Perturbations in neuregulin-1 (NRG1)/ErbB4 function have been associated with schizophrenia. Affected patients exhibit altered levels of these proteins and display hypofunction of glutamatergic synapses as well as altered neuronal circuitry. However, the role of NRG1/ErbB4 in regulating synapse maturation and neuronal process formation has not been extensively examined. Here we demonstrate that ErbB4 is expressed in inhibitory interneurons at both excitatory and inhibitory postsynaptic sites. Overexpression of ErbB4 postsynaptically enhances size but not number of presynaptic inputs. Conversely, knockdown of ErbB4 using shRNA decreases the size of presynaptic inputs, demonstrating a specific role for endogenous ErbB4 in synapse maturation. Using ErbB4 mutant constructs, we demonstrate that ErbB4-mediated synapse maturation requires its extracellular domain, whereas its tyrosine kinase activity is dispensable for this process. We also demonstrate that depletion of ErbB4 decreases the number of primary neurites and that stimulation of ErbB4 using a soluble form of NRG1 results in exuberant dendritic arborization through activation of the tyrosine kinase domain of ErbB4 and the phosphoinositide 3-kinase pathway. These findings demonstrate that NRG1/ErbB4 signaling differentially regulates synapse maturation and dendritic morphology via two distinct mechanisms involving trans-synaptic signaling and tyrosine kinase activity, respectively.Although central nervous system synapses utilize a variety of brain-specific molecules to mediate contact formation and maturation, some of the proteins implicated in this process are also major players in neuromuscular junction development. Among these shared molecules are NRG1 3 and its receptor, ErbB4, which are expressed in both the developing and adult brain. Neuregulins comprise a family of four related genes (nrg1-4), each producing a large number of isoforms via differential promoter usage and alternative splicing (1, 2). NRGs contain EGF-like repeats, which enable them to bind to and activate EGF family receptors (ErbB2-4). Previous studies showed that NRG1 is initially synthesized as a transmembrane protein, which then undergoes proteolytic processing, whereby the extracellular EGF-containing fragment is released into the extracellular environment. The remaining intracellular fragment has been shown to translocate into the nucleus, where it regulates neuronal survival and transcription of PSD-95 (3, 4). Proteolytic processing of NRG1 is also regulated by neuronal activity and by interaction with ErbB receptors (3, 5). NRG1 is widely expressed throughout development and adulthood, with the highest expression in nervous tissue (6) and is essential for survival. In the central nervous system NRG1 is also required for differentiation, migration, and development of neurons and glia as well as for axonal myelination and pathfinding, dendritic development, and neurotransmitter receptor maintenance. During development, NRG1-ErbB signaling mediates radial glia maintenance and elonga...

The goal of glioma surgery is maximal safe resection. These intrinsic brain neoplasms, however, lack a clear margin and frequently infiltrate eloquent areas of the brain thus making their surgical resection challenging. This review first focuses on discussion of preoperative investigations that aid in anatomical and functional tumor characterization that help define tumor extent and determine the feasibility of complete resection. The second part of this review outlines intraoperative adjuncts that help identify tumor infiltrated tissues during surgery to maximize the extent of resection. In addition, we discuss the principles of intraoperative functional cortical and subcortical mapping and monitoring that enable maximal tumor resection while minimizing the risk of postoperative neurological deficit. Combined use of different modalities before and during surgery is encouraged to meet surgical goals and to ensure best patient outcome.

Glioblastoma is a devastating disease with poor prognosis. Few effective chemotherapeutics are currently available, and much effort has been extended to identify new drugs capable of slowing tumor progression. The phase 0 trial design was developed to facilitate early identification of promising agents for cancer that should undergo accelerated approval. This design features an early in-human study that enrolls a small number of patients that receive sub-therapeutic doses of medication with the goals of describing pharmacokinetics through drug blood level measurements, and by determining intra-tumoral concentrations of the investigational compound as well as pharmacodynamics by studying the biochemical and physiological effects of drugs. In neuro-oncology, however, the presence of the blood-brain barrier and difficulty in obtaining brain tumor tissue warrant a separate set of considerations. In this manuscript, we critically reviewed the protocols used in all brain tumor related in-human phase 0 and phase 0-like (“window of opportunity”) studies between 1993 and 2018, as well as ongoing clinical trials, and identified major challenges in trial design as applied to central nervous system tumors that include surgical specimen collection and storage, brain tumor drug level analysis, and confirmation of drug action. We therefore propose that phase 0 trials in neuro-oncology should include 1) only patients in whom a resection of the tumor is planned, 2) use of clinical doses of an investigational agent, 3) tissue sampling from enhancing and non-enhancing portions of the tumor, and 4) assessment of drug-specific target effects. Standardization of clinical protocols for phase 0/window of opportunity studies can help accelerate the development of effective treatments for glioblastoma.

C erebellar liponeurocytomas are typically lowgrade tumors that arise in the cerebellar hemispheres or vermis and contain cells of neuronal, astrocytic, and lipomatous differentiation. 17 The biology and long-term outcomes of these tumors are undefined, and to our knowledge, familial occurrences have not been described. We present here the case of a young woman with a cerebellar liponeurocytoma and multiple immediate family members, including her mother, with similar lesions. This report describes the tumors from the patient and her mother and provides a brief overview of the histopathology and genetic changes associated with this disease. case report Clinical PresentationA 37-year-old woman presented with a 2-year history of worsening morning and daytime headaches in the occipital area that radiated over the cranium. She also described intermittent paresthesia in her hands and feet, which was of variable distribution and duration. The patient was otherwise healthy with a grossly normal neurological examination. She smoked cigarettes but had no other known medical problems. CT and MRI of the head and spine revealed a solitary fat-containing tumor arising from the region of the superior cerebellar hemisphere and vermis. The heterogeneous lesion had numerous ill-defined septations with patchy enhancement and measured 4.4 × 4.1 × 4.3 cm in the anterior-posterior, medial-lateral, and superior-inferior dimensions, respectively. It extended through the incisura and involved the tectal plate and several deep veins, including the left basal vein of Rosenthal. There was complete effacement of the fourth ventricle and compensated dilation of the third and lateral ventricles. There was displacement of the cerebellar tonsils through the foramen magnum, with compression of the cervicomedullary junction ( Fig. 1A and B).abbreviatioNs GFAP = glial fibrillary acidic protein; IDH1 = isocitrate dehydrogenase 1; MAP-2 = microtubule-associated protein 2; MIB-1 = monoclonal antihuman Ki 67. The biological origin of cerebellar liponeurocytomas is unknown, and hereditary forms of this disease have not been described. Here, the authors present clinical and histopathological findings of a young patient with a cerebellar liponeurocytoma who had multiple immediate family members who harbored similar intracranial tumors. A 37-year-old otherwise healthy woman presented with a history of progressive headaches. Lipomatous medulloblastoma had been diagnosed previously in her mother and maternal grandfather, and her maternal uncle had a supratentorial liponeurocytoma. MRI revealed a large, poorly enhancing, lipomatous mass emanating from the superior vermis that produced marked compression of posterior fossa structures. An uncomplicated supracerebellar infratentorial approach was used to resect the lesion. Genetic and histopathological analyses of the lesion revealed neuronal, glial, and lipomatous differentiation and confirmed the diagnosis of cerebellar liponeurocytoma. A comparison of the tumors resected from the patient and, 22 years previo...