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On page 1 showing 1 ~ 20 papers out of 33 papers

Comprehensive behavioral analysis of calcium/calmodulin-dependent protein kinase IV knockout mice.

  • Keizo Takao‎ et al.
  • PloS one‎
  • 2010‎

Calcium-calmodulin dependent protein kinase IV (CaMKIV) is a protein kinase that activates the transcription factor CREB, the cyclic AMP-response element binding protein. CREB is a key transcription factor in synaptic plasticity and memory consolidation. To elucidate the behavioral effects of CaMKIV deficiency, we subjected CaMKIV knockout (CaMKIV KO) mice to a battery of behavioral tests. CaMKIV KO had no significant effects on locomotor activity, motor coordination, social interaction, pain sensitivity, prepulse inhibition, attention, or depression-like behavior. Consistent with previous reports, CaMKIV KO mice exhibited impaired retention in a fear conditioning test 28 days after training. In contrast, however, CaMKIV KO mice did not show any testing performance deficits in passive avoidance, one of the most commonly used fear memory paradigms, 28 days after training, suggesting that remote fear memory is intact. CaMKIV KO mice exhibited intact spatial reference memory learning in the Barnes circular maze, and normal spatial working memory in an eight-arm radial maze. CaMKIV KO mice also showed mildly decreased anxiety-like behavior, suggesting that CaMKIV is involved in regulating emotional behavior. These findings indicate that CaMKIV might not be essential for fear memory or spatial memory, although it is possible that the activities of other neural mechanisms or signaling pathways compensate for the CaMKIV deficiency.


LAMP5 in presynaptic inhibitory terminals in the hindbrain and spinal cord: a role in startle response and auditory processing.

  • Michinori Koebis‎ et al.
  • Molecular brain‎
  • 2019‎

Lysosome-associated membrane protein 5 (LAMP5) is a mammalian ortholog of the Caenorhabditis elegans protein, UNC-46, which functions as a sorting factor to localize the vesicular GABA transporter UNC-47 to synaptic vesicles. In the mouse forebrain, LAMP5 is expressed in a subpopulation of GABAergic neurons in the olfactory bulb and the striato-nigral system, where it is required for fine-tuning of GABAergic synaptic transmission. Here we focus on the prominent expression of LAMP5 in the brainstem and spinal cord and suggest a role for LAMP5 in these brain regions. LAMP5 was highly expressed in several brainstem nuclei involved with auditory processing including the cochlear nuclei, the superior olivary complex, nuclei of the lateral lemniscus and grey matter in the spinal cord. It was localized exclusively in inhibitory synaptic terminals, as has been reported in the forebrain. In the absence of LAMP5, localization of the vesicular inhibitory amino acid transporter (VIAAT) was unaltered in the lateral superior olive and the ventral cochlear nuclei, arguing against a conserved role for LAMP5 in trafficking VIAAT. Lamp5 knockout mice showed no overt behavioral abnormality but an increased startle response to auditory and tactile stimuli. In addition, LAMP5 deficiency led to a larger intensity-dependent increase of wave I, II and V peak amplitude of auditory brainstem response. Our results indicate that LAMP5 plays a pivotal role in sensorimotor processing in the brainstem and spinal cord.


Comprehensive analysis of a novel mouse model of the 22q11.2 deletion syndrome: a model with the most common 3.0-Mb deletion at the human 22q11.2 locus.

  • Ryo Saito‎ et al.
  • Translational psychiatry‎
  • 2020‎

The 22q11.2 deletion syndrome (22q11.2DS) is associated with an increased risk for psychiatric disorders. Although most of the 22q11.2DS patients have a 3.0-Mb deletion, existing mouse models only mimic a minor mutation of 22q11.2DS, a 1.5-Mb deletion. The role of the genes existing outside the 1.5-Mb deletion in psychiatric symptoms of 22q11.2DS is unclear. In this study, we generated a mouse model that reproduced the 3.0-Mb deletion of the 22q11.2DS (Del(3.0 Mb)/ +) using the CRISPR/Cas9 system. Ethological and physiological phenotypes of adult male mutants were comprehensively evaluated by visual-evoked potentials, circadian behavioral rhythm, and a series of behavioral tests, such as measurement of locomotor activity, prepulse inhibition, fear-conditioning memory, and visual discrimination learning. As a result, Del(3.0 Mb)/ + mice showed reduction of auditory prepulse inhibition and attenuated cue-dependent fear memory, which is consistent with the phenotypes of existing 22q11.2DS models. In addition, Del(3.0 Mb)/ + mice displayed an impaired early visual processing that is commonly seen in patients with schizophrenia. Meanwhile, unlike the existing models, Del(3.0 Mb)/ + mice exhibited hypoactivity over several behavioral tests, possibly reflecting the fatigability of 22q11.2DS patients. Lastly, Del(3.0 Mb)/ + mice displayed a faster adaptation to experimental jet lag as compared with wild-type mice. Our results support the validity of Del(3.0 Mb)/ + mice as a schizophrenia animal model and suggest that our mouse model is a useful resource to understand pathogenic mechanisms of schizophrenia and other psychiatric disorders associated with 22q11.2DS.


