Editorial: role of protein palmitoylation in synaptic plasticity and neuronal differentiation

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Yoshii, A., & Green, W. N. Editorial: role of protein palmitoylation in synaptic plasticity and neuronal differentiation. Frontiers in Synaptic Neuroscience, 12(27), (2020), doi:10.3389/fnsyn.2020.00027.Protein palmitoylation, the reversible addition of palmitate to proteins, is a dynamic post-translational modification. Both membrane (e.g., channels, transporters, and receptors) and cytoplasmic proteins (e.g., cell adhesion, scaffolding, cytoskeletal, and signaling molecules) are substrates. In mammals, palmitoylation is mediated by 23-24 palmitoyl acyltransferases (PATs), also called ZDHHCs for their catalytic aspartate-histidine-histidine-cysteine (DHCC) domain. PATs are integral membrane proteins found in cellular membranes. In the palmitoylation cycle, palmitate is removed by the depalmitoylation enzymes, acyl palmitoyl transferases (APT1 and 2), and α/β Hydrolase domain-containing protein 17 (ABHD17A-C). These are cytoplasmic proteins that are targeted to membranes where they are substrates for PATs. The second class of depalmitoylating enzymes are palmitoyl thioesterases, PPT1 and 2, discovered through their association with infantile neuronal ceroid lipofuscinosis. These are secreted proteins found in the lumen of intracellular organelles, primarily lysosomes, where their function as depalmitoylating enzymes is unclear.This work was supported by University of Illinois start-up fund (to AY) and NIH/NIDA (grant DA044760 to WG)

Editorial: Cell and molecular signaling, and transport pathways involved in growth factor control of synaptic development and function

Since the discovery of nerve growth factor (NGF) more than a half century ago (Levi-Montalcini and Cohen, 1960), the prototypic neurotrophin family has included brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). Neurotrophins bind to the Trk family of receptors, as well as the p75 receptor, to activate multiple intracellular signaling cascades (reviewed by Reichardt, 2006). BDNF receptor tropomyosin receptor kinase B (TrkB) signaling has been extensively studied for its roles in the central nervous system (CNS) ranging from cell survival, axonal and dendritic growth and synapse formation. The pathway mediates long-lasting activity-modulated synaptic changes on excitatory and inhibitory neurons and plays critical roles in circuit development and maintenance. In addition to BDNF, many studies have identified other “growth” or signaling factors in the CNS that play important roles in the development, maintenance, and control of synaptic and circuit function. However, details of the intracellular signaling systems downstream of these events are frequently unexplored. In this Research Topic, we have collected original studies and review articles that present cellular and molecular mechanisms concerning activity-dependent synapse formation and their implications for behavior and brain disorders.National Institutes of Health (U.S.) (Grant 5R01EY006039-27)National Institutes of Health (U.S.) (Grant 5R01EY014074-15

Nonparametric Bayesian Dereverberation of Power Spectrograms Based on Infinite-Order Autoregressive Processes

This paper describes a monaural audio dereverberation method that operates in the power spectrogram domain. The method is robust to different kinds of source signals such as speech or music. Moreover, it requires little manual intervention, including the complexity of room acoustics. The method is based on a non-conjugate Bayesian model of the power spectrogram. It extends the idea of multi-channel linear prediction to the power spectrogram domain, and formulates a model of reverberation as a non-negative, infinite-order autoregressive process. To this end, the power spectrogram is interpreted as a histogram count data, which allows a nonparametric Bayesian model to be used as the prior for the autoregressive process, allowing the effective number of active components to grow, without bound, with the complexity of data. In order to determine the marginal posterior distribution, a convergent algorithm, inspired by the variational Bayes method, is formulated. It employs the minorization-maximization technique to arrive at an iterative, convergent algorithm that approximates the marginal posterior distribution. Both objective and subjective evaluations show advantage over other methods based on the power spectrum. We also apply the method to a music information retrieval task and demonstrate its effectiveness

Age- and sun exposure-dependent differences in 8-hydroxy-2'-deoxyguanosine and Nε-(carboxymethyl)lysine in human epidermis

