Dendritic Pruning Research Articles

An ultra-compact and high-speed FFT-based large-integer multiplier for fully homomorphic encryption using a dual spike-based arithmetic circuit over GF(p)

During last years, fully homomorphic encryption (FHE) has attracted great interest since enables computation on encrypted data and thus can be considered as a potential solution in advanced applications, such as privacy-preserving cloud computing, genomics, electronic voting and bio-metric authentication. Nowadays, software simulations of the FHE schemes on general purpose computers are extremely slow. Therefore, the development of specific hardware architectures open up new horizons in efficient simulation of FHE schemes. Until date, the implementation of FHE schemes in embedded devices remain impractical due to very high processing time and area consumption required to process very large-integer numbers. Specifically, the development of efficient very large-integer finite-field adder and multiplier potentially allows the throughput and area consumption to be improved since these circuits are the most used components in the computation of FHE schemes. This work presents, for the first time, the development of a compact and highly dual finite-field circuit based on spiking neural P systems (SN P), dendritic growth, dendritic pruning, communication on request and structural plasticity. Specifically, this circuit performs either the finite-field addition or multiplication of two variable integers by only reconnecting their synapses dynamically. Hence, the proposed circuit performs both operations employing the same neural network. In this way, we achieve a significant improvement in terms of area consumption and throughput. Since the computation of FHE schemes requires the multiplication of very large-integer numbers, we use the proposed dual finite-field circuit as the basic processing unit to create a very large-integer multiplier based on fast Fourier transform (FFT). Specifically, the creation of the proposed very large-integer multiplier has allowed us to accelerate the key generation and encryption processes involved in the computation of FHE algorithm. This multiplier was implemented in scalable compact neuromorphic architecture, which mimic the dynamic dendritic phenomena, such as dendritic growth and dendritic pruning. To achieve this, we propose a dynamic multiplexing mechanism based on simple multiplexers and an optimized control unit. This have allowed us to significantly improve the area consumption compared with previously reported solution.

AMPK activates the Nrf2-Keap1 pathway to govern dendrite pruning via the insulin pathway in Drosophila.

During Drosophila metamorphosis, the ddaC dendritic arborisation sensory neurons selectively prune their larval dendrites in response to steroid hormone ecdysone signalling. The Nrf2-Keap1 pathway acts downstream of ecdysone signalling to promote proteasomal degradation and thereby dendrite pruning. However, how the Nrf2-Keap1 pathway is activated remains largely unclear. Here, we demonstrate that the metabolic regulator AMP-activated protein kinase (AMPK) plays a cell-autonomous role in dendrite pruning. Importantly, AMPK is required for Mical and Headcase expression and for activation of the Nrf2-Keap1 pathway. We reveal that AMPK promotes the Nrf2-Keap1 pathway and dendrite pruning partly via inhibition of the insulin pathway. Moreover, the AMPK-insulin pathway is required for ecdysone signalling to activate the Nrf2-Keap1 pathway during dendrite pruning. Overall, this study reveals an important mechanism whereby ecdysone signalling activates the Nrf2-Keap1 pathway via the AMPK-insulin pathway to promote dendrite pruning, and further suggests that during the nonfeeding prepupal stage metabolic alterations lead to activation of the Nrf2-Keap1 pathway and dendrite pruning.

MTOR-Dependent Spine Dynamics in Autism.

Autism Spectrum Conditions (ASC) are a group of neurodevelopmental disorders characterized by deficits in social communication and interaction as well as repetitive behaviors and restricted range of interests. ASC are complex genetic disorders with moderate to high heritability, and associated with atypical patterns of neural connectivity. Many of the genes implicated in ASC are involved in dendritic spine pruning and spine development, both of which can be mediated by the mammalian target of rapamycin (mTOR) signaling pathway. Consistent with this idea, human postmortem studies have shown increased spine density in ASC compared to controls suggesting that the balance between autophagy and spinogenesis is altered in ASC. However, murine models of ASC have shown inconsistent results for spine morphology, which may underlie functional connectivity. This review seeks to establish the relevance of changes in dendritic spines in ASC using data gathered from rodent models. Using a literature survey, we identify 20 genes that are linked to dendritic spine pruning or development in rodents that are also strongly implicated in ASC in humans. Furthermore, we show that all 20 genes are linked to the mTOR pathway and propose that the mTOR pathway regulating spine dynamics is a potential mechanism underlying the ASC signaling pathway in ASC. We show here that the direction of change in spine density was mostly correlated to the upstream positive or negative regulation of the mTOR pathway and most rodent models of mutant mTOR regulators show increases in immature spines, based on morphological analyses. We further explore the idea that these mutations in these genes result in aberrant social behavior in rodent models that is due to these altered spine dynamics. This review should therefore pave the way for further research on the specific genes outlined, their effect on spine morphology or density with an emphasis on understanding the functional role of these changes in ASC.

