In Silico Analyses of Vertebrate G-Protein-Coupled Receptor Fusions United With or Without an Additional Transmembrane Sequence Indicate Classification into Three Groups of Linkers.

Natural G-protein-coupled receptors (GPCRs) rarely have an additional transmembrane (TM) helix, such as an artificial TM-linker that can unite two class A GPCRs in tandem as a single-polypeptide chain (sc). Here, we report that three groups of TM-linkers exist in the intervening regions of natural GPCR fusions from vertebrates: (1) the original consensus (i.e., consensus 1) and consensus 2~4 (related to GPCR itself or its receptor-interacting proteins); (2) the consensus but GPCR-unrelated ones, 1~7; and (3) the inability to apply 1/2 that show no similarity to any other proteins. In silico analyses indicated that all natural GPCR fusions from Amphibia lack a TM-linker, and reptiles have no GPCR fusions; moreover, in either the GPCR-GPCR fusion or fusion protein of (GPCR monomer) and non-GPCR proteins from vertebrates, excluding tetrapods, i.e., so-called fishes, TM-linkers differ from previously reported mammalian and are avian sequences and are classified as Groups 2 and 3. Thus, previously reported TM-linkers were arranged: Consensus 1 is [T(I/A/P)(A/S)-(L/N)(I/W/L)(I/A/V)GL(L/G)(A/T)(S/L/G)(I/L)] first identified in invertebrate sea anemone Exaiptasia diaphana (LOC110241027) and (330-SPSFLCI-L-SLL-340) identified in a tropical bird Opisthocomus hoazin protein LOC104327099 (XP_009930279.1); GPCR-related consensus 2~4 are, respectively, (371-prlilyavfc fgtatg-386) in the desert woodrat Neotoma lepida A6R68_19462 (OBS78147.1), (363-lsipfcll yiaallgnfi llfvi-385) in Gavia stellate (red-throated loon) LOC104264164 (XP_009819412.1), and (479-ti vvvymivcvi glvgnflvmy viir-504) in a snailfish GPCR (TNN80062.1); In Mammals Neotoma lepida, Aves Erythrura gouldiae, and fishes protein (respectively, OBS83645.1, RLW13346.1 and KPP79779.1), the TM-linkers are Group 2. Here, we categorized, for the first time, natural TM-linkers as rare evolutionary events among all vertebrates.

Disease specific brain capillary angiopathy in schizophrenia, bipolar disorder, and Alzheimer's disease.

Schizophrenia (SZ) and bipolar disorder (BD), which are both psychiatric disorders, share some common clinical evidence. We recently discovered that brain capillary angiopathy is another common feature of these psychiatric disorders using fibrin accumulation in vascular endothelial cells as an indicator. This study aimed to characterize the similarities and differences in cerebral capillary injuries in various brain diseases to provide new diagnostic methods for SZ and BD and to develop new therapeutic strategies. We evaluated whether discrepancies exist in the degree of vascular damage among SZ and BD and other brain disorders (amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD)) using postmortem brains. Our results demonstrate that fibrin was strongly accumulated in the capillaries of the grey matter (GM) of brains of patients with SZ and AD and in the capillaries of the white matter (WM) in those of patients with SZ, BD, and AD when compared with control subjects without any psychiatric or neurological disease history. However, ALS and PD brains did not present a significant increase in the amount of accumulated fibrin, either in the capillaries of WM or GM. Furthermore, significant leakage of fibrin into the brain parenchyma, indicating a vascular physical disruption, was observed in the brains of patients with AD but not in the brains of other patients compared with control subjects. In conclusion, our work reveals that Fibrin-accumulation in the brain capillaries are observed in psychiatric disorders, such as SZ, BD, and AD. Furthermore, fibrin-accumulating, nonbreaking type angiopathy is characteristic of SZ and BD, even though there are regional differences between these diseases.

Serotonergic neurons control cortical neuronal intracellular energy dynamics by modulating astrocyte-neuron lactate shuttle.

