Role of LECT2 in exacerbating atopic dermatitis: insight from in vivo and in vitro models via NF-κB signaling pathway.

Leukocyte cell-derived chemotaxin 2 (LECT2) is linked to various immune diseases. Previously, we reported that serum LECT2 levels correlate with disease severity in atopic dermatitis (AD) patients. To investigate the role of LECT2 in AD and elucidate its potential mechanisms, we used LECT2 to treat an AD mouse model induced by 1-Chloro-2,4-dinitrobenzene (DNCB) in LECT2 knockout (KO) and wild-type (WT) mice, and an AD cell model using TNF-α/IFN-γ-induced HaCaT cells. Inflammatory factors and barrier proteins were analyzed by histology, immunohistochemistry, RT-qPCR, ELISA, and Western Blot. Activation of the NF-κB signaling pathway was evaluated by Western Blot and immunofluorescence. In the AD mouse model, LECT2 treatment increased epidermal and dermal thickness, mast cell infiltration, and downregulated barrier proteins. Inflammatory factors were increased in skin lesions and serum. In the AD cell model, LECT2 decreased barrier protein levels and increased inflammatory factor levels, enhancing NF-κB P65 nuclear translocation. These results indicate that LECT2 exacerbates AD-like responses by dysregulating the NF-κB signaling pathway, highlighting its potential as a therapeutic target for AD management.

Norditerpenoid alkaloids from Aconitum refractum var. circinatum as autophagy inducers.

A total of twenty-two diterpenoid alkaloids, including ten unprecedented ones, namely refractines C-L, were isolated from the roots of Aconitum refractum (Finet et Gagnep.) Hand.-Mazz. Refractine C was the first example of a natural diterpenoid alkaloid wherein C-19 is linked to N position by an oxaziridine ring. Refractine L was a rare glycosidic diterpenoid alkaloid with fructofuranoside. Most of the isolated compounds obtained from a previous study were screened for their anti-inflammatory and myocardial protective activities. The autophagy-inducing effects of some of these compounds on RAW 264.7 cells were evaluated by assessing the expression of microtubule-associated protein 1 light chain 3 (LC3-II/LC3-I). Results revealed that some compounds exerted varying levels of inhibitory effects on the proliferative activity of RAW 264.7 cells.

Modern techniques in addressing facial acne scars: A thorough analysis.

BACKGROUND: Facial acne scars are a prevalent concern, leading to the development of various treatment modalities. OBJECTIVES: This review aims to explore the latest advancements in the treatment of facial acne scars, focusing on both surgical and non-surgical methods. METHODS: The non-surgical treatments reviewed include topical medications (such as retinoids and alpha hydroxy acids) and non-invasive procedures (like microdermabrasion and chemical peels). Surgical options discussed are punch excision, subcision, and fractional laser treatments. RESULTS: Combination therapy, integrating both surgical and non-surgical approaches, is frequently utilized to achieve optimal results in scar improvement. CONCLUSION: Recent advancements in the treatment of facial acne scars provide promising options for individuals seeking improvement. However, these treatments have associated risks and potential adverse effects, highlighting the importance of consulting a dermatologist before beginning any treatment regimen.

USP48/USP31 Is a Nuclear Deubiquitinase that Potently Regulates Synapse Remodeling.

Deubiquitinases present locally at synapses regulate synaptic development, function, and plasticity. It remains largely unknown, however, whether deubiquitinases localized outside of the synapse control synapse remodeling. Here we identify ubiquitin specific protease 48 (USP48; formerly USP31) as a nuclear deubiquitinase mediating robust synapse removal. USP48 is expressed primarily during the first postnatal week in the rodent brain and is virtually restricted to nuclei, mediated by a conserved, 13-amino acid nuclear localization signal. When exogenously expressed, USP48, in a deubiquitinase and nuclear localization-dependent manner, induces striking filopodia elaboration, marked spine loss, and significantly reduced synaptic protein clustering in vitro, and erases ~70% of functional synapses in vivo. USP48 interacts with the transcription factor NF-κB, deubiquitinates NF-κB subunit p65 and promotes its stability and activation, and up-regulates NF-κB target genes known to inhibit synaptogenesis. Depleting NF-κB prevents USP48-dependent spine pruning. These findings identify a novel nucleus-enriched deubiquitinase that plays critical roles in synapse remodeling.