Role of the DUB enzyme USP7 in dendritic arborization, neuronal migration, and autistic-like behaviors in mice

SummaryDuplication and haploinsufficiency of the USP7 gene are implicated in autism spectrum disorders (ASD), but the role for USP7 in neurodevelopment and contribution to ASD pathogenesis remain unknown. We find that in primary neurons, overexpression of USP7 increases dendritic branch number and total dendritic length, whereas knockdown leads to opposite alterations. Besides, USP7 deubiquitinates the X-linked inhibitor of apoptosis protein (XIAP). The USP7-induced increase in XIAP suppresses caspase 3 activity, leading to a reduction in tubulin cleavage and suppression of dendritic pruning. When USP7 is introduced into the brains of prenatal mice via in utero electroporation (IUE), it results in abnormal migration of newborn neurons and increased dendritic arborization. Importantly, intraventricular brain injection of AAV-USP7 in P0 mice leads to autistic-like phenotypes including aberrant social interactions, repetitive behaviors, as well as changes in somatosensory sensitivity. These findings provide new insights in USP7-related neurobiological functions and its implication in ASD.

Gestational immune activation disrupts hypothalamic neurocircuits of maternal care behavior

Immune activation is one of the most common complications during pregnancy, predominantly evoked by viral infections. Nevertheless, how immune activation affects mother–offspring relationships postpartum remains unknown. Here, by using the polyinosinic-polycytidylic acid (Poly I:C) model of gestational infection we show that viral-like immune activation at mid-gestation persistently changes hypothalamic neurocircuit parameters in mouse dams and, consequently, is adverse to parenting behavior. Poly I:C-exposed dams favor non-pup-directed exploratory behavior at the expense of pup retrieval. These behavioral deficits are underlain by dendrite pruning and lesser immediate early gene activation in Galanin (Gal)+ neurons with dam-specific transcriptional signatures that reside in the medial preoptic area (mPOA). Reduced activation of an exclusively inhibitory contingent of these distal-projecting Gal+ neurons allows for increased feed-forward inhibition onto putative dopaminergic neurons in the ventral tegmental area (VTA) in Poly I:C-exposed dams. Notably, destabilized VTA output specifically accompanies post-pup retrieval epochs. We suggest that gestational immunogenic insults bias both threat processing and reward perception, manifesting as disfavored infant caregiving.

Drosophila CLASP regulates microtubule orientation and dendrite pruning by suppressing Par-1 kinase.

The evolutionarily conserved CLASPs (cytoplasmic linker-associated proteins) are microtubule-associated proteins that inhibit microtubule catastrophe and promote rescue. CLASPs can regulate axonal elongation and dendrite branching in growing neurons. However, their roles in microtubule orientation and neurite pruning in remodeling neurons remain unknown. Here, we identify the Drosophila CLASP homolog Orbit/MAST, which is required for dendrite pruning in ddaC sensory neurons during metamorphosis. Orbit is important for maintenance of the minus-end-out microtubule orientation in ddaC dendrites. Our structural analysis reveals that the microtubule lattice-binding TOG2 domain is required for Orbit to regulate dendritic microtubule orientation and dendrite pruning. In a genetic modifier screen, we further identify the conserved Par-1 kinase as a suppressor of Orbit in dendritic microtubule orientation. Moreover, elevated Par-1 function impairs dendritic microtubule orientation and dendrite pruning, phenocopying orbit mutants. Overall, our study demonstrates that Drosophila CLASP governs dendritic microtubule orientation and dendrite pruning at least partly via suppressing Par-1 kinase.