Impact of chronic endometritis on endometrial receptivity analysis results and pregnancy outcomes.

  • Keiji Kuroda‎ et al.
  • Immunity, inflammation and disease‎
  • 2020‎

The aim of this study is to evaluate the relationship between chronic endometritis (CE) and a personalized window of implantation (WOI), identified by results of endometrial receptivity analysis (ERA), and pregnancy outcomes following embryo transfer (ET) based on the ERA outcomes.


Combined glyoxalase 1 dysfunction and vitamin B6 deficiency in a schizophrenia model system causes mitochondrial dysfunction in the prefrontal cortex.

  • Kazuya Toriumi‎ et al.
  • Redox biology‎
  • 2021‎

Methylglyoxal (MG) is a reactive and cytotoxic α-dicarbonyl byproduct of glycolysis. Our bodies have several bio-defense systems to detoxify MG, including an enzymatic system by glyoxalase (GLO) 1 and GLO2. We identified a subtype of schizophrenia patients with novel mutations in the GLO1 gene that results in reductions of enzymatic activity. Moreover, we found that vitamin B6 (VB6) levels in peripheral blood of the schizophrenia patients with GLO1 dysfunction are significantly lower than that of healthy controls. However, the effects of GLO1 dysfunction and VB6 deficiency on the pathophysiology of schizophrenia remains poorly understood. Here, we generated a novel mouse model for this subgroup of schizophrenia patients by feeding Glo1 knockout mice VB6-deficent diets (KO/VB6(-)) and evaluated the combined effects of GLO1 dysfunction and VB6 deficiency on brain function. KO/VB6(-) mice accumulated homocysteine in plasma and MG in the prefrontal cortex (PFC), hippocampus, and striatum, and displayed behavioral deficits, such as impairments of social interaction and cognitive memory and a sensorimotor deficit in the prepulse inhibition test. Furthermore, we found aberrant gene expression related to mitochondria function in the PFC of the KO/VB6(-) mice by RNA-sequencing and weighted gene co-expression network analysis (WGCNA). Finally, we demonstrated abnormal mitochondrial respiratory function and subsequently enhanced oxidative stress in the PFC of KO/VB6(-) mice in the PFC. These findings suggest that the combination of GLO1 dysfunction and VB6 deficiency may cause the observed behavioral deficits via mitochondrial dysfunction and oxidative stress in the PFC.


Phosphatidic acid (PA)-preferring phospholipase A1 regulates mitochondrial dynamics.

  • Takashi Baba‎ et al.
  • The Journal of biological chemistry‎
  • 2014‎

Recent studies have suggested that phosphatidic acid (PA), a cone-shaped phospholipid that can generate negative curvature of lipid membranes, participates in mitochondrial fusion. However, precise mechanisms underling the production and consumption of PA on the mitochondrial surface are not fully understood. Phosphatidic acid-preferring phospholipase A1 (PA-PLA1)/DDHD1 is the first identified intracellular phospholipase A1 and preferentially hydrolyzes PA in vitro. Its cellular and physiological functions have not been elucidated. In this study, we show that PA-PLA1 regulates mitochondrial dynamics. PA-PLA1, when ectopically expressed in HeLa cells, induced mitochondrial fragmentation, whereas its depletion caused mitochondrial elongation. The effects of PA-PLA1 on mitochondrial morphology appear to counteract those of MitoPLD, a mitochondrion-localized phospholipase D that produces PA from cardiolipin. Consistent with high levels of expression of PA-PLA1 in testis, PA-PLA1 knock-out mice have a defect in sperm formation. In PA-PLA1-deficient sperm, the mitochondrial structure is disorganized, and an abnormal gap structure exists between the middle and principal pieces. A flagellum is bent at that position, leading to a loss of motility. Our results suggest a possible mechanism of PA regulation of the mitochondrial membrane and demonstrate an in vivo function of PA-PLA1 in the organization of mitochondria during spermiogenesis.