Fecal microbiota transplantation affects the recovery of AD-skin lesions and enhances gut microbiota homeostasis.

BACKGROUND: Accumulating evidence has shown that gut microbiota plays a key role in the progression of atopic dermatitis (AD). Fecal microbiota transplantation (FMT), as an effective method to restore gut microbiota homeostasis, has been successfully applied for treating many inflammatory diseases. However, the therapeutic effect of FMT on AD remains unclear. The following study examined the effect and mechanism of FMT on AD-skin lesions in an AD mouse model. METHODS: In this study, we exposed the shaved back skin of BALB/c mice to calcipotriol (MC903) to induce AD model. Mice were then treated with FMT, which was performed with gut microbiota from healthy mice. The gut microbiota of treated mice was tracked by 16S rRNA gene sequencing. Mice skin tissues were examined by histopathology and inflammatory cytokines change in serum by ELISA. RESULTS: FMT had a faster trend on the reversion of the increases in skin epidermal layer thicknesses and suppressed some of the representative inflammatory cytokines. The gut microbial community in the natural recovery process varied significantly in the FMT group at day 7 (ANOSIM P = 0.0229, r = 0.2593). Notably, FMT had a long-lasting and beneficial impact on the gut microbial compositions of AD mice by increasing the ratio of Firmicutes to Bacteroidetes and the amount of butyric-producing bacteria (BPB), including Erysipelotrichaceae, Lactobacillaceae, and Eubacteriacea. Furthermore, the relative abundances of gut microbiota-mediated functional pathways involved in the cell growth and death, amino acid, energy, lipid, and carbohydrate metabolisms, and immune system increased after FMT treatment. CONCLUSION: FMT modulated the gut microbiota homeostasis and affected the recovery from AD-related inflammations, suggesting that it could be used as a treatment strategy for AD patients in the clinic.

Mechanisms underlying pathological scarring by fibroblasts during wound healing.

Pathological scarring is an abnormal outcome of wound healing, which often manifests as excessive proliferation and transdifferentiation of fibroblasts (FBs), and excessive deposition of the extracellular matrix. FBs are the most important effector cells involved in wound healing and scar formation. The factors that promote pathological scar formation often act on the proliferation and function of FB. In this study, we describe the factors that lead to abnormal FB formation in pathological scarring in terms of the microenvironment, signalling pathways, epigenetics, and autophagy. These findings suggest that understanding the causes of abnormal FB formation may aid in the development of precise and effective preventive and treatment strategies for pathological scarring that are associated with improved quality of life of patients.

The epigenetic reader PHF21B modulates murine social memory and synaptic plasticity-related genes.

Synaptic dysfunction is a manifestation of several neurobehavioral and neurological disorders. A major therapeutic challenge lies in uncovering the upstream regulatory factors controlling synaptic processes. Plant homeodomain (PHD) finger proteins are epigenetic readers whose dysfunctions are implicated in neurological disorders. However, the molecular mechanisms linking PHD protein deficits to disease remain unclear. Here, we generated a PHD finger protein 21B-depleted (Phf21b-depleted) mutant CRISPR mouse model (hereafter called Phf21bΔ4/Δ4) to examine Phf21b's roles in the brain. Phf21bΔ4/Δ4 animals exhibited impaired social memory. In addition, reduced expression of synaptic proteins and impaired long-term potentiation were observed in the Phf21bΔ4/Δ4 hippocampi. Transcriptome profiling revealed differential expression of genes involved in synaptic plasticity processes. Furthermore, we characterized a potentially novel interaction of PHF21B with histone H3 trimethylated lysine 36 (H3K36me3), a histone modification associated with transcriptional activation, and the transcriptional factor CREB. These results establish PHF21B as an important upstream regulator of synaptic plasticity-related genes and a candidate therapeutic target for neurobehavioral dysfunction in mice, with potential applications in human neurological and psychiatric disorders.

Cylindromatosis drives synapse pruning and weakening by promoting macroautophagy through Akt-mTOR signaling.