HMGB1‐mediated microglial activation as a mechanism for cognitive dysfunction in neuropsychiatric lupus

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the presence of anti‐nuclear antibodies as well as a broad array of clinical manifestations spanning nearly every organ system. Neuropsychiatric syndromes affect over one half of SLE patients, presenting most commonly as cognitive dysfunction or headache. The pathophysiology of neuropsychiatric lupus is not fully understood; however, a critical mechanism has been identified, which involves passage of inflammatory cytokines and anti‐brain antibodies through the blood‐brain barrier.We previously developed a mouse model to study the effects of anti‐dsDNA antibodies that cross‐react with the NMDA receptor (NMDAR), termed DNRAbs, which are present in approximately 30% of SLE patients and whose presence in the CSF is associated with non‐focal CNS manifestations of neuropsychiatric lupus. In this mouse model, non‐spontaneously autoimmune mice are immunized with DWEYS peptide, a DNA mimotope that elicits production of DNRAb antibodies, which act as positive allosteric modulators of the NMDAR. DNRAbs only enter the brain when the blood‐brain barrier is porous; so, we administer LPS, which breaches the blood‐brain barrier in the hippocampus. In this model, we discovered two stages of brain injury. In the first stage, lasting up to a week, we observed excitotoxic neuronal death, secondary to DNRAb‐mediated NMDAR activation. In the second stage, lasting months, we identified an inflammatory homeostasis, consisting of microglial activation, loss of dendritic arborization in surviving hippocampal neurons, and neuronal secretion of HMGB1, a chromatin protein that can be secreted to act as a damage‐associated molecular pattern (DAMP). Once secreted by neurons, HMGB1 interacts with two important receptors —RAGE and TLR4 — inducing a cascade of downstream inflammatory events. In addition, HMGB1 binds to the GluN2B subunit of NMDARs and the complement component C1q, forming a molecular bridge that facilitates synaptic pruning.Here we show that HMGB1 acts directly on microglia, where it activates microglia through RAGE and TLR4 signaling. We found that HMGB1 stimulates microglia to secrete IFNa, transcriptionally upregulating interferon regulatory factors, including IRF7. We also show that IFNa secreted by microglia acts in an autocrine fashion, regulating IFN‐response genes such as MX1; IFNa also induces C3 and C1q transcription in microglia. HMGB1 also stimulates microglia to secrete TNFa and IL‐1b, which enhances the inflammatory milieu in surrounding neurons.In addition, we found that the ACE‐inhibitor captopril reverses dendritic pruning in DWEYS‐immunized mice­­ — an essential component of the second stage of DNRAb‐related damage — by regulating expression of the inhibitory receptor LAIR1 in microglia. Whereas captopril reverses dendritic pruning in DWEYS‐immunized wildtype mice, captopril has no such effect on LAIR1 knockout mice. We are currently analyzing RNA sequencing data from microglia isolated from captopril‐treated, DWEYS immunized mice, to characterize the transcriptional program responsible for this process.

Influences of Glaucoma on the Structure and Function of Synapses in the Visual System.

Significance: Glaucoma is an age-related neurodegenerative disorder of the visual system associated with sensitivity to intraocular pressure (IOP). It is the leading irreversible cause of vision loss worldwide, and vision loss results from damage and dysfunction of the retinal output neurons known as retinal ganglion cells (RGCs). Recent Advances: Elevated IOP and optic nerve injury triggers pruning of RGC dendrites, altered morphology of excitatory inputs from presynaptic bipolar cells, and disrupted RGC synaptic function. Less is known about RGC outputs, although evidence to date indicates that glaucoma is associated with altered mitochondrial and synaptic structure and function in RGC-projection targets in the brain. These early functional changes likely contribute to vision loss and might be a window into early diagnosis and treatment. Critical Issues: Glaucoma affects different RGC populations to varying extents and along distinct time courses. The influence of glaucoma on RGC synaptic function as well as the mechanisms underlying these effects remain to be determined. Since RGCs are an especially energetically demanding population of neurons, altered intracellular axon transport of mitochondria and mitochondrial function might contribute to RGC synaptic dysfunction in the retina and brain as well as RGC vulnerability in glaucoma. Future Directions: The mechanisms underlying differential RGC vulnerability remain to be determined. Moreover, the timing and mechanisms of RGCs synaptic dysfunction and degeneration will provide valuable insight into the disease process in glaucoma. Future work will be able to capitalize on these findings to better design diagnostic and therapeutic approaches to detect disease and prevent vision loss. Antioxid. Redox Signal. 37, 842-861.