Aging and exposure to sunlight are two major factors in the deterioration of skin function. In this study, thirty-six fixed human skin samples from sun-exposed and unexposed areas from young and old individuals were used to evaluate the localization of oxidative stress according to levels and distribution of 8-hydroxy-2'-deoxyguanosine and Nε-(carboxymethyl)lysine in samples using immunohistochemistry. In the epidermis of the young, negligible amounts of 8-hydroxy-2'-deoxyguanosine and Nε-(carboxymethyl)lysine were detected in unexposed areas, whereas nuclear 8-hydroxy-2'-deoxyguanosine and cytoplasmic Nε-(carboxymethyl)lysine were increased in the lower epidermis in sun-exposed areas. In contrast, the aged presented prominent nuclear 8-hydroxy-2'-deoxyguanosine and nuclear Nε-(carboxymethyl)lysine in the epidermis of unexposed areas, concomitant with dermal increase in Nε-(carboxymethyl)lysine. However, the immunostaining of 8-hydroxy-2'-deoxyguanosine and Nε-(carboxymethyl)lysine revealed a decrease in the epidermis of sun-exposed areas in the aged. These results suggest an age-dependent difference in the adaptation and protective mechanisms of the epidermis against sunlight-associated oxidative stress, thus necessitating distinct standards for evaluation in each age group. Further investigation is warranted to elucidate underlying molecular mechanisms

A Myosin Va Mutant Mouse with Disruptions in Glutamate Synaptic Development and Mature Plasticity in Visual Cortex

Myosin Va (MyoVa) mediates F-actin-based vesicular transport toward the plasma membrane and is found at neuronal postsynaptic densities (PSDs), but the role of MyoVa in synaptic development and function is largely unknown. Here, in studies using the dominantnegative MyoVa neurological mutant mouse Flailer, we find that MyoVa plays an essential role in activity-dependent delivery of PSD-95 and other critical PSD molecules to synapses and in endocytosis of AMPA-type glutamate receptors (AMPAR) in the dendrites of CNS neurons. MyoVa is known to carry a complex containing the major scaffolding proteins of the mature PSD, PSD-95, SAPAP1/GKAP, Shank, and Homer to dendritic spine synapses. In Flailer, neurons show abnormal dendritic shaft localization of PSD-95, stargazin, dynamin3, AMPARs and abnormal spine morphology. Flailer neurons also have abnormally highAMPARminiature current frequencies and spontaneous AMPAR currents that are more frequent and larger than in wild-type while numbers of NMDAR containing synapses remain normal. The AMPAR abnormalities are consistent with a severely disrupted developmental regulation of long-term depression that we find in cortical Flailer neurons. Thus MyoVa plays a fundamentally important role both in localizing mature glutamate synapses to spines and in organizing the synapse for normal function. For this reason Flailer mice will be valuable in further dissecting the role of MyoVa in normal synaptic and circuit refinement and also in studies of neurological and neuropsychiatric diseases where disruptions of normal glutamate synapses are frequently observed.National Institutes of Health (U.S.) (Grant R01-EY014074–17)National Institutes of Health (U.S.) (Grant EY014420

Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed Brain

Tuberous sclerosis complex (TSC) is an autosomal dominant neurogenetic disorder affecting the brain and other vital organs. Neurological symptoms include epilepsy, intellectual disability, and autism. TSC is caused by a loss-of-function mutation in the TSC1 or TSC2 gene. These gene products form a protein complex and normally suppress mammalian target of rapamycin (mTOR) activity. mTOR inhibitors have been used to treat subependymal glioma (SEGA) that is a brain tumor characteristic of TSC. However, neuropathology of TSC also involves dysregulated cortical circuit formation including neuronal migration, axodendritic differentiation, and synapse formation. It is currently unknown to what extent mTOR signaling inhibitors correct an alteration in neuronal morphology that have already formed prior to the treatment. Here, we address the efficacy of rapamycin treatment on neuronal migration and dendrite formation. Using in utero electroporation, we suppressed Tsc1 expression in a fraction of neuronal progenitor cells during the fetal period. In embryonic brain slices, we found that more Tsc1-suppressed cells remained within the periventricular zone, and rapamycin treatment facilitated neuronal migration. Postnatally, Tsc1-suppressed pyramidal neurons showed more complex branching of basal dendrites and a higher spine density at postnatal day (P) 28. Aberrant arborization was normalized by rapamycin administration every other day between P1 and P13 but not P15 and P27. In contrast, abnormal spine maturation improved by rapamycin treatment between P15 and P27 but not P1 and P13. Our results indicate that there are multiple critical windows for correcting different aspects of structural abnormalities in TSC, and the responses depend on the stage of neuronal circuit formation. These data warrant a search for an additional therapeutic target to treat neurological symptoms of TSC