The central serotonergic system has multiple roles in animal physiology and behavior, including sleep-wake control. However, its function in controlling brain energy metabolism according to the state of animals remains undetermined. Through in vivo monitoring of energy metabolites and signaling, we demonstrated that optogenetic activation of raphe serotonergic neurons increased cortical neuronal intracellular concentration of ATP, an indispensable cellular energy molecule, which was suppressed by inhibiting neuronal uptake of lactate derived from astrocytes. Raphe serotonergic neuronal activation induced cortical astrocytic Ca2+ and cAMP surges and increased extracellular lactate concentrations, suggesting the facilitation of lactate release from astrocytes. Furthermore, chemogenetic inhibition of raphe serotonergic neurons partly attenuated the increase in cortical neuronal intracellular ATP levels as arousal increased in mice. Serotonergic neuronal activation promoted an increase in cortical neuronal intracellular ATP levels, partly mediated by the facilitation of the astrocyte-neuron lactate shuttle, contributing to state-dependent optimization of neuronal intracellular energy levels.

The mouse model of intellectual disability by ZBTB18/RP58 haploinsufficiency shows cognitive dysfunction with synaptic impairment.

ZBTB18/RP58 (OMIM *608433) is one of the pivotal genes responsible for 1q43q44 microdeletion syndrome (OMIM #612337) and its haploinsufficiency induces intellectual disability. However, the underlying pathological mechanism of ZBTB18/RP58 haploinsufficiency is unknown. In this study, we generated ZBTB18/RP58 heterozygous mice and found that these mutant mice exhibit multiple behavioral deficits, including impairment in motor learning, working memory, and memory flexibility, which are related to behaviors in people with intellectual disabilities, and show no gross abnormalities in their cytoarchitectures but dysplasia of the corpus callosum, which has been reported in certain population of patients with ZBTB18 haploinsufficiency as well as in those with 1q43q44 microdeletion syndrome, indicating that these mutant mice are a novel model of ZBTB18/RP58 haploinsufficiency, which reflects heterozygotic ZBTB18 missense, truncating variants and some phenotypes of 1q43q44 microdeletion syndrome based on ZBTB18/RP58 haploinsufficiency. Furthermore, these mice show glutamatergic synaptic dysfunctions, including a reduced glutamate receptor expression, altered properties of NMDA receptor-mediated synaptic responses, a decreased saturation level of long-term potentiation of excitatory synaptic transmission, and distinct morphological characteristics of the thick-type spines. Therefore, these results suggest that ZBTB18/RP58 haploinsufficiency leads to impaired excitatory synaptic maturation, which in turn results in cognitive dysfunction in ZBTB18 haploinsufficiency.

GAD67-mediated GABA Synthesis and Signaling Impinges on Directing Basket Cell Axonal Projections Toward Purkinje Cells in the Cerebellum.

Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the central nervous system, synthesized by two isoforms of glutamate decarboxylase (GAD): GAD65 and GAD67. GABA may act as a trophic factor during brain development, but its contribution to the development and maturation of cerebellar neural circuits is not known. To understand the roles of GABA in cerebellar organization and associated functions in motor coordination and balance, we examined GAD65 conventional knock out (KO) mice and mice in which GAD67 was eliminated in parvalbumin-expressing neurons (PV-Cre; GAD67flox/flox mice). We found aberrant subcellular localization of the Shaker-type K channel Kv1.1 in basket cell collaterals of PV-Cre; GAD67 flox/flox mice and abnormal projections from basket cells to Purkinje cells in both mouse strains. We also found that altered synaptic properties of basket cell terminals to Purkinje cells in PV-Cre; GAD67flox/flox mice. Furthermore, PV-Cre; GAD67 flox/flox mice exhibited abnormal motor coordination in the rotarod test. These results indicate that GABA signaling in the cerebellum is critical for establishing appropriate connections between basket cells and Purkinje cells and is associated with motor coordination in mice.

High-sucrose diets contribute to brain angiopathy with impaired glucose uptake and psychosis-related higher brain dysfunctions in mice.

Metabolic dysfunction is thought to contribute to the severity of psychiatric disorders; however, it has been unclear whether current high­simple sugar diets contribute to pathogenesis of these diseases. Here, we demonstrate that a high-sucrose diet during adolescence induces psychosis-related behavioral endophenotypes, including hyperactivity, poor working memory, impaired sensory gating, and disrupted interneuron function in mice deficient for glyoxalase-1 (GLO1), an enzyme involved in detoxification of sucrose metabolites. Furthermore, the high-sucrose diet induced microcapillary impairments and reduced brain glucose uptake in brains of Glo1-deficient mice. Aspirin protected against this angiopathy, enhancing brain glucose uptake and preventing abnormal behavioral phenotypes. Similar vascular damage to our model mice was found in the brains of randomly collected schizophrenia and bipolar disorder patients, suggesting that psychiatric disorders are associated with angiopathy in the brain caused by various environmental stresses, including metabolic stress.

