Aberrant survival of hippocampal Cajal-Retzius cells leads to memory deficits, gamma rhythmopathies and susceptibility to seizures in adult mice

Article https://doi.org/10.1038/s41467-023-37249-7 Aberrant survival of hippocampal CajalRetzius cells leads to memory deficits, gamma rhythmopathies and susceptibility to seizures in adult mice Received: 3 August 2022 1234567890():,; 1234567890():,; Accepted: 8 March 2023 Check for updates Martina Riva1,2, Stéphanie Moriceau3, Annunziato Morabito4,12, Elena Dossi 5,12, Candela Sanchez-Bellot6,12, Patrick Azzam 1,2,12, Andrea Navas-Olive 6, Beatriz Gal6,7, Francesco Dori1,2, Elena Cid 6, Fanny Ledonne2, Sabrina David8, Fabrice Trovero8, Magali Bartolomucci 9, Eva Coppola2, Nelson Rebola4, Antoine Depaulis9, Nathalie Rouach 5, Liset Menendez de la Prida 6, Franck Oury 10 & Alessandra Pierani 1,2,11 Cajal-Retzius cells (CRs) are transient neurons, disappearing almost completely in the postnatal neocortex by programmed cell death (PCD), with a percentage surviving up to adulthood in the hippocampus. Here, we evaluate CR’s role in the establishment of adult neuronal and cognitive function using a mouse model preventing Bax-dependent PCD. CRs abnormal survival resulted in impairment of hippocampus-dependent memory, associated in vivo with attenuated theta oscillations and enhanced gamma activity in the dorsal CA1. At the cellular level, we observed transient changes in the number of NPY+ cells and altered CA1 pyramidal cell spine density. At the synaptic level, these changes translated into enhanced inhibitory currents in hippocampal pyramidal cells. Finally, adult mutants displayed an increased susceptibility to lethal tonic-clonic seizures in a kainate model of epilepsy. Our data reveal that aberrant survival of a small proportion of postnatal hippocampal CRs results in cognitive deficits and epilepsy-prone phenotypes in adulthood. Cognitive impairments and epilepsy are common comorbidities in the majority of patients with abnormal brain development, including cortical malformations and autism spectrum disorders1. While cellular processes like neurogenesis, migration, synaptogenesis or myelination are recognized building blocks of circuit formation, an emerging player in the assembly of cortical networks is programmed cell death (PCD). In the nervous system, PCD finely tunes the density of neuronal populations and their targets. About 20-30% of the prenatally overproduced neurons die as they fail to compete for survival signals and to integrate into neuronal networks shortly after birth2,3. In addition, 1 Université Paris Cité, Imagine Institute, Team Genetics and Development of the Cerebral Cortex, 75015 Paris, France. 2Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, 75014 Paris, France. 3Platform for Neurobehavioral and metabolism, Structure Fédérative de Recherche Necker, 26 INSERM US24/CNRS UAR, 3633 Paris, France. 4Sorbonne Université, Institut Du Cerveau-Paris Brain Institute-ICM, Inserm U1127, CNRS UMR 7225, 47 Boulevard de l’Hopital, 75013 Paris, France. 5Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS, INSERM, Labex Memolife, Université PSL, Paris, France. 6Instituto Cajal, CSIC, Madrid, Spain. 7Universidad Camilo José Cela, Madrid, Spain. 8Key-Obs SAS, 13 avenue Buffon, 45100 Orléans, France. 9Université Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000 Grenoble, France. 10Université Paris Cité, CNRS, INSERM, Institut Necker Enfants Malades-INEM, 75015 Paris, France. 11GHU Paris Psychiatrie et Neurosciences, Hôpital Sainte Anne, 75014 Paris, France. 12These authors e-mail: contributed equally: Annunziato Morabito, Elena Dossi, Candela Sanchez-Bellot, Patrick Azzam. Nature Communications | (2023)14:1531 1 Article proper cortical development also depends on the action of specific cell types that stay transiently during the construction of neural circuits. These transient cell types include Cajal-Retzius cells (CRs), subplate neurons, cortical plate transient neurons and the first wave of embryonic oligodendrocyte precursors. These cell populations are unique, as they almost completely disappear in the neocortex towards the end of cortical maturation shortly after birth in mice3–13. Although still controversial, the persistence of CRs during advanced postnatal life is reported in different pathologies14. In particular, abnormal persistence of transient cells with molecular signatures of CRs is found in cases of temporal lobe epilepsy (TLE), Ammon’s horn sclerosis, focal cortical dysplasia and polymicrogyria15–17. The anomalous distribution of CR subtypes in cortical layer 1 and the presence of neurons in the white matter of the prefrontal cortex in schizophrenic patients have also been attributed to altered PCD of transient cells18,19. Together, this evidence raises the intriguing hypothesis that the maintenance/persistence of transient cell populations contributes to cortical circuit dysfunction. CRs are amongst the first-born neurons in the developing cerebral cortex and comprise three molecularly and functionally distinct subtypes identified by their spatial origins: septum, hem and pallial–subpallial boundary (PSB)20. At embryonic stages, they play roles in controlling migration of excitatory and inhibitory neurons, as well as the phenotype of precursor cells, the development of hippocampal connections and the size of cortical areas21–26. Notably, before their number is reduced by the end of the second postnatal week in the neocortex, CRs are embedded into immature circuits where they mainly receive GABAergic synaptic inputs, suggesting a role in early cortical connectivity (for reviews, see refs. 12,14,22). Strikingly, developmental decline of hippocampal CRs is slower than that in the neocortex, with roughly 30% of CRs remaining integrated into the adult microcircuit27,28. Recently, we developed a murine model (i.e. BaxCKOΔNp73Cre, herein BaxCKO) in which CRs death is prevented by invalidation of the proapoptotic factor Bax in a Cre-specific manner targeting both septumand hem-derived CRs. Using this model, we found that only septumderived neocortical CRs can be rescued from PCD in a Bax-dependent manner13. In the somatosensory cortex of BaxCKO juvenile mutants, layer 2–3 pyramidal neurons displayed hypertrophy and increased number of dendrites and spines, resulting in an enhanced excitatory/ inhibitory (E/I) ratio, and hyperexcitability of upper layer circuits29. Nevertheless, whether hippocampal CRs undergo Bax-mediated PCD and whether their persistence throughout development and into adulthood may lead to behavioral alterations and pro-epileptic phenotypes remained unexplored. To address these questions, we exploit the BaxCKO model to evaluate the impact of preventing CR demise in adults. Results Altered hippocampal-dependent behavior in BaxCKO mutant mice In order to test whether the persistence of transient CRs could cause changes in cognitive functions along the animals’ lifespan, we first performed behavioral tests on BaxCKO mice and control littermat (...truncated)