Requirement of the immediate early gene vesl-1S/homer-1a for fear memory formation.

  • Naoko Inoue‎ et al.
  • Molecular brain‎
  • 2009‎

The formation of long-term memory (LTM) and the late phase of long-term potentiation (L-LTP) depend on macromolecule synthesis, translation, and transcription in neurons. vesl-1S (VASP/Ena-related gene upregulated during seizure and LTP, also known as homer-1a) is an LTP-induced immediate early gene. The short form of Vesl (Vesl-1S) is an alternatively spliced isoform of the vesl-1 gene, which also encodes the long form of the Vesl protein (Vesl-1L). Vesl-1L is a postsynaptic scaffolding protein that binds to and modulates the metabotropic glutamate receptor 1/5 (mGluR1/5), the IP3 receptor, and the ryanodine receptor. Vesl-1 null mutant mice show abnormal behavior, which includes anxiety- and depression-related behaviors, and an increase in cocaine-induced locomotion; however, the function of the short form of Vesl in behavior is poorly understood because of the lack of short-form-specific knockout mice.


New Features on the Expression and Trafficking of mGluR1 Splice Variants Exposed by Two Novel Mutant Mouse Lines.

  • Rika Naito‎ et al.
  • Frontiers in molecular neuroscience‎
  • 2018‎

Metabotropic glutamate receptors (mGluRs) couple to G-proteins to modulate slow synaptic transmission via intracellular second messengers. The first cloned mGluR, mGluR1, regulates motor coordination, synaptic plasticity and synapse elimination. mGluR1 undergoes alternative splicing giving rise to four translated variants that differ in their intracellular C-terminal domains. Our current knowledge about mGluR1 relates almost entirely to the long mGluR1α isoform, whereas little is known about the other shorter variants. To study the expression of mGluR1γ, we have generated by means of the CRISPR/Cas9 system a new knock-in (KI) mouse line in which the C-terminus of this variant carries two short tags. Using this mouse line, we could establish that mGluR1γ is either untranslated or in amounts that are undetectable in the mouse cerebellum, indicating that only mGluR1α and mGluR1β are present and active at cerebellar synapses. The trafficking and function of mGluR1 appear strongly influenced by adaptor proteins such as long Homers that bind to the C-terminus of mGluR1α. We generated a second transgenic (Tg) mouse line in which mGluR1α carries a point mutation in its Homer binding domain and studied whether disruption of this interaction influenced mGluR1 subcellular localization at cerebellar parallel fiber (PF)-Purkinje cell (PC) synapses by means of the freeze-fracture replica immunolabeling technique. These Tg animals did not show any overt behavioral phenotype, and despite the typical mGluR1 perisynaptic distribution was not significantly changed, we observed a higher probability of intrasynaptic diffusion suggesting that long Homers regulate the lateral mobility of mGluR1. We extended our ultrastructural analysis to other mouse lines in which only one mGluR1 variant was reintroduced in PC of mGluR1-knock out (KO) mice. This work revealed that mGluR1α preferentially accumulates closer to the edge of the postsynaptic density (PSD), whereas mGluR1β has a less pronounced perijunctional distribution and, in the absence of mGluR1α, its trafficking to the plasma membrane is impaired with an accumulation in intracellular organelles. In conclusion, our study sets several firm points on largely disputed matters, namely expression of mGluR1γ and role of the C-terminal domain of mGluR1 splice variants on their perisynaptic clustering.


Identification of GLUT12/SLC2A12 as a urate transporter that regulates the blood urate level in hyperuricemia model mice.

  • Yu Toyoda‎ et al.
  • Proceedings of the National Academy of Sciences of the United States of America‎
  • 2020‎

Recent genome-wide association studies have revealed some genetic loci associated with serum uric acid levels and susceptibility to gout/hyperuricemia which contain potential candidates of physiologically important urate transporters. One of these novel loci is located upstream of SGK1 and SLC2A12, suggesting that variations in these genes increase the risks of hyperuricemia and gout. We herein focused on SLC2A12 encoding a transporter, GLUT12, the physiological function of which remains unclear. As GLUT12 belongs to the same protein family as a well-recognized urate transporter GLUT9, we hypothesized that GLUT12 mediates membrane transport of urate. Therefore, we conducted functional assays and analyzed Glut12 knockout hyperuricemia model mice, generated using the CRISPR-Cas9 system. Our results revealed that GLUT12 acts as a physiological urate transporter and its dysfunction elevates the blood urate concentration. This study provides insights into the deeper understanding of the urate regulatory system in the body, which is also important for pathophysiology of gout/hyperuricemia.