Nervous system regulated by POZ domain Krüppel-like zinc finger (POK) family transcription repressor RP58.

The POZ domain Krüppel-like zinc finger transcription repressor (POK family) contains many important molecules, including RP58, Bcl6 and PLZF. They function as transcription repressors via chromatin remodelling and histone deacetylation and are known to be involved in the development and tumourigenesis of various organs. Furthermore, they are important in the formation and function of the nervous system. This review summarizes the role of the POK family transcription repressors in the nervous system. We particularly targeted Rp58 (also known as Znf238, Znp238 and Zbtb18), a sequence-specific transcriptional repressor that is strongly expressed in developing glutamatergic projection neurons in the cerebral cortex. It regulates various physiological processes, including neuronal production, neuronal migration and neuronal maturation. Human studies suggest that reduced RP58 levels are involved in cognitive function impairment and brain tumour formation. This review particularly focuses on the mechanisms underlying RP58-mediated neuronal development and function. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.4/issuetoc.

Early-life stress induces the development of Alzheimer's disease pathology via angiopathy.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is a major societal, scientific, and economic problem. Several early-life factors associated with an increased risk for the clinical diagnosis of AD have recently been identified. In the present study, we investigated the involvement of early-life stress in the pathogenesis of AD using heterozygous amyloid precursor protein (APP) mutant mice (AppNL-G-F/wt) and wild-type (Appwt/wt) mice. We found that maternal-separated Appwt/wt mice showed narrowing of vessels and decreased pericyte coverage of capillaries in the prefrontal cortex, while maternal-separated AppNL-G-F/wt mice additionally showed the impairment of cognitive function, earlier formation of Aß plaques, increased vessel-associated microglia, and disruption of the blood-brain barrier. Substantial activation of microglia was detected in the maternal-separated AppNL-G-F/wt mice and maternal-separated Appwt/wt mice. At an early stage, morphological changes and inflammatory responses were observed in the microglia of the maternal-separated AppNL-G-F/wt mice and maternal-separated Appwt/wt mice, and morphological changes in the microglia were observed in the non-maternal-separated AppNL-G-F/wt mice. Microglia activation induced by maternal separation in combination with the APP mutation may impair the vascular system, leading to AD progression. These findings therefore suggest that maternal separation results in the early induction of AD-related pathology via angiopathy.

Corticobasal ganglia projecting neurons are required for juvenile vocal learning but not for adult vocal plasticity in songbirds.

Birdsong, like human speech, consists of a sequence of temporally precise movements acquired through vocal learning. The learning of such sequential vocalizations depends on the neural function of the motor cortex and basal ganglia. However, it is unknown how the connections between cortical and basal ganglia components contribute to vocal motor skill learning, as mammalian motor cortices serve multiple types of motor action and most experimentally tractable animals do not exhibit vocal learning. Here, we leveraged the zebra finch, a songbird, as an animal model to explore the function of the connectivity between cortex-like (HVC) and basal ganglia (area X), connected by HVC(X) projection neurons with temporally precise firing during singing. By specifically ablating HVC(X) neurons, juvenile zebra finches failed to copy tutored syllable acoustics and developed temporally unstable songs with less sequence consistency. In contrast, HVC(X)-ablated adults did not alter their learned song structure, but generated acoustic fluctuations and responded to auditory feedback disruption by the introduction of song deterioration, as did normal adults. These results indicate that the corticobasal ganglia input is important for learning the acoustic and temporal aspects of song structure, but not for generating vocal fluctuations that contribute to the maintenance of an already learned vocal pattern.

Zfp238 Regulates the Thermogenic Program in Cooperation with Foxo1.

Obesity has become an explicit public health concern because of its relevance to metabolic syndrome. Evidence points to the significance of beige adipocytes in regulating energy expenditure. Here, using yeast two-hybrid screening, we show that Zfp238 is a Foxo1 co-repressor and that adipose-tissue-specific ablation of Zfp238 (Adipo-Zfp238KO) in mice leads to obesity, decreased energy expenditure, and insulin resistance under normal chow diet. Adipo-Zfp238KO inhibits induction of Ucp1 expression in subcutaneous adipose tissue upon cold exposure or CL316243, but not in brown adipose tissue. Furthermore, knockdown of Zfp238 in 3T3-L1 cells decreases Ucp1 expression in response to cool incubation or forskolin significantly compared with control cells. In contrast, overexpression of Zfp238 in 3T3-L1 cells significantly increases Ucp1 expression in response to forskolin. Finally, double knockdown of both Zfp238 and Foxo1 normalizes Ucp1 induction. These data suggest that Zfp238 in adipose tissue regulates the thermogenic program in cooperation with Foxo1.

