RESUMO
Reelin (RELN) is a secreted glycoprotein essential for cerebral cortex development. In humans, recessive RELN variants cause cortical and cerebellar malformations, while heterozygous variants were associated with epilepsy, autism, and mild cortical abnormalities. However, the functional effects of RELN variants remain unknown. We identified inherited and de novo RELN missense variants in heterozygous patients with neuronal migration disorders (NMDs) as diverse as pachygyria and polymicrogyria. We investigated in culture and in the developing mouse cerebral cortex how different variants impacted RELN function. Polymicrogyria-associated variants behaved as gain-of-function, showing an enhanced ability to induce neuronal aggregation, while those linked to pachygyria behaved as loss-of-function, leading to defective neuronal aggregation/migration. The pachygyria-associated de novo heterozygous RELN variants acted as dominant-negative by preventing WT RELN secretion in culture, animal models, and patients, thereby causing dominant NMDs. We demonstrated how mutant RELN proteins in vitro and in vivo predict cortical malformation phenotypes, providing valuable insights into the pathogenesis of such disorders.
Assuntos
Moléculas de Adesão Celular Neuronais , Movimento Celular , Proteínas da Matriz Extracelular , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso , Proteína Reelina , Serina Endopeptidases , Humanos , Animais , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Camundongos , Feminino , Masculino , Movimento Celular/genética , Neurônios/metabolismo , Neurônios/patologia , Polimicrogiria/genética , Polimicrogiria/patologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Heterozigoto , Lisencefalia/genética , Lisencefalia/patologia , AlelosRESUMO
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.
Assuntos
Hipocampo , Neurônios , Hipocampo/fisiologia , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Neurônios/metabolismo , Células Piramidais/fisiologia , Convulsões/genética , Convulsões/metabolismo , Animais , CamundongosRESUMO
Night sleep and parental bedtime practices have rarely been investigated in late talkers. This study aimed to explore: night sleep, parental bedtime practices, and their associations in late talkers as well as individual, socio-demographic, and socio-relational factors affecting them. Parents of 47 30-month-old late talkers, born low-risk preterm (n = 24) or full-term (n = 23), with an expressive vocabulary size ≤10th percentile measured by the MacArthur-Bates Communicative Development Inventory Words and Sentences, and normal cognitive abilities measured by the Bayley Scales, completed the Infant Sleep Questionnaire, the Parental Interactive Bedtime Behaviour Scale, and the Parenting Stress Index Short Form. Results showed slight settling difficulties, night wakings, and frequent co-sleeping in late talkers. Encouraging autonomy practices were frequently used by parents, rather than active physical comforting ones. Recurrent settling difficulties were reported by parents who often applied encouraging autonomy practices, whereas greater night waking problems and frequent co-sleeping were reported by parents who often left their child crying. Low-risk preterm birth and mother's parenting stress predicted total sleep difficulties and night wakings; first-born, high maternal education level and mother's parenting stress predicted settling difficulties; mother's parenting stress was the only predictor for co-sleeping and leaving to cry. These findings have relevant implications for improving late talkers' night sleep and their parents' bedtime practices.
RESUMO
Programmed cell death and early activity contribute to the emergence of functional cortical circuits. While most neuronal populations are scaled-down by death, some subpopulations are entirely eliminated, raising the question of the importance of such demise for cortical wiring. Here, we addressed this issue by focusing on Cajal-Retzius neurons (CRs), key players in cortical development that are eliminated in postnatal mice in part via Bax-dependent apoptosis. Using Bax-conditional mutants and CR hyperpolarization, we show that the survival of electrically active subsets of CRs triggers an increase in both dendrite complexity and spine density of upper layer pyramidal neurons, leading to an excitation/inhibition imbalance. The survival of these CRs is induced by hyperpolarization, highlighting an interplay between early activity and neuronal elimination. Taken together, our study reveals a novel activity-dependent programmed cell death process required for the removal of transient immature neurons and the proper wiring of functional cortical circuits.
Assuntos
Apoptose/genética , Neurogênese/genética , Células Piramidais/metabolismo , Proteína X Associada a bcl-2/genética , Animais , Animais Recém-Nascidos , Polaridade Celular/genética , Córtex Cerebral/metabolismo , Estimulação Elétrica , Células Intersticiais de Cajal/metabolismo , Camundongos , Proteínas Mutantes/genética , Células Piramidais/patologiaRESUMO
The prevalence rates of overweight and obesity are, internationally as well as in Switzerland, increasing in recent years. The neurobiology tries to explore an improved understanding of the central nervous causes of obesity. Findings from addiction research seem very useful because there are certain similarities between addiction and obesity in terms of neurobiological causes. An improved understanding of the disease of obesity could help to develop more effective therapies for obese patients in the future. Further research, e. g. in the field of stress regulation, is thus urgently needed.