Apical constriction in distal visceral endoderm cells initiates global, collective cell rearrangement in embryonic visceral endoderm to form anterior visceral endoderm.

  • Go Shioi‎ et al.
  • Developmental biology‎
  • 2017‎

The behavior of visceral endoderm cells was examined as the anterior visceral endoderm (AVE) formed from the distal visceral endoderm (DVE) using the mouse lines R26-H2B-EGFP and R26-PHA7-EGFP to visualize cell nuclei and adherens junction, respectively. The analysis using R26-H2B-EGFP demonstrated global cell rearrangement that was not specific to the DVE cells in the monolayer embryonic visceral endoderm sheet; each population of the endoderm cells moved collectively in a swirling movement as a whole. Most of the AVE cells at E6.5 were not E5.5 DVE cells but were E5.5 cells that were located caudally behind them, as previously reported (Hoshino et al., 2015; Takaoka et al., 2011). In the rearrangement, the posterior embryonic visceral endoderm cells did not move, as extraembryonic visceral endoderm cells did not, and they constituted a distinct population during the process of anterior-posterior axis formation. The analysis using R26-PHA7-EGFP suggested that constriction of the apical surfaces of the cells in prospective anterior portion of the DVE initiated the global cellular movement of the embryonic visceral endoderm to drive AVE formation.


Loss of calsyntenin paralogs disrupts interneuron stability and mouse behavior.

  • Keita Mori‎ et al.
  • Molecular brain‎
  • 2022‎

Calsyntenins (CLSTNs) are important synaptic molecules whose molecular functions are not fully understood. Although mutations in calsyntenin (CLSTN) genes have been associated with psychiatric disorders in humans, their function is still unclear. One of the reasons why the function of CLSTNs in the nervous system has not been clarified is the functional redundancy among the three paralogs. Therefore, to investigate the functions of mammalian CLSTNs, we generated triple knockout (TKO) mice lacking all CLSTN paralogs and examined their behavior. The mutant mice tended to freeze in novel environments and exhibited hypersensitivity to stress. Consistent with this, glucose levels under stress were significantly higher in the mutant mice than in the wild-type controls. In particular, phenotypes such as decreased motivation, which had not been reported in single Clstn KO mice, were newly discovered. The TKO mice generated in this study represent an important mouse model for clarifying the function of CLSTN in the future.


Distorted neurocomputation by a small number of extra-large spines in psychiatric disorders.

  • Kisho Obi-Nagata‎ et al.
  • Science advances‎
  • 2023‎

Human genetics strongly support the involvement of synaptopathy in psychiatric disorders. However, trans-scale causality linking synapse pathology to behavioral changes is lacking. To address this question, we examined the effects of synaptic inputs on dendrites, cells, and behaviors of mice with knockdown of SETD1A and DISC1, which are validated animal models of schizophrenia. Both models exhibited an overrepresentation of extra-large (XL) synapses, which evoked supralinear dendritic and somatic integration, resulting in increased neuronal firing. The probability of XL spines correlated negatively with working memory, and the optical prevention of XL spine generation restored working memory impairment. Furthermore, XL synapses were more abundant in the postmortem brains of patients with schizophrenia than in those of matched controls. Our findings suggest that working memory performance, a pivotal aspect of psychiatric symptoms, is shaped by distorted dendritic and somatic integration via XL spines.


Tagging active neurons by soma-targeted Cal-Light.

  • Jung Ho Hyun‎ et al.
  • Nature communications‎
  • 2022‎

Verifying causal effects of neural circuits is essential for proving a direct circuit-behavior relationship. However, techniques for tagging only active neurons with high spatiotemporal precision remain at the beginning stages. Here we develop the soma-targeted Cal-Light (ST-Cal-Light) which selectively converts somatic calcium rise triggered by action potentials into gene expression. Such modification simultaneously increases the signal-to-noise ratio of reporter gene expression and reduces the light requirement for successful labeling. Because of the enhanced efficacy, the ST-Cal-Light enables the tagging of functionally engaged neurons in various forms of behaviors, including context-dependent fear conditioning, lever-pressing choice behavior, and social interaction behaviors. We also target kainic acid-sensitive neuronal populations in the hippocampus which subsequently suppress seizure symptoms, suggesting ST-Cal-Light's applicability in controlling disease-related neurons. Furthermore, the generation of a conditional ST-Cal-Light knock-in mouse provides an opportunity to tag active neurons in a region- or cell-type specific manner via crossing with other Cre-driver lines. Thus, the versatile ST-Cal-Light system links somatic action potentials to behaviors with high temporal precision, and ultimately allows functional circuit dissection at a single cell resolution.