Regulation of brain development and brain function by the transcriptional repressor RP58.

The mechanisms regulating the formation of the cerebral cortex have been well studied. In the developing cortex, (also known Znf238, Zfp238, and Zbtb18), which encodes a sequence-specific transcriptional repressor, is expressed in glutamatergic projection neurons and progenitor cells. Targeted deletion of Rp58 leads to dysplasia of the neocortex and hippocampus, a reduction in the number of mature cortical neurons, and defects in laminar organization due to abnormal neuronal migration within the cortical plate. During late embryogenesis, Rp58-deficient mice have larger numbers of progenitor cells due to a delay in cell cycle exit. RP58 represses all four Id genes (Id1-Id4), which regulate cell cycle exit in the developing cerebral cortex, and is essential for transcriptional repression of Ngn2 and Rnd2, which regulate the multipolar-to-bipolar transition during neuronal migration independently of its role in cell cycle exit.

Recruitment of calbindin into nigral dopamine neurons protects against MPTP-Induced parkinsonism.

BACKGROUND: Parkinson's disease is caused by dopamine deficiency in the striatum, which is a result of loss of dopamine neurons from the substantia nigra pars compacta. There is a consensus that a subpopulation of nigral dopamine neurons that expresses the calcium-binding protein calbindin is selectively invulnerable to parkinsonian insults. The objective of the present study was to test the hypothesis that dopamine neuron degeneration might be prevented by viral vector-mediated gene delivery of calbindin into the dopamine neurons that do not normally contain it. METHODS: A calbindin-expressing adenoviral vector was injected into the striatum of macaque monkeys to be conveyed to cell bodies of nigral dopamine neurons through retrograde axonal transport, or the calbindin-expressing lentiviral vector was injected into the nigra directly because of its predominant uptake from cell bodies and dendrites. The animals in which calbindin was successfully recruited into nigral dopamine neurons were administered systemically with MPTP. RESULTS: In the monkeys that had received unilateral vector injections, parkinsonian motor deficits, such as muscular rigidity and akinesia/bradykinesia, appeared predominantly in the limbs corresponding to the non-calbindin-recruited hemisphere after MPTP administration. Data obtained from tyrosine hydroxylase immunostaining and PET imaging for the dopamine transporter revealed that the nigrostriatal dopamine system was preserved better on the calbindin-recruited side. Conversely, on the non-calbindin-recruited control side, many more dopamine neurons expressed α-synuclein. CONCLUSIONS: The present results indicate that calbindin recruitment into nigral dopamine neurons protects against the onset of parkinsonian insults, thus providing a novel approach to PD prevention. © 2018 International Parkinson and Movement Disorder Society.

Maternal diabetes in early pregnancy, and psychotic experiences and depressive symptoms in 10-year-old offspring: A population-based birth cohort study.

Epidemiological studies have suggested that maternal diabetes in pregnancy increases the risk of schizophrenia in offspring. A recent cohort study observed that maternal diabetes in early pregnancy is also associated with psychotic experiences in the general adolescent population. However, it remains unclear whether maternal diabetes in early pregnancy is specifically associated with psychotic experiences, or is generally associated with broader mental health problems, including depressive symptoms in adolescence. The present study investigated the longitudinal associations between maternal diabetes in early pregnancy, and psychotic experiences and depressive symptoms in 10-year-old offspring. Our data were derived from the Tokyo Early Adolescence Survey, a population-based survey of early adolescents (N = 4478) and their primary caregivers. Diabetes in early pregnancy was determined by records in the mother's Maternal and Child Health Handbook, documented during the pregnancy. Psychotic experiences and depressive symptoms were established through self-report by the offspring at 10 years of age. Diabetes in early pregnancy was associated with an increased risk of hallucination in the offspring (auditory hallucination [odds ratio {OR} 4.33, 95% confidence interval {CI} 1.12-16.75]; visual hallucination [OR 6.58, 95% CI 1.69-25.66]), even after adjusting for depressive symptoms and other covariates. However, the association between maternal diabetes and delusional thoughts was not significant and diabetes in early pregnancy was not associated with adolescent depressive symptoms. Our investigation suggests that maternal diabetes in early pregnancy may specifically affect the risk of hallucinatory experiences in adolescent offspring.