Multiple Mild Stimulations Reduce Membrane Distribution of CX3CR1 Promoted by Annexin a1 in Microglia to Attenuate Excessive Dendritic Spine Pruning and Cognitive Deficits Caused by a Transient Ischemic Attack in Mice.

A transient ischemic attack (TIA) can cause reversible and delayed impairment of cognition, but the specific mechanisms are still unclear. Annexin a1 (ANXA1) is a phospholipid-binding protein. Here, we confirmed that cognition and hippocampal synapses were impaired in TIA-treated mice, and this could be rescued by multiple mild stimulations (MMS). TIA promoted the interaction of ANXA1 and CX3CR1, increased the membrane distribution of CX3CR1 in microglia, and thus enhanced the CX3CR1 and CX3CL1 interaction. These phenomena induced by TIA could be reversed by MMS. Meanwhile, the CX3CR1 membrane distribution and CX3CR1-CX3CL1 interaction were upregulated in primary cultured microglia overexpressing ANXA1, and the spine density was significantly reduced in co-cultured microglia overexpressing ANXA1 and neurons. Moreover, ANXA1 overexpression in microglia abolished the protection of MMS after TIA. Collectively, our study provides a potential strategy for treating the delayed synaptic injury caused by TIA.

Bax Contributes to Retinal Ganglion Cell Dendritic Degeneration During Glaucoma

The BCL-2 (B-cell lymphoma-2) family of proteins contributes to mitochondrial-based apoptosis in models of neurodegeneration, including glaucomatous optic neuropathy (glaucoma), which degrades the retinal ganglion cell (RGC) axonal projection to the visual brain. Glaucoma is commonly associated with increased sensitivity to intraocular pressure (IOP) and involves a proximal program that leads to RGC dendritic pruning and a distal program that underlies axonopathy in the optic projection. While genetic deletion of the Bcl2-associated X protein (Bax-/-) prolongs RGC body survival in models of glaucoma and optic nerve trauma, axonopathy persists, thus raising the question of whether dendrites and the RGC light response are protected. Here, we used an inducible model of glaucoma in Bax-/- mice to determine if Bax contributes to RGC dendritic degeneration. We performed whole-cell recordings and dye filling in RGCs signaling light onset (αON-Sustained) and offset (αOFF-Sustained). We recovered RGC dendritic morphologies by confocal microscopy and analyzed dendritic arbor complexity and size. Additionally, we assessed RGC axon function by measuring anterograde axon transport of cholera toxin subunit B to the superior colliculus and behavioral spatial frequency threshold (i.e., spatial acuity). We found 1 month of IOP elevation did not cause significant RGC death in either WT or Bax-/- retinas. However, IOP elevation reduced dendritic arbor complexity of WT αON-Sustained and αOFF-Sustained RGCs. In the absence of Bax, αON- and αOFF-Sustained RGC dendritic arbors remained intact following IOP elevation. In addition to dendrites, neuroprotection by Bax-/- generalized to αON-and αOFF-Sustained RGC light- and current-evoked responses. Both anterograde axon transport and spatial acuity declined during IOP elevation in WT and Bax-/- mice. Collectively, our results indicate Bax contributes to RGC dendritic degeneration and distinguishes the proximal and distal neurodegenerative programs involved during the progression of glaucoma.

A high-precision multi-arithmetic neural circuit for the efficient computation of the new filtered-X Kronecker product APL-NLMS algorithm applied to active noise control

