistence of CRs, highlighting their critical role in cortical circuit maturation.