Microarray analysis of microRNA expression in the developing mammalian brain

BACKGROUND: MicroRNAs are a large new class of tiny regulatory RNAs found in nematodes, plants, insects and mammals. MicroRNAs are thought to act as post-transcriptional modulators of gene expression. In invertebrates microRNAs have been implicated as regulators of developmental timing, neuronal differentiation, cell proliferation, programmed cell death and fat metabolism. Little is known about the roles of microRNAs in mammals. RESULTS: We isolated 18-26 nucleotide RNAs from developing rat and monkey brains. From the sequences of these RNAs and the sequences of the rat and human genomes we determined which of these small RNAs are likely to have derived from stem-loop precursors typical of microRNAs. Next, we developed a microarray technology suitable for detecting microRNAs and printed a microRNA microarray representing 138 mammalian microRNAs corresponding to the sequences of the microRNAs we cloned as well as to other known microRNAs. We used this microarray to determine the profile of microRNAs expressed in the developing mouse brain. We observed a temporal wave of expression of microRNAs, suggesting that microRNAs play important roles in the development of the mammalian brain. CONCLUSION: We describe a microarray technology that can be used to analyze the expression of microRNAs and of other small RNAs. MicroRNA microarrays offer a new tool that should facilitate studies of the biological roles of microRNAs. We used this method to determine the microRNA expression profile during mouse brain development and observed a temporal wave of gene expression of sequential classes of microRNAs

Immunohistochemical study of the Landolt\u27s club cells in the chicken retina

The immunohistochemical specificity of the Landolt\u27s club cells of the chicken retina were studied by the indirect immunofluorescence and immunoperoxidase bridge methods with specific antiserum against neuronal filament proteins of these cells. In the tissue, the Landolt\u27s club cells were selectively stained with the specific antiserum (antigen : isoelectric point=6.29, molecular weight=69,000). It appeared that the cells were bipolar and that the cell body lay in the superficial part of the internal nuclear layer. However, it was difficult to observe the dendrites like those of typical bipolar cells which synapse with photoreceptors. No reaction was found in ganglion cells, amacrine cells, horizontal cells and other types of bipolar cells which occupy the zone just inside the external plexiform layer. From the 6th day of tissue culture, the selectively stained bipolar cells appeared on the surface of the monolayer cells. They were small and oval with large, spherical and eccentric nuclei. The cytoplasm was slightly less dense than other neuron cells

Reduction of neuroinflammation and seizures in a mouse model of CLN1 batten disease using the small molecule enzyme mimetic, N-Tert-butyl hydroxylamine

Infantile neuronal ceroid lipofuscinosis (CLN1 Batten Disease) is a devastating pediatric lysosomal storage disease caused by pathogenic variants in the CLN1 gene, which encodes the depalmitoylation enzyme, palmitoyl-protein thioesterase 1 (PPT1). CLN1 patients present with visual deterioration, psychomotor dysfunction, and recurrent seizures until neurodegeneration results in death, typically before fifteen years of age. Histopathological features of CLN1 include aggregation of lysosomal autofluorescent storage material (AFSM), as well as profound gliosis. The current management of CLN1 is relegated to palliative care. Here, we examine the therapeutic potential of a small molecule PPT1 mimetic, N-tert-butyl hydroxylamine (NtBuHA), in a Cln1−/− mouse model. Treatment with NtBuHA reduced AFSM accumulation both in vitro and in vivo. Importantly, NtBuHA treatment in Cln1−/− mice reduced neuroinflammation, mitigated epileptic episodes, and normalized motor function. Live cell imaging of Cln1−/− primary cortical neurons treated with NtBuHA partially rescued aberrant synaptic calcium dynamics, suggesting a potential mechanism contributing to the therapeutic effects of NtBuHA in vivo. Taken together, our findings provide supporting evidence for NtBuHA as a potential treatment for CLN1 Batten Disease