Use-dependent downregulation of neuronal activity (negative feedback) can act as a homeostatic mechanism to maintain neuronal activity at a particular specified value. Disruption of this negative feedback might lead to neurological pathologies, such as epilepsy, but the precise mechanisms by which this feedback can occur remain incompletely understood. At one glutamatergic synapse, the Drosophila neuromuscular junction, a mutation in the group II metabotropic glutamate receptor gene (DmGluRA) increased motor neuron excitability by disrupting an autocrine, glutamate-mediated negative feedback. We show that DmGluRA mutations increase neuronal excitability by preventing PI3 kinase (PI3K) activation and consequently hyperactivating the transcription factor Foxo. Furthermore, glutamate application increases levels of phospho-Akt, a product of PI3K signaling, within motor nerve terminals in a DmGluRA-dependent manner. Finally, we show that PI3K increases both axon diameter and synapse number via the Tor/S6 kinase pathway, but not Foxo. In humans, PI3K and group II mGluRs are implicated in epilepsy, neurofibromatosis, autism, schizophrenia, and other neurological disorders; however, neither the link between group II mGluRs and PI3K, nor the role of PI3K-dependent regulation of Foxo in the control of neuronal excitability, had been previously reported. Our work suggests that some of the deficits in these neurological disorders might result from disruption of glutamate-mediated homeostasis of neuronal excitability.

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The type 2 lysine methyltransferases KMT2C and KMT2D are large, enzymatically active scaffold proteins that form the core of nuclear regulatory structures known as KMT2C/D COMPASS complexes (complex of proteins associating with Set1). These evolutionarily conserved proteins regulate DNA promoter and enhancer elements, modulating the activity of diverse cell types critical for embryonic morphogenesis, central nervous system development, and post-natal survival. KMT2C/D COMPASS complexes and their binding partners enhance active gene expression of specific loci via the targeted modification of histone-3 tail residues, in general promoting active euchromatic conformations. Over the last 20 years, mutations in five key COMPASS complex genes have been linked to three human congenital syndromes: Kabuki syndrome (type 1 [KMT2D] and 2 [KDM6A]), Rubinstein-Taybi syndrome (type 1 [CBP] and 2 [EP300]), and Kleefstra syndrome type 2 (KMT2C). Here, we review the composition and biochemical function of the KMT2 complexes. The specific cellular and embryonic roles of the KMT2C/D COMPASS complex are highlight with a focus on clinically relevant mechanisms sensitive to haploinsufficiency. The phenotypic similarities and differences between the members of this new family of disorders are outlined and emerging therapeutic strategies are detailed.

Drosophila peripheral nerves, structured similarly to their mammalian counterparts, comprise a layer of motor and sensory axons wrapped by an inner peripheral glia (analogous to the mammalian Schwann cell) and an outer perineurial glia (analogous to the mammalian perineurium). Growth and proliferation within mammalian peripheral nerves are increased by Ras pathway activation: loss-of-function mutations in Nf1, which encodes the Ras inhibitor neurofibromin, cause the human genetic disorder neurofibromatosis, which is characterized by formation of neurofibromas (tumors of peripheral nerves). However, the signaling pathways that control nerve growth downstream of Ras remain incompletely characterized. Here we show that expression specifically within the Drosophila peripheral glia of the constitutively active Ras V12 increases perineurial glial thickness. Using chromosomal loss-of-function mutations and transgenes encoding dominant-negative and constitutively active proteins, we show that this nonautonomous effect of Ras V12 is mediated by the Ras effector phosphatidylinositol 3-kinase (PI3K) and its downstream kinase Akt. We also show that the nonautonomous, growthpromoting effects of activated PI3K are suppressed by coexpression within the peripheral glia of FOXO ϩ (forkhead box O) a transcription factor inhibited by Akt-dependent phosphorylation. We suggest that Ras-PI3K-Akt activity in the peripheral glia promotes growth of the perineurial glia by inhibiting FOXO. In mammalian peripheral nerves, the Schwann cell releases several growth factors that affect the proliferative properties of neighbors. Some of these factors are oversecreted in Nf1 mutants. Our results raise the possibility that neurofibroma formation in individuals with neurofibromatosis might result in part from a Ras-PI3K-Akt-dependent inhibition of FOXO within Schwann cells.

The reduced ocular blood flow in DBA/2J mice compared with C57BL/6 control mice suggests that ischemia or hypoxia should be considered as a possible contributing factor in the optic neuropathy in the DBA/2J mouse model of glaucoma.

A B S T R A C TBackground: The increasing incidence of pediatric food allergy results in significant health care burden and family stress. Oral immunotherapy (OIT) can induce tolerance to peanut, milk, and egg. OIT for other foods, particularly multiple foods simultaneously, has not been thoroughly studied. Objective: To summarize our experience with OIT for multiple foods in a pediatric allergy clinic setting. Methods: Medical records were reviewed for patients undergoing OIT for multiple foods. Methods and outcomes of OIT were summarized. Outcomes were analyzed for correlation with baseline food allergen skin prick tests (SPTs) and specific IgE (sIgE) test results. Results: Forty-five patients aged 1.5 to 18 years undertook OIT for up to 12 foods, including peanut, tree nuts, seeds, legumes, and egg. At the time of review, 35 patients were receiving daily maintenance dosing, 4 had completed OIT and were continuing to eat their foods 3 times weekly, and 6 had stopped OIT because of anxiety, inconvenience, or allergy symptoms. A total of 49% of patients had reactions during the up-dosing process, mostly oral itching (33%), perioral hives (40%), and abdominal pain (35%). There was no correlation of baseline skin prick test (SPT) and sIgE test results with reaction threshold for baseline food challenge, lowest dose causing reactions during up-dosing, or time to reach maintenance. Higher baseline sIgE level but not baseline SPT result was associated with an increased number of allergic reactions during OIT. Baseline SPT correlated with stopping OIT. Conclusion: A similar approach to that used for peanut OIT can be taken for nonpeanut foods and for multiple foods simultaneously. High baseline allergy test results are not a contraindication to OIT.

Hereditary angioedema (HAE) is defined as a rare genetic disease with recurrent episodes of localized bradykinin-mediated swelling of the deep tissues of the skin, respiratory, and gastrointestinal tracts that can be life threatening. Classification of HAE has evolved over time with our further understanding of clinical phenotypes, underlying causes, and available testing. In most cases, HAE is caused by a deficiency of C1-esterase inhibitor (C1-INH) on the Serpin Family G Member 1 (SERPING1) gene, either through decreased amounts of C1-INH protein (C1-INH‐HAE, type 1) or decreased function of C1-INH (C1-INH‐HAE, type 2). HAE with normal C1-INH levels and function are divided into unknown cause or into non‐C1-INH‐HAE forms, which include known mutational defects in factor XII (called FXII-HAE in the Hereditary Angioedema International Working Group consensus), angiopoietin-1, plasminogen, and kininogen 1 genes. It is possible that, after an initial workup, a patient without a family history of HAE could be classified with an acquired form of angioedema (nonhereditary) that may later prove to be HAE due to a de-novo SERPING1 mutation. Because there are forms of nonhistaminergic (H1-antihistamine unresponsive) angioedema that appear clinically very similar to HAE, it is essential that the patient undergoes a thorough clinical history and diagnostic evaluation to ensure that he or she is properly diagnosed and classified.