Developmental Roles and Evolutionary Significance of AMPA-Type Glutamate Receptors.

Organogenesis and metamorphosis require the intricate orchestration of multiple types of cellular interactions and signaling pathways. Glutamate (Glu) is an excitatory extracellular signaling molecule in the nervous system, while Ca2+ is a major intracellular signaling molecule. The first Glu receptors to be cloned are Ca2+ -permeable receptors in mammalian brains. Although recent studies have focused on Glu signaling in synaptic mechanisms of the mammalian central nervous system, it is unclear how this signaling functions in development. Our recent article demonstrated that Ca2+ -permeable AMPA-type Glu receptors (GluAs) are essential for formation of a photosensitive organ, development of some neurons, and metamorphosis, including tail absorption and body axis rotation, in ascidian embryos. Based on findings in these embryos and mammalian brains, we formed several hypotheses regarding the evolution of GluAs, the non-synaptic function of Glu, the origin of GluA-positive neurons, and the neuronal network that controls metamorphosis in ascidians.

Locally induced neuronal synchrony precisely propagates to specific cortical areas without rhythm distortion.

Propagation of oscillatory spike firing activity at specific frequencies plays an important role in distributed cortical networks. However, there is limited evidence for how such frequency-specific signals are induced or how the signal spectra of the propagating signals are modulated during across-layer (radial) and inter-areal (tangential) neuronal interactions. To directly evaluate the direction specificity of spectral changes in a spiking cortical network, we selectively photostimulated infragranular excitatory neurons in the rat primary visual cortex (V1) at a supra-threshold level with various frequencies, and recorded local field potentials (LFPs) at the infragranular stimulation site, the cortical surface site immediately above the stimulation site in V1, and cortical surface sites outside V1. We found a significant reduction of LFP powers during radial propagation, especially at high-frequency stimulation conditions. Moreover, low-gamma-band dominant rhythms were transiently induced during radial propagation. Contrastingly, inter-areal LFP propagation, directed to specific cortical sites, accompanied no significant signal reduction nor gamma-band power induction. We propose an anisotropic mechanism for signal processing in the spiking cortical network, in which the neuronal rhythms are locally induced/modulated along the radial direction, and then propagate without distortion via intrinsic horizontal connections for spatiotemporally precise, inter-areal communication.

C9ORF72 dipeptide repeat poly-GA inclusions promote intracellular aggregation of phosphorylated TDP-43.

Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are neurodegenerative diseases characterized by accumulation of insoluble aggregates of phosphorylated 43 kDa TAR DNA-binding protein (TDP-43) and linked with abnormal expansion of a hexanucleotide repeat in an intron of chromosome 9 open reading frame 72 (C9ORF72). However, the relationship between C9ORF72 mutations and TDP-43 aggregation remains unknown. Non-ATG-dependent translation of C9ORF72 repeats produces dipeptide repeat proteins, which form p62-positive aggregates in cerebral cortex and cerebellum of patients. Here, we show that the formation of poly-GA protein inclusions induced intracellular aggregation of endogenous and exogenous TDP-43 in cultured cells. Poly-GA aggregation preceded accumulation of phosphorylated TDP-43. These inclusions induced intracellular aggregation of phosphorylated TDP-43, but not tau or α-synuclein. Formation of phosphorylated TDP-43 aggregates depends on the number of poly-GA repeats. Detergent-insoluble fraction from cells co-expressing poly-GA and TDP-43 could function as seeds for further TDP-43 aggregation. These findings suggest a novel pathogenic mechanism that poly-GA protein aggregation directly promotes pathogenic changes of TDP-43 without the formation of nuclear RNA foci containing GGGGCC repeat expansion or loss-of-function of the C9ORF72 protein.

Synaptic transmission from subplate neurons controls radial migration of neocortical neurons.