The lysine-63 deubiquitinase cylindromatosis (CYLD) is long recognized as a tumor suppressor in immunity and inflammation, and its loss-of-function mutations lead to familial cylindromatosis. However, recent studies reveal that CYLD is enriched in mammalian brain postsynaptic densities, and a gain-of-function mutation causes frontotemporal dementia (FTD), suggesting critical roles at excitatory synapses. Here we report that CYLD drives synapse elimination and weakening by acting on the Akt-mTOR-autophagy axis. Mice lacking CYLD display abnormal sociability, anxiety- and depression-like behaviors, and cognitive inflexibility. These behavioral impairments are accompanied by excessive synapse numbers, increased postsynaptic efficacy, augmented synaptic summation, and impaired NMDA receptor-dependent hippocampal long-term depression (LTD). Exogenous expression of CYLD results in removal of established dendritic spines from mature neurons in a deubiquitinase activity-dependent manner. In search of underlying molecular mechanisms, we find that CYLD knockout mice display marked overactivation of Akt and mTOR and reduced autophagic flux, and conversely, CYLD overexpression potently suppresses Akt and mTOR activity and promotes autophagy. Consequently, abrogating the Akt-mTOR-autophagy signaling pathway abolishes CYLD-induced spine loss, whereas enhancing autophagy in vivo by the mTOR inhibitor rapamycin rescues the synaptic pruning and LTD deficits in mutant mice. Our findings establish CYLD, via Akt-mTOR signaling, as a synaptic autophagy activator that exerts critical modulations on synapse maintenance, function, and plasticity.

Distinct Aging-Vulnerable and -Resilient Trajectories of Specific Motor Circuit Functions in Oxidation- and Temperature-Stressed Drosophila.

In Drosophila, molecular pathways affecting longevity have been extensively studied. However, corresponding neurophysiological changes underlying aging-related functional and behavioral deteriorations remain to be fully explored. We examined different motor circuits in Drosophila across the life span and uncovered distinctive age-resilient and age-vulnerable trajectories in their established functional properties. In the giant fiber (GF) and downstream circuit elements responsible for the jump-and-flight escape reflex, we observed relatively mild deterioration toward the end of the life span. In contrast, more substantial age-dependent modifications were seen in the plasticity of GF afferent processing, specifically in use dependence and habituation properties. In addition, there were profound changes in different afferent circuits that drive flight motoneuron activities, including flight pattern generation and seizure spike discharges evoked by electroconvulsive stimulation. Importantly, in high-temperature (HT)-reared flies (29°C), the general trends in these age-dependent trajectories were largely maintained, albeit over a compressed time scale, lending support for the common practice of HT rearing for expediting Drosophila aging studies. We discovered that shortened life spans in Cu/Zn superoxide dismutase (Sod) mutant flies were accompanied by altered aging trajectories in motor circuit properties distinct from those in HT-reared flies, highlighting differential effects of oxidative versus temperature stressors. This work helps to identify several age-vulnerable neurophysiological parameters that may serve as quantitative indicators for assessing genetic and environmental influences on aging progression in Drosophila.

Loss of mGluR1-LTD following cocaine exposure accumulates Ca2+-permeable AMPA receptors and facilitates synaptic potentiation in the prefrontal cortex.

Addiction results from drug-elicited alterations of synaptic plasticity mechanisms in dopaminergic reward circuits. Impaired metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) and accumulation of synaptic Ca2+-permeable AMPA receptors (CP-AMPARs) following drug exposure have emerged as important mechanisms underlying drug craving and relapse. Here we show that repeated cocaine exposure in vivo causes transient but complete loss of mGluR1- and mTOR (mammalian target of rapamycin)-dependent LTD in layer 5 pyramidal neurons of mouse prefrontal cortex (PFC), a major dopaminergic target in the reward circuitry. This mGluR1-LTD impairment was prevented by in vivo administration of an mGluR1 positive allosteric modulator (PAM) and rescued by inhibition of dopamine D1 receptors, suggesting that impaired mGluR1 tone and excessive D1 signaling underlie this LTD deficit. Concurrently, CP-AMPARs were generated, indicated by increased sensitivity to the CP-AMPAR inhibitor Naspm and rectification of synaptic AMPAR currents, which were reversed by PAM in cocaine-exposed mice. Finally, these CP-AMPARs mediate an abnormal spike-timing-dependent long-term potentiation enabled by cocaine exposure. Our findings reveal a mechanism by which cocaine impairs LTD and remodels synaptic AMPARs to influence Hebbian plasticity in the PFC. Failure to undergo LTD may prevent the reversal of drug-potentiated brain circuits to their baseline states, perpetuating addictive behaviors.HIGHLIGHTSA mGluR1- and mTOR-dependent LTD is present in the mouse medial prefrontal cortex.Repeated cocaine exposure in vivo temporally but completely abolishes prefrontal mGluR1-LTD.Impaired mGluR1 function and excessive D1 DA signaling likely underlie cocaine impairment of mGluR1-LTD.Ca2+-permeable AMPA receptors are generated by cocaine exposure, likely resulting from mGluR1-LTD impairment, and contribute to a cocaine-induced extended spike timing LTP.

