Emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of type I lissencephaly

Type I lissencephaly is a neuronal migration disorder caused by haploinsuffiency of the PAFAH1B1 (mouse: Pafah1b1) gene and is characterized by brain malformation, developmental delays, and epilepsy. Here, we investigate the impact of Pafah1b1 mutation on the cellular migration, morphophysiology, microcircuitry, and transcriptomics of mouse hippocampal CA1 parvalbumin-containing inhibitory interneurons (PV+INTs). We find that WT PV+INTs consist of two physiological subtypes (80% fast-spiking (FS), 20% non-fast-spiking (NFS)) and four morphological subtypes. We find that cell-autonomous mutations within interneurons disrupts morphophysiological development of PV+INTs and results in the emergence of a non-canonical ‘intermediate spiking (IS)’ subset of PV+INTs. We also find that now dominant IS/NFS cells are prone to entering depolarization block, causing them to temporarily lose the ability to initiate action potentials and control network excitation, potentially promoting seizures. Finally, single-cell nuclear RNAsequencing of PV+INTs revealed several misregulated genes related to morphogenesis, cellular excitability, and synapse formation.

Sevoflurane postconditioning ameliorates neuronal migration disorder through Reelin/Dab1 and improves long-term cognition in neonatal rats after hypoxic-ischemic injury

Sevoflurane postconditioning (SPC) had been reported to attenuate developing brain injury after hypoxia-ischemia encephalopathy (HIE)via inhibiting neural necrosis and autophagy process. Moreover, recent report elucidated sevoflurane may involve in neural cells migration after injury. Here we hypothesize neuronal migration and long-term cognition were ruined after HIE and SPC alleviated these injuries .Classical Rice–Vannucci model of Hypoxia-ischemia was conducted on P7 pups , which was followed by SPC at the 1 minimum alveolar concentration (MAC 2.4%) for 30 min. Piceatannol which can cleave Reelin into proteolytic fragments was used to detect whether Reelin/Dab1 is involved in neuroprotection exerted by SPC. Our findings suggest that hypoxia-ischemia disrupted cytoarchitecture of dentate gyrus (DG) by inhibiting the migration of dentate neurons of hippocampus, which may eventually lead to long-term cognition deficits. However, SPC could relieve the restricted hippocampal neurons from the subgranular zone of hippocampi combined with the repair of hippocampal-dependent memory function damaged by HIE through attenuating the overactivation of the Reelin/Dab1pathway. Taken together, these results demonstrate that SPC plays a pivotal role in ameliorating neuronal migration disorder and maintain normal cytoarchitecture and spatial learning ability of DG by regulating the Reelin/Dab1 downstream signaling pathway. This indicates the potential therapeutic use of SPC in treating HIE perinatally.

Megalencephaly and Epileptic Encephalopathy: Bad luck or a common pathway?

Megalencephaly is a neuronal migration disorder characterized by an abnormally large brain. Numerous associated syndromes and various molecular mutations have been identified as an etiology for megalencephaly, however, SCN2A mutations have not been previously described. This report highlights a case of a term male megalencephalic neonate who presents with intractable seizures, who was found to have SCN2A gene variant that has now been identified as pathogenic. This patient expands our knowledge of the phenotypic spectrum of SNC2A mutations by adding consideration for macroscopic brain findings. Currently, we have no direct link between SCN2A mutations and megalencephaly, but our patient highlights the potential overlap in disease processes. It is possible that the biochemical disturbance associated with abnormal neuronal migration also affects the neuronal circuitry, thus increasing the propensity for electrical dysfunction and manifesting as seizures.