In recent years, active noise control (ANC) systems have attracted a lot of attention since they are considered as potential alternative for solving acoustic noise problems. Until now, some practical ANC applications have employed filtered-x least-mean-square (FXLMS) adaptive algorithm since exhibits low computational cost, however, it provides a slow convergence speed. The filtered-x affine projection-like (FXAPL) algorithm can be seen as a potential strategy to improve this factor. However, the achievement of a significant improvement of this property and computational cost are still remaining challenges. In this work, we present a new variant of the FXAPL algorithm based on nearest Kronecker product decomposition to create an efficient algorithm in terms of convergence speed and tracking capabilities because in ANC systems is essential to cancel the noise signal as quickly as possible. In addition, we use the normalized least mean square (NLMS) to update the right-singular vectors of the adaptive filter coefficients. As consequence, the computational cost of the proposed FXAPL algorithm is decreased. From the engineering point of view, the implementation of the Kronecker product decomposition demands a large number of matrix additions, subtractions and multiplications, which represents a large area consumption. Hence, we introduce, for the first time, a new high-precision multi-arithmetic neural circuit based on spiking neural P systems along with their cutting-edge variants, such as synaptic weights, astrocyte-like controls, rules on the synapses and dendritic behavior, to perform either the addition, subtraction or multiplication of two numbers efficiently. Specifically, we use the dendritic pruning feature to enable dynamic dendritic connectivity. As a consequence, the circuit can support multiple arithmetic operations using the same neurons with simple and homogeneous spiking rules. Besides, we develop an compact FPGA-based neuromorphic architecture, which supports dynamic dendritic connectivity, to efficiently implement the proposed parallel adder/subtractor/multiplier neural circuit. Our results demonstrate that the resulting filtered-x Kronecker product affine projection-like and normalized least mean square (FXKAPL-NLMS) algorithm along with the neuromorphic architecture have allowed us to develop practical real-time ANC applications.

Altered cell and RNA isoform diversity in aging Down syndrome brains

Down syndrome (DS), trisomy of human chromosome 21 (HSA21), is characterized by lifelong cognitive impairments and the development of the neuropathological hallmarks of Alzheimer's disease (AD). The cellular and molecular modifications responsible for these effects are not understood. Here we performed single-nucleus RNA sequencing (snRNA-seq) employing both short- (Illumina) and long-read (Pacific Biosciences) sequencing technologies on a total of 29 DS and non-DS control prefrontal cortex samples. In DS, the ratio of inhibitory-to-excitatory neurons was significantly increased, which was not observed in previous reports examining sporadic AD. DS microglial transcriptomes displayed AD-related aging and activation signatures in advance of AD neuropathology, with increased microglial expression of C1q complement genes (associated with dendritic pruning) and the HSA21 transcription factor gene RUNX1 Long-read sequencing detected vast RNA isoform diversity within and among specific cell types, including numerous sequences that differed between DS and control brains. Notably, over 8,000 genes produced RNAs containing intra-exonic junctions, including amyloid precursor protein (APP) that had previously been associated with somatic gene recombination. These and related results illuminate large-scale cellular and transcriptomic alterations as features of the aging DS brain.

Neurodevelopmental Processes in the Prefrontal Cortex Derailed by Chronic HIV-1 Viral Protein Exposure.

Due to the widespread access to, and implementation of, combination antiretroviral therapy, individuals perinatally infected with human immunodeficiency virus type 1 (HIV-1) are living into adolescence and adulthood. Perinatally infected adolescents living with HIV-1 (pALHIV) are plagued by progressive, chronic neurocognitive impairments; the pathophysiological mechanisms underlying these deficits, however, remain understudied. A longitudinal experimental design from postnatal day (PD) 30 to PD 180 was utilized to establish the development of pyramidal neurons, and associated dendritic spines, from layers II-III of the medial prefrontal cortex (mPFC) in HIV-1 transgenic (Tg) and control animals. Three putative neuroinflammatory markers (i.e., IL-1β, IL-6, and TNF-α) were evaluated early in development (i.e., PD 30) as a potential mechanism underlying synaptic dysfunction in the mPFC. Constitutive expression of HIV-1 viral proteins induced prominent neurodevelopmental alterations and progressive synaptodendritic dysfunction, independent of biological sex, in pyramidal neurons from layers II-III of the mPFC. From a neurodevelopmental perspective, HIV-1 Tg rats exhibited prominent deficits in dendritic and synaptic pruning. With regards to progressive synaptodendritic dysfunction, HIV-1 Tg animals exhibited an age-related population shift towards dendritic spines with decreased volume, increased backbone length, and decreased head diameter; parameters associated with a more immature dendritic spine phenotype. There was no compelling evidence for neuroinflammation in the mPFC during early development. Collectively, progressive neuronal and dendritic spine dysmorphology herald synaptodendritic dysfunction as a key neural mechanism underlying chronic neurocognitive impairments in pALHIV.

AMPK adapts metabolism to developmental energy requirement during dendrite pruning in Drosophila.

