SUMMARY Individuals with 22q11.2 microdeletions have cognitive deficits and a high risk of developing schizophrenia. Here, we provide evidence that primary hippocampal neurons from a 22q11.2 deletion mouse model [Df(16)A+/−] have decreased density of dendritic spines and glutamatergic synapses, as well as impaired dendritic growth. These deficits can be prevented by introduction of enzymatically active ZDHHC8 palmitoyltransferase encoded by a gene located in the 22q11.2 locus and they are also observed in primary cultures from Zdhhc8-deficient mice. We show that many of these deficits are also present in the hippocampus of adult Df(16)A+/− and Zdhhc8-deficient mice. Finally, we provide evidence that PSD95 is one of the substrates of ZDHHC8. Our analysis reveals that 22q11.2 microdeletion results in deficits in neuronal development and suggests that impaired neuronal protein palmitoylation contributes to many of these deficits.

Combustion is a complex chemical system which involves thousands of chemical reactions and generates hundreds of molecular species and radicals during the process. In this work, a neural network-based molecular dynamics (MD) simulation is carried out to simulate the benchmark combustion of methane. During MD simulation, detailed reaction processes leading to the creation of specific molecular species including various intermediate radicals and the products are intimately revealed and characterized. Overall, a total of 798 different chemical reactions were recorded and some new chemical reaction pathways were discovered. We believe that the present work heralds the dawn of a new era in which neural network-based reactive MD simulation can be practically applied to simulating important complex reaction systems at ab initio level, which provides atomic-level understanding of chemical reaction processes as well as discovery of new reaction pathways at an unprecedented level of detail beyond what laboratory experiments could accomplish.

We establish and experimentally validate a genetic in vivo axonal-competition paradigm in the mammalian CNS. By using this paradigm, we provide evidence for a specific effect of BDNF signaling on terminal-arbor pruning under competition in vivo. Our results have implications for the formation and refinement of the olfactory and other sensory maps, as well as for neuropsychiatric diseases and traits modulated by the BDNF val66met variant.

Large-conductance voltage and Ca 2 þ -activated potassium channels (BKCa) play a critical role in modulating contractile tone of smooth muscle, and neuronal processes. In most mammalian tissues, activation of b-adrenergic receptors and protein kinase A (PKA c ) increases BKCa channel activity, contributing to sympathetic nervous system/hormonal regulation of membrane excitability. Here we report the requirement of an association of the b2-adrenergic receptor (b2AR) with the pore forming a subunit of BKCa and an A-kinase-anchoring protein (AKAP79/150) for b2 agonist regulation. b2AR can simultaneously interact with both BKCa and L-type Ca 2 þ channels (Ca v 1.2) in vivo, which enables the assembly of a unique, highly localized signal transduction complex to mediate Ca 2 þ -and phosphorylation-dependent modulation of BKCa current. Our findings reveal a novel function for G protein-coupled receptors as a scaffold to couple two families of ion channels into a physical and functional signaling complex to modulate b-adrenergic regulation of membrane excitability.

The Aβ peptide aggregates into amyloid plaques at presymptomatic stages of Alzheimer's disease, but the temporal relationship between plaque formation and neuronal dysfunction is poorly understood. Here, we demonstrate that the connectivity of the peripheral olfactory neural circuit is perturbed in mice overexpressing human APPsw (Swedish mutation) prior to the onset of plaques. Expression of hAPPsw exclusively in olfactory sensory neurons (OSNs) also perturbs connectivity with associated reductions in odor-evoked gene expression and olfactory acuity. By contrast, OSN axons project correctly in mice overexpressing wild type human APP throughout the brain and in mice overexpressing human APPmv, a missense mutation that reduces Aβ production, exclusively in OSNs. Furthermore, expression of Aβ40 or Aβ42 solely in the olfactory epithelium disrupts OSN axon targeting. Our data indicate that altering the structural connectivity and function of highly plastic neural circuits is one of the pleiotropic actions of soluble human Aβ.