The neocortex exhibits a six-layered structure that is formed by radial migration of excitatory neurons, for which the multipolar-to-bipolar transition of immature migrating multipolar neurons is required. Here, we report that subplate neurons, one of the first neuron types born in the neocortex, manage the multipolar-to-bipolar transition of migrating neurons. By histochemical, imaging, and microarray analyses on the mouse embryonic cortex, we found that subplate neurons extend neurites toward the ventricular side of the subplate and form transient glutamatergic synapses on the multipolar neurons just below the subplate. NMDAR (N-methyl-d-aspartate receptor)-mediated synaptic transmission from subplate neurons to multipolar neurons induces the multipolar-to-bipolar transition, leading to a change in migration mode from slow multipolar migration to faster radial glial-guided locomotion. Our data suggested that transient synapses formed on early immature neurons regulate radial migration.

Silencing of FUS in the common marmoset (Callithrix jacchus) brain via stereotaxic injection of an adeno-associated virus encoding shRNA.

Fused in sarcoma (FUS) is an RNA binding protein that is involved in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). To establish the common marmoset (Callithrix jacchus) as a model for FTLD, we generated a stereotaxic injection-based marmoset model of FUS-silencing. We designed shRNAs against the marmoset FUS gene and generated an AAV9 virus encoding the most effective shRNA against FUS (shFUS). The AAV encoding shFUS (AAV-shFUS) was introduced into the frontal cortex of young adult marmosets, whereas AAV encoding a control shRNA was injected into the contralateral side. We obtained approximately 70-80% silencing of FUS following AAV-shFUS injection. Interestingly, FUS-silencing provoked a proliferation of astrocytes and microglias. Since FTLD is characterized by various emotional deficits, it would be helpful to establish a marmoset model of FUS-silencing in various brain tissues for investigating the pathomechanism of higher cognitive and behavioral dysfunction.

Altered GluA1 (Gria1) Function and Accumbal Synaptic Plasticity in the ClockΔ19 Model of Bipolar Mania.

BACKGROUND: Disruptions in circadian rhythms are associated with an increased risk for bipolar disorder. Moreover, studies show that the circadian protein CLOCK (circadian locomotor output cycles kaput) is involved in regulating monoaminergic systems and mood-related behavior. However, the molecular and synaptic mechanisms underlying this relationship remain poorly understood. METHODS: Using ex vivo whole-cell patch-clamp electrophysiology in ClockΔ19 mutant and wild-type mice we characterized alterations in excitatory synaptic transmission, strength, and intrinsic excitability of nucleus accumbens (NAc) neurons. We performed protein crosslinking and Western blot analysis to examine surface and intracellular levels and rhythm of the glutamate receptor subunit, GluA1, in the NAc. Viral-mediated overexpression of Gria1 in the NAc and behavioral assays were also used. RESULTS: Compared with wild-type mice, ClockΔ19 mice display reduced alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-mediated excitatory synaptic responses at NAc medium spiny neurons. These alterations are likely postsynaptic, as presynaptic release of glutamate onto medium spiny neurons is unaltered in mutant mice. Additionally, NAc surface protein levels and the rhythm of GRIA1 are decreased in ClockΔ19 mice diurnally, consistent with reduced functional synaptic response. Furthermore, we observed a significantly hyperpolarized resting membrane potential of ClockΔ19 medium spiny neurons, suggesting lowered intrinsic excitability. Last, overexpression of functional Gria1 in the NAc of mutant mice was able to normalize increased exploratory drive and reward sensitivity behavior when mice are in a manic-like state. CONCLUSIONS: Together, our findings demonstrate that NAc excitatory signaling via Gria1 expression is integral to the effects of Clock gene disruption on manic-like behaviors.

3'UTR Length-Dependent Control of SynGAP Isoform α2 mRNA by FUS and ELAV-like Proteins Promotes Dendritic Spine Maturation and Cognitive Function.

FUS is an RNA-binding protein associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Previous reports have demonstrated intrinsic roles of FUS in synaptic function. However, the mechanism underlying FUS's regulation of synaptic morphology has remained unclear. We found that reduced mature spines after FUS depletion were associated with the internalization of PSD-95 within the dendritic shaft. Mass spectrometry of PSD-95-interacting proteins identified SynGAP, whose expression decreased after FUS depletion. Moreover, FUS and the ELAV-like proteins ELAVL4 and ELAVL1 control SynGAP mRNA stability in a 3'UTR length-dependent manner, resulting in the stable expression of the alternatively spliced SynGAP isoform α2. Finally, abnormal spine maturation and FTLD-like behavioral deficits in FUS-knockout mice were ameliorated by SynGAP α2. Our findings establish an important link between FUS and ELAVL proteins for mRNA stability control and indicate that this mechanism is crucial for the maintenance of synaptic morphology and cognitive function.