Transcription factor POU3F2 regulates TRIM8 expression contributing to cellular functions implicated in schizophrenia.

Schizophrenia (SCZ) is a neuropsychiatric disorder with aberrant expression of multiple genes. However, identifying its exact causal genes remains a considerable challenge. The brain-specific transcription factor POU3F2 (POU domain, class 3, transcription factor 2) has been recognized as a risk factor for SCZ, but our understanding of its target genes and pathogenic mechanisms are still limited. Here we report that POU3F2 regulates 42 SCZ-related genes in knockdown and RNA-sequencing experiments of human neural progenitor cells (NPCs). Among those SCZ-related genes, TRIM8 (Tripartite motif containing 8) is located in SCZ-associated genetic locus and is aberrantly expressed in patients with SCZ. Luciferase reporter and electrophoretic mobility shift assays (EMSA) showed that POU3F2 induces TRIM8 expression by binding to the SCZ-associated SNP (single nucleotide polymorphism) rs5011218, which affects POU3F2-binding efficiency at the promoter region of TRIM8. We investigated the cellular functions of POU3F2 and TRIM8 as they co-regulate several pathways related to neural development and synaptic function. Knocking down either POU3F2 or TRIM8 promoted the proliferation of NPCs, inhibited their neuronal differentiation, and impaired the excitatory synaptic transmission of NPC-derived neurons. These results indicate that POU3F2 regulates TRIM8 expression through the SCZ-associated SNP rs5011218, and both genes may be involved in the etiology of SCZ by regulating neural development and synaptic function.

The ubiquitin-editing enzyme A20 regulates synapse remodeling and efficacy.

Ubiquitination and its reverse process, deubiquitination, play essential roles in neural development, function, and plasticity. A20, a ubiquitin editing enzyme that can remove K63-polyubiquitin chains from substrates and attach K48-polyubiquitin chains to them, is a critical component in the NF-κB signaling pathway in the immune system. This dual ubiquitin enzyme is also present in mammalian brains, but its potential role in neurons and synapses is unknown. We show that A20 in pyramidal neurons potently regulates dendritic arborization, spine morphogenesis, and synaptic transmission through an NF-κB-dependent mechanism. In cultured hippocampal neurons, overexpression of A20 reduced dendritic complexity and spine size and density, whereas A20 knockdown increased spine size and density, as well as clustering of the postsynaptic scaffold PSD-95 and glutamate receptor subunit GluA1. A20 effects in vitro were recapitulated in vivo where increasing or decreasing A20 expression in mouse brains reduced and enhanced spine density, respectively. Functionally, A20 knockdown significantly increased the amplitude, but not frequency of miniature excitatory postsynaptic currents, suggesting a role in postsynaptic efficacy. A20 negatively regulated NF-κB activation in neurons and A20 mutants deficient in either the deubiquitinase or the ubiquitin ligase activity failed to suppress NF-κB activation or reduce spine morphogenesis. Finally, selective inhibition of NF-κB abolished A20 knockdown-elicited spine formation, suggesting that A20 exerts its modulation on synapses through NF-κB signaling. Together, our study reveals a previously unknown role for A20, the only known ubiquitin editing enzyme with both deubiquitinase and ubiquitin ligase activity, in dendritic arborization, spine remodeling, and synaptic plasticity.

Generation and characterization of new alleles of quiver (qvr) that encodes an extracellular modulator of the Shaker potassium channel.

