Antibodies to the region-specific transcription factors Bf1, Dlx, En1, and Pax6 were used to explore whether functional donor cell integration depends on the acquisition of a regional phenotype. Our data show that incorporated neurons frequently exhibit a lacking or ectopic expression of these transcription factors. Thus, the lack of an appropriate regional "code" does not preclude morphological and synaptic integration of ES cell-derived neurons.

Background: Following stroke, acute symptomatic seizures (manifestation within seven days) and epilepsy, i.e. occurrence of at least one unprovoked seizure (manifestation after more than seven days), are reported in 3-6% and up to 12% of patients, respectively. Incidence of acute symptomatic seizures is higher in intracranial haemorrhage (10-16%) than in ischaemic stroke (2-4%). Acute symptomatic seizures and unprovoked seizure may be associated with unfavourable functional outcome and increased mortality. In view of the clinical relevance, the European Stroke Organisation has issued evidence-based guidelines on the management of post-stroke seizures and epilepsy. Method: A writing committee of six clinicians and researchers from five European countries and Israel identified seven questions relating to prevention of (further) post-stroke seizures and epilepsy and to amelioration of functional outcome and prevention of mortality. Recommendations are based on findings in randomised controlled trials and observational studies using the grading of recommendations assessment, development and evaluation approach. Results: In the absence of adequately powered randomised controlled trials, evidence for all recommendations is very low. Based on findings in observational studies, some weak recommendations have been made. In most instances, we suggest not to administer antiepileptic drugs. Due to high incidence of seizure recurrence after one post-stroke unprovoked seizure, secondary antiepileptic drugs prophylaxis needs to be considered. Conclusion: Due to very low evidence, these guidelines only give some weak recommendations on prevention of occurrence and recurrence of post-stroke acute symptomatic seizures and unprovoked seizure. Adequately powered randomised controlled trials are required to assess interventions for post-stroke seizure management.

Herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2) are human neurotropic viruses that establish latent infection in dorsal root ganglia (DRG) for the entire life of the host. From the DRG they can reactivate to cause human morbidity and mortality. Although they vary, in part, in the clinical disorders they cause, and in their molecular structure, they share several features that govern the biology of their infection of the human nervous system. HSV-1 is the causative agent of encephalitis, corneal blindness, and several peripheral nervous system disorders; HSV-2 is responsible for meningoencephalitis in neonates and meningitis in adults. The biology of their ability to establish latency, maintain it for the entire life of the host, reactivate, and cause primary and recurrent disease is being studied in animal models and in humans. This review covers recent advances in understanding the biology and pathogenesis of HSV-related disease.

The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion of individuals. To explore whether statistical support for genetic etiologies can be generated on the basis of phenotypic features, we analyzed whole-exome sequencing data and phenotypic similarities by using Human Phenotype Ontology (HPO) in 314 individuals with DEEs. We identified a de novo c.508C>T (p.Arg170Trp) variant in AP2M1 in two individuals with a phenotypic similarity that was higher than expected by chance (p ¼ 0.003) and a phenotype related to epilepsy with myoclonic-atonic seizures. We subsequently found the same de novo variant in two individuals with neurodevelopmental disorders and generalized epilepsy in a cohort of 2,310 individuals who underwent diagnostic whole-exome sequencing. AP2M1 encodes the m-subunit of the adaptor protein complex 2 (AP-2), which is involved in clathrin-mediated endocytosis (CME) and synaptic vesicle recycling. Modeling of protein dynamics indicated that the p.Arg170Trp variant impairs the conformational activation and thermodynamic entropy of the AP-2 complex. Functional complementation of both the m-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2m conditional knockout mice revealed a significant impairment of CME of transferrin. In contrast, stability, expression levels, membrane recruitment, and localization were not impaired, suggesting a functional alteration of the AP-2 complex as the underlying disease mechanism. We establish a recurrent pathogenic variant in AP2M1 as a cause of DEEs with distinct phenotypic features, and we implicate dysfunction of the early steps of endocytosis as a disease mechanism in epilepsy.