To reshape neuronal connectivity in adult stages, Drosophila sensory neurons prune their dendrites during metamorphosis using a genetic degeneration program that is induced by the steroid hormone ecdysone. Metamorphosis is a nonfeeding stage that imposes metabolic constraints on development. We find that AMP-activated protein kinase (AMPK), a regulator of energy homeostasis, is cell-autonomously required for dendrite pruning. AMPK is activated by ecdysone and promotes oxidative phosphorylation and pyruvate usage, likely to enable neurons to use noncarbohydrate metabolites such as amino acids for energy production. Loss of AMPK or mitochondrial deficiency causes specific defects in pruning factor translation and the ubiquitin-proteasome system. Our findings distinguish pruning from pathological neurite degeneration, which is often induced by defects in energy production, and highlight how metabolism is adapted to fit energy-costly developmental transitions.

Red Light Irradiation In Vivo Upregulates DJ-1 in the Retinal Ganglion Cell Layer and Protects against Axotomy-Related Dendritic Pruning.

Retinal ganglion cells (RGCs) undergo dendritic pruning in a variety of neurodegenerative diseases, including glaucoma and autosomal dominant optic atrophy (ADOA). Axotomising RGCs by severing the optic nerve generates an acute model of RGC dendropathy, which can be utilized to assess the therapeutic potential of treatments for RGC degeneration. Photobiomodulation (PBM) with red light provided neuroprotection to RGCs when administered ex vivo to wild-type retinal explants. In the current study, we used aged (13–15-month-old) wild-type and heterozygous B6;C3-Opa1Q285STOP (Opa1+/−) mice, a model of ADOA exhibiting RGC dendropathy. These mice were pre-treated with 4 J/cm2 of 670 nm light for five consecutive days before the eyes were enucleated and the retinas flat-mounted into explant cultures for 0-, 8- or 16-h ex vivo. RGCs were imaged by confocal microscopy, and their dendritic architecture was quantified by Sholl analysis. In vivo 670 nm light pretreatment inhibited the RGC dendropathy observed in untreated wild-type retinas over 16 h ex vivo and inhibited dendropathy in ON-center RGCs in wild-type but not Opa1+/− retinas. Immunohistochemistry revealed that aged Opa1+/− RGCs exhibited increased nitrosative damage alongside significantly lower activation of NF-κB and upregulation of DJ-1. PBM restored NF-κB activation in Opa1+/− RGCs and enhanced DJ-1 expression in both genotypes, indicating a potential molecular mechanism priming the retina to resist future oxidative insult. These data support the potential of PBM as a treatment for diseases involving RGC degeneration.

A systematic analysis of microtubule-destabilizing factors during dendrite pruning in Drosophila.

It has long been thought that microtubule disassembly, one of the earliest cellular events, contributes to neuronal pruning and neurodegeneration in development and disease. However, how microtubule disassembly drives neuronal pruning remains poorly understood. Here, we conduct a systematic investigation of various microtubule-destabilizing factors and identify exchange factor for Arf6 (Efa6) and Stathmin (Stai) as new regulators of dendrite pruning in ddaC sensory neurons during Drosophila metamorphosis. We show that Efa6 is both necessary and sufficient to regulate dendrite pruning. Interestingly, Efa6 and Stai facilitate microtubule turnover and disassembly prior to dendrite pruning without compromising the minus-end-out microtubule orientation in dendrites. Moreover, our pharmacological and genetic manipulations strongly support a key role of microtubule disassembly in promoting dendrite pruning. Thus, this systematic study highlights the importance of two selective microtubule destabilizers in dendrite pruning and substantiates a causal link between microtubule disassembly and neuronal pruning.

The Nrf2-Keap1 pathway is activated by steroid hormone signaling to govern neuronal remodeling.