Our earlier genetic screen uncovered a paraquat-sensitive leg-shaking mutant quiver1 (qvr1), whose gene product interacts with the Shaker (Sh) K+ channel. We also mapped the qvr locus to EY04063 and noticed altered day-night activity patterns in these mutants. Such circadian behavioral defects were independently reported by another group, who employed the qvr1 allele we supplied them, and attributed the extreme restless phenotype of EY04063 to the qvr gene. However, their report adopted a new noncanonical gene name sleepless (sss) for qvr. In addition to qvr1 and qvrEY, our continuous effort since the early 2000s generated a number of novel recessive qvr alleles, including ethyl methanesulfonate (EMS)-induced mutations qvr2 and qvr3, and P-element excision lines qvrip6 (imprecise jumpout), qvrrv7, and qvrrv9 (revertants) derived from qvrEY. Distinct from the original intron-located qvr1 allele that generates abnormal-sized mRNAs, qvr2, and qvr3 had their lesion sites in exons 6 and 7, respectively, producing nearly normal-sized mRNA products. A set of RNA-editing sites are nearby the lesion sites of qvr3 and qvrEY on exon 7. Except for the revertants, all qvr alleles display a clear ether-induced leg-shaking phenotype just like Sh, and weakened climbing abilities to varying degrees. Unlike Sh, all shaking qvr alleles (except for qvrf01257) displayed a unique activity-dependent enhancement in excitatory junction potentials (EJPs) at larval neuromuscular junctions (NMJs) at very low stimulus frequencies, with qvrEY displaying the largest EJP and more significant NMJ overgrowth than other alleles. Our detailed characterization of a collection of qvr alleles helps to establish links between novel molecular lesions and different behavioral and physiological consequences, revealing how modifications of the qvr gene lead to a wide spectrum of phenotypes, including neuromuscular hyperexcitability, defective motor ability and activity-rest cycles.

Proteasome-independent polyubiquitin linkage regulates synapse scaffolding, efficacy, and plasticity.

Ubiquitination-directed proteasomal degradation of synaptic proteins, presumably mediated by lysine 48 (K48) of ubiquitin, is a key mechanism in synapse and neural circuit remodeling. However, more than half of polyubiquitin (polyUb) species in the mammalian brain are estimated to be non-K48; among them, the most abundant is Lys 63 (K63)-linked polyUb chains that do not tag substrates for degradation but rather modify their properties and activity. Virtually nothing is known about the role of these nonproteolytic polyUb chains at the synapse. Here we report that K63-polyUb chains play a significant role in postsynaptic protein scaffolding and synaptic strength and plasticity. We found that the postsynaptic scaffold PSD-95 (postsynaptic density protein 95) undergoes K63 polyubiquitination, which markedly modifies PSD-95's scaffolding potentials, enables its synaptic targeting, and promotes synapse maturation and efficacy. TNF receptor-associated factor 6 (TRAF6) is identified as a direct E3 ligase for PSD-95, which, together with the E2 complex Ubc13/Uev1a, assembles K63-chains on PSD-95. In contrast, CYLD (cylindromatosis tumor-suppressor protein), a K63-specific deubiquitinase enriched in postsynaptic densities, cleaves K63-chains from PSD-95. We found that neuronal activity exerts potent control of global and synaptic K63-polyUb levels and, through NMDA receptors, drives rapid, CYLD-mediated PSD-95 deubiquitination, mobilizing and depleting PSD-95 from synapses. Silencing CYLD in hippocampal neurons abolishes NMDA-induced chemical long-term depression. Our results unveil a previously unsuspected role for nonproteolytic polyUb chains in the synapse and illustrate a mechanism by which a PSD-associated K63-linkage-specific ubiquitin machinery acts on a major postsynaptic scaffold to regulate synapse organization, function, and plasticity.

Cocaine Promotes Coincidence Detection and Lowers Induction Threshold during Hebbian Associative Synaptic Potentiation in Prefrontal Cortex.