Runx2 regulates chromatin accessibility to direct the osteoblast program at neonatal stages.

  • Hironori Hojo‎ et al.
  • Cell reports‎
  • 2022‎

The transcriptional regulator Runx2 (runt-related transcription factor 2) has essential but distinct roles in osteoblasts and chondrocytes in skeletal development. However, Runx2-mediated regulatory mechanisms underlying the distinctive programming of osteoblasts and chondrocytes are not well understood. Here, we perform an integrative analysis to investigate Runx2-DNA binding and chromatin accessibility ex vivo using neonatal osteoblasts and chondrocytes. We find that Runx2 engages with cell-type-distinct chromatin-accessible regions, potentially interacting with different combinations of transcriptional regulators, forming cell-type-specific hotspots, and potentiating chromatin accessibility. Genetic analysis and direct cellular reprogramming studies suggest that Runx2 is essential for establishment of chromatin accessibility in osteoblasts. Functional enhancer studies identify an Sp7 distal enhancer driven by Runx2-dependent binding and osteoblast-specific chromatin accessibility, contributing to normal osteoblast differentiation. Our findings provide a framework for understanding the regulatory landscape encompassing Runx2-mediated and cell-type-distinct enhancer networks that underlie the specification of osteoblasts.


Efficient marmoset genome engineering by autologous embryo transfer and CRISPR/Cas9 technology.

  • Yukiko Abe‎ et al.
  • Scientific reports‎
  • 2021‎

Genetic engineering of non-human primates, which are most closely related to humans, has been expected to generate ideal animal models for human genetic diseases. The common marmoset (Callithrix jacchus) is a non-human primate species adequate for the production of genetically modified animals because of their small body size and high reproductive capacity. Autologous embryo transfer (AET) is routinely utilized in assisted reproductive technologies for humans but not for experimental animals. This study has developed a novel method for efficiently producing mutant marmosets using AET and CRISPR/Cas9 systems. The embryos were recovered from oviducts of naturally mated females, injected with Cas9/guide RNA, and transferred into the oviducts of the donors. This AET method can reduce the time for in vitro culture of embryos to less than 30 min. This method uses an embryo donor as the recipient, thus reducing the number of animals and allowing for "Reduction" in the 3R principles of humane experimental technique. Furthermore, this method can utilize nulliparous females as well as parous females. We applied our novel method and generated the 6 marmosets carrying mutations in the fragile X mental retardation 1 (FMR1) gene using only 18 females including 14 nulliparous females.


Circadian regulation of intracellular G-protein signalling mediates intercellular synchrony and rhythmicity in the suprachiasmatic nucleus.

  • Masao Doi‎ et al.
  • Nature communications‎
  • 2011‎

Synchronous oscillations of thousands of cellular clocks in the suprachiasmatic nucleus (SCN), the circadian centre, are coordinated by precisely timed cell-cell communication, the principle of which is largely unknown. Here we show that the amount of RGS16 (regulator of G protein signalling 16), a protein known to inactivate Gαi, increases at a selective circadian time to allow time-dependent activation of intracellular cyclic AMP signalling in the SCN. Gene ablation of Rgs16 leads to the loss of circadian production of cAMP and as a result lengthens circadian period of behavioural rhythm. The temporally precise regulation of the cAMP signal by clock-controlled RGS16 is needed for the dorsomedial SCN to maintain a normal phase-relationship to the ventrolateral SCN. Thus, RGS16-dependent temporal regulation of intracellular G protein signalling coordinates the intercellular synchrony of SCN pacemaker neurons and thereby defines the 24 h rhythm in behaviour.


Rhythmic transcription of Bmal1 stabilizes the circadian timekeeping system in mammals.