The evolutionarily conserved Nrf2-Keap1 pathway is a key antioxidant response pathway that protects cells/organisms against detrimental effects of oxidative stress. Impaired Nrf2 function is associated with cancer and neurodegenerative diseases in humans. However, the function of the Nrf2-Keap1 pathway in the developing nervous systems has not been established. Here we demonstrate a cell-autonomous role of the Nrf2-Keap1 pathway, composed of CncC/Nrf2, Keap1, and MafS, in governing neuronal remodeling during Drosophila metamorphosis. Nrf2-Keap1 signaling is activated downstream of the steroid hormone ecdysone. Mechanistically, the Nrf2-Keap1 pathway is activated via cytoplasmic-to-nuclear translocation of CncC in an importin- and ecdysone-signaling-dependent manner. Moreover, Nrf2-Keap1 signaling regulates dendrite pruning independent of its canonical antioxidant response pathway, acting instead through proteasomal degradation. This study reveals an epistatic link between the Nrf2-Keap1 pathway and steroid hormone signaling and demonstrates an antioxidant-independent but proteasome-dependent role of the Nrf2-Keap1 pathway in neuronal remodeling.

Neuronal VCP loss of function recapitulates FTLD-TDP pathology.

SUMMARYThe pathogenic mechanism by which dominant mutations in VCP cause multisystem proteinopathy (MSP), a rare neurodegenerative disease that presents as fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), remains unclear. To explore this, we inactivate VCP in murine postnatal forebrain neurons (VCP conditional knockout [cKO]). VCP cKO mice have cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction, and TDP-43 inclusions resembling FTLD-TDP pathology. Conditional expression of a single disease-associated mutation, VCP-R155C, in a VCP null background similarly recapitulates features of VCP inactivation and FTLD-TDP, suggesting that this MSP mutation is hypomorphic. Comparison of transcriptomic and proteomic datasets from genetically defined patients with FTLD-TDP reveal that progranulin deficiency and VCP insufficiency result in similar profiles. These data identify a loss of VCP-dependent functions as a mediator of FTLD-TDP and reveal an unexpected biochemical similarity with progranulin deficiency.

Microtubule disruption upon CNS damage triggers mitotic entry via TNF signaling activation.

Repair after traumatic injury often starts with mitotic activation around the lesion edges. Early midline cells in the Drosophila embryonic CNS can enter into division following the traumatic disruption of microtubules. We demonstrate that microtubule disruption activates non-canonical TNF signaling by phosphorylation of TGF-β activated kinase 1 (Tak1) and its target IkappaB kinase (Ik2), culminating in Dorsal/NfkappaB nuclear translocation and Jra/Jun expression. Tak1 and Ik2 are necessary for the damaged-induced divisions. Microtubule disruption caused by Tau accumulation is also reported in Alzheimer's disease (AD). Human Tau expression in Drosophila midline cells is sufficient to induce Tak1 phosphorylation, Dorsal and Jra/Jun expression, and entry into mitosis. Interestingly, activation of Tak1 and Tank binding kinase 1 (Tbk1), the human Ik2 ortholog, and NfkappaB upregulation are observed in AD brains.

Altered hippocampal dendritic spine maturation after hypoxia-induced seizures in neonatal rats

Cognitive comorbidities often follow early-life seizures (ELS), especially in the setting of autism and other neurodevelopmental syndromes. However, there is an incomplete understanding of whether neuronal and synaptic development are concomitantly dysregulated. We have previously shown that hypoxia-induced seizures (HS) in postnatal day (P)10 rats increase acute and later-life hippocampal glutamatergic neurotransmission and spontaneous recurrent seizures, and impair cognition and behavior. As dendritic spines critically regulate synaptic function, we hypothesized that ELS can induce developmentally specific changes in dendritic spine maturation. At intervals during one month following HS in P10 rats, we assessed dendritic spine development on pyramidal neurons in the stratum radiatum of hippocampal area CA1. Compared to control rats in which spine density significantly decreased from P10 to early adulthood (P38), post-seizure rats failed to show a developmental decrease in spine density, and spines from P38 post-seizure rats appeared more immature-shaped (long, thin). In addition, compared to P38 control rats, post-seizure P38 rats expressed significantly more synaptic PSD-95, a marker of mature synapses. These changes were preceded by a transient increase in hippocampal expression of cofilin phosphorylated at Ser3, representing a decrease in cofilin activity. These results suggest that early-life seizures may impair normal dendritic spine maturation and pruning in CA1 during development, resulting in an excess of less efficient synapses, via activity-dependent modification of actin-regulating proteins such as cofilin. Given that multiple neurodevelopmental disorders show similar failures in developmental spine pruning, the current findings may represent a deficit in structural plasticity that could be a component of a mechanism leading to later-life cognitive consequences associated with early-life seizures.