Addictive drugs usurp neural plasticity mechanisms that normally serve reward-related learning and memory, primarily by evoking changes in glutamatergic synaptic strength in the mesocorticolimbic dopamine circuitry. Here, we show that repeated cocaine exposure in vivo does not alter synaptic strength in the mouse prefrontal cortex during an early period of withdrawal, but instead modifies a Hebbian quantitative synaptic learning rule by broadening the temporal window and lowers the induction threshold for spike-timing-dependent LTP (t-LTP). After repeated, but not single, daily cocaine injections, t-LTP in layer V pyramidal neurons is induced at +30 ms, a normally ineffective timing interval for t-LTP induction in saline-exposed mice. This cocaine-induced, extended-timing t-LTP lasts for ∼1 week after terminating cocaine and is accompanied by an increased susceptibility to potentiation by fewer pre-post spike pairs, indicating a reduced t-LTP induction threshold. Basal synaptic strength and the maximal attainable t-LTP magnitude remain unchanged after cocaine exposure. We further show that the cocaine facilitation of t-LTP induction is caused by sensitized D1-cAMP/protein kinase A dopamine signaling in pyramidal neurons, which then pathologically recruits voltage-gated l-type Ca2+ channels that synergize with GluN2A-containing NMDA receptors to drive t-LTP at extended timing. Our results illustrate a mechanism by which cocaine, acting on a key neuromodulation pathway, modifies the coincidence detection window during Hebbian plasticity to facilitate associative synaptic potentiation in prefrontal excitatory circuits. By modifying rules that govern activity-dependent synaptic plasticity, addictive drugs can derail the experience-driven neural circuit remodeling process important for executive control of reward and addiction. SIGNIFICANCE STATEMENT: It is believed that addictive drugs often render an addict's brain reward system hypersensitive, leaving the individual more susceptible to relapse. We found that repeated cocaine exposure alters a Hebbian associative synaptic learning rule that governs activity-dependent synaptic plasticity in the mouse prefrontal cortex, characterized by a broader temporal window and a lower threshold for spike-timing-dependent LTP (t-LTP), a cellular form of learning and memory. This rule change is caused by cocaine-exacerbated D1-cAMP/protein kinase A dopamine signaling in pyramidal neurons that in turn pathologically recruits l-type Ca2+ channels to facilitate coincidence detection during t-LTP induction. Our study provides novel insights on how cocaine, even with only brief exposure, may prime neural circuits for subsequent experience-dependent remodeling that may underlie certain addictive behavior.

MicroRNA miR124 is required for the expression of homeostatic synaptic plasticity.

Homeostatic synaptic plasticity is a compensatory response to alterations in neuronal activity. Chronic deprivation of neuronal activity results in an increase in synaptic AMPA receptors (AMPARs) and postsynaptic currents. The biogenesis of GluA2-lacking, calcium-permeable AMPARs (CP-AMPARs) plays a crucial role in the homeostatic response; however, the mechanisms leading to CP-AMPAR formation remain unclear. Here we show that the microRNA, miR124, is required for the generation of CP-AMPARs and homeostatic plasticity. miR124 suppresses GluA2 expression via targeting its 3'-UTR, leading to the formation of CP-AMPARs. Blockade of miR124 function abolishes the homeostatic response, whereas miR124 overexpression leads to earlier induction of homeostatic plasticity. miR124 transcription is controlled by an inhibitory transcription factor EVI1, acting by association with the deacetylase HDAC1. Our data support a cellular cascade in which inactivity relieves EVI1/HDAC-mediated inhibition of miR124 gene transcription, resulting in enhanced miR124 expression, formation of CP-AMPARs and subsequent induction of homeostatic synaptic plasticity.

[System Design of a Medical Constnt Temperature Flushing Pump].

The flushing pump which is applied to clean operative wound has no temperature controlling function up to now, and doctors have to prepare the flushing fluid that has previously been warmed. The flushing pump system with medical constant temperature designed in our laboratory can absorb flushing fluid at the room temperature, and then eject flushing fluid with the temperature in accordance with the requirements of operations at a controlled constant flow rate. The system combines flow rate control with temperature control functions. The flushing pump system includes flushing part, temperature controlling part, key inputting part, liquid crystal displaying part and exceptional situation monitoring part. The present paper introduces the design method and principle of each part of the system at first, and then gives the debug method of all the system parameters. Finally the paper discusses the performance of the system according to the result of the experiment.

Neuronal Kmt2a/Mll1 histone methyltransferase is essential for prefrontal synaptic plasticity and working memory.