  • Yasuko O Abe‎ et al.
  • Nature communications‎
  • 2022‎

In mammals, the circadian clock consists of transcriptional and translational feedback loops through DNA cis-elements such as E-box and RRE. The E-box-mediated core feedback loop is interlocked with the RRE-mediated feedback loop, but biological significance of the RRE-mediated loop has been elusive. In this study, we established mutant cells and mice deficient for rhythmic transcription of Bmal1 gene by deleting its upstream RRE elements and hence disrupted the RRE-mediated feedback loop. We observed apparently normal circadian rhythms in the mutant cells and mice, but a combination of mathematical modeling and experiments revealed that the circadian period and amplitude of the mutants were more susceptible to disturbance of CRY1 protein rhythm. Our findings demonstrate that the RRE-mediated feedback regulation of Bmal1 underpins the E-box-mediated rhythm in cooperation with CRY1-dependent posttranslational regulation of BMAL1 protein, thereby conferring the perturbation-resistant oscillation and chronologically-organized output of the circadian clock.


Effects of Periconceptional Multivitamin Supplementation on Folate and Homocysteine Levels Depending on Genetic Variants of Methyltetrahydrofolate Reductase in Infertile Japanese Women.

  • Keiji Kuroda‎ et al.
  • Nutrients‎
  • 2021‎

Methylenetetrahydrofolate reductase (MTHFR) has various polymorphisms, and the effects of periconceptional folic acid supplementation for decreasing neural tube defects (NTDs) risk differ depending on the genotypes. This study analyzed the effectiveness of multivitamin supplementation on folate insufficiency and hyperhomocysteinemia, depending on MTHFR polymorphisms. Of 205 women, 72 (35.1%), 100 (48.8%) and 33 (16.1%) had MTHFR CC, CT and TT, respectively. Serum folate and homocysteine levels in women with homozygous mutant TT were significantly lower and higher, respectively, than those in women with CC and CT. In 54 women (26.3% of all women) with a risk of NTDs, multivitamin supplementation containing folic acid and vitamin D for one month increased folate level (5.8 ± 0.9 to 19.2 ± 4.0 ng/mL, p < 0.0001) and decreased the homocysteine level (8.2 ± 3.1 to 5.8 ± 0.8 nmol/mL, p < 0.0001) to minimize the risk of NTDs in all women, regardless of MTHFR genotype. Regardless of MTHFR genotype, multivitamin supplements could control folate and homocysteine levels. Tests for folate and homocysteine levels and optimal multivitamin supplementation in women with risk of NTDs one month or more before pregnancy should be recommended to women who are planning a pregnancy.


Combining electrophysiology and optogenetics for functional screening of pyramidal neurons in the mouse prefrontal cortex.

  • Kenichiro Nagahama‎ et al.
  • STAR protocols‎
  • 2021‎

Here, we present a comprehensive protocol to analyze the roles of disease-related genes in synaptic transmission. We have developed a pipeline of electrophysiological techniques and combined these with optogenetics in the medial prefrontal cortex of mice. This methodology provides a cost-effective, faster, and easier screening approach to elucidate functional aspects of single genes in several regions in the mouse brain such as a specific layer of the mPFC. For complete details on the use and execution of this protocol, please refer to Nagahama et al. (2020) and Sacai et al. (2020).


Setd1a Insufficiency in Mice Attenuates Excitatory Synaptic Function and Recapitulates Schizophrenia-Related Behavioral Abnormalities.

  • Kenichiro Nagahama‎ et al.
  • Cell reports‎
  • 2020‎

SETD1A encodes a histone methyltransferase whose de novo mutations are identified in schizophrenia (SCZ) patients and confer a large increase in disease risk. Here, we generate Setd1a mutant mice carrying the frameshift mutation that closely mimics a loss-of-function variant of SCZ. Our Setd1a (+/-) mice display various behavioral abnormalities relevant to features of SCZ, impaired excitatory synaptic transmission in layer 2/3 (L2/3) pyramidal neurons of the medial prefrontal cortex (mPFC), and altered expression of diverse genes related to neurodevelopmental disorders and synaptic functions in the mPFC. RNAi-mediated Setd1a knockdown (KD) specifically in L2/3 pyramidal neurons of the mPFC only recapitulates impaired sociality among multiple behavioral abnormalities of Setd1a (+/-) mice. Optogenetics-assisted selective stimulation of presynaptic neurons combined with Setd1a KD reveals that Setd1a at postsynaptic site is essential for excitatory synaptic transmission. Our findings suggest that reduced SETD1A may attenuate excitatory synaptic function and contribute to the pathophysiology of SCZ.


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