Neuronal histone H3-lysine 4 methylation landscapes are defined by sharp peaks at gene promoters and other cis-regulatory sequences, but molecular and cellular phenotypes after neuron-specific deletion of H3K4 methyl-regulators remain largely unexplored. We report that neuronal ablation of the H3K4-specific methyltransferase, Kmt2a/Mixed-lineage leukemia 1 (Mll1), in mouse postnatal forebrain and adult prefrontal cortex (PFC) is associated with increased anxiety and robust cognitive deficits without locomotor dysfunction. In contrast, only mild behavioral phenotypes were observed after ablation of the Mll1 ortholog Kmt2b/Mll2 in PFC. Impaired working memory after Kmt2a/Mll1 ablation in PFC neurons was associated with loss of training-induced transient waves of Arc immediate early gene expression critical for synaptic plasticity. Medial prefrontal layer V pyramidal neurons, a major output relay of the cortex, demonstrated severely impaired synaptic facilitation and temporal summation, two forms of short-term plasticity essential for working memory. Chromatin immunoprecipitation followed by deep sequencing in Mll1-deficient cortical neurons revealed downregulated expression and loss of the transcriptional mark, trimethyl-H3K4, at <50 loci, including the homeodomain transcription factor Meis2. Small RNA-mediated Meis2 knockdown in PFC was associated with working memory defects similar to those elicited by Mll1 deletion. Therefore, mature prefrontal neurons critically depend on maintenance of Mll1-regulated H3K4 methylation at a subset of genes with an essential role in cognition and emotion.

Alterations in microRNA-124 and AMPA receptors contribute to social behavioral deficits in frontotemporal dementia.

Neurodegenerative diseases, such as frontotemporal dementia (FTD), are often associated with behavioral deficits, but the underlying anatomical and molecular causes remain poorly understood. Here we show that forebrain-specific expression of FTD-associated mutant CHMP2B in mice causes several age-dependent neurodegenerative phenotypes, including social behavioral impairments. The social deficits were accompanied by a change in AMPA receptor (AMPAR) composition, leading to an imbalance between Ca(2+)-permeable and Ca(2+)-impermeable AMPARs. Expression of most AMPAR subunits was regulated by the brain-enriched microRNA miR-124, whose abundance was markedly decreased in the superficial layers of the cerebral cortex of mice expressing the mutant CHMP2B. We found similar changes in miR-124 and AMPAR levels in the frontal cortex and induced pluripotent stem cell-derived neurons from subjects with behavioral variant FTD. Moreover, ectopic miR-124 expression in the medial prefrontal cortex of mutant mice decreased AMPAR levels and partially rescued behavioral deficits. Knockdown of the AMPAR subunit Gria2 also alleviated social impairments. Our results identify a previously undescribed mechanism involving miR-124 and AMPARs in regulating social behavior in FTD and suggest a potential therapeutic avenue.

Dopamine-enabled anti-Hebbian timing-dependent plasticity in prefrontal circuitry.

Spike timing-dependent plasticity (STDP) of glutamatergic synapses is a Hebbian associative plasticity that may underlie certain forms of learning. A cardinal feature of STDP is its dependence on the temporal order of presynaptic and postsynaptic spikes during induction: pre-post (positive) pairings induce t-LTP (timing-dependent long-term potentiation) whereas post-pre (negative) pairings induce t-LTD (timing-dependent long-term depression). Dopamine (DA), a reward signal for behavioral learning, is believed to exert powerful modulations on synapse strength and plasticity, but its influence on STDP has remained incompletely understood. We previously showed that DA extends the temporal window of t-LTP in the prefrontal cortex (PFC) from +10 to +30 ms, gating Hebbian t-LTP. Here, we examined DA modulation of synaptic plasticity induced at negative timings in layer V pyramidal neurons on mouse medial PFC slices. Using a negative timing STDP protocol (60 post-pre pairings at 0.1 Hz, δt = -30 ms), we found that DA applied during post-pre pairings did not produce LTD, but instead enabled robust LTP. This anti-Hebbian t-LTP depended on GluN2B-containing NMDA receptors. Blocking D1- (D1Rs), but not D2- (D2Rs) class DA receptors or disrupting cAMP/PKA signaling in pyramidal neurons also abolished this atypical t-LTP, indicating that it was mediated by postsynaptic D1R-cAMP/PKA signaling in excitatory synapses. Unlike DA-enabled Hebbian t-LTP that requires suppression of GABAergic inhibition and cooperative actions of both D1Rs and D2Rs in separate PFC excitatory and inhibitory circuits, DA-enabled anti-Hebbian t-LTP occurred under intact inhibitory transmission and only required D1R activation in excitatory circuit. Our results establish DA as a potent modulator of coincidence detection during associative synaptic plasticity and suggest a mechanism by which DA facilitates input-target association during reward learning and top-down information processing in PFC circuits.