Type-I-interferon-responsive microglia shape cortical development and behavior.

Microglia are brain-resident macrophages that shape neural circuit development and are implicated in neurodevelopmental diseases. Multiple microglial transcriptional states have been defined, but their functional significance is unclear. Here, we identify a type I interferon (IFN-I)-responsive microglial state in the developing somatosensory cortex (postnatal day 5) that is actively engulfing whole neurons. This population expands during cortical remodeling induced by partial whisker deprivation. Global or microglial-specific loss of the IFN-I receptor resulted in microglia with phagolysosomal dysfunction and an accumulation of neurons with nuclear DNA damage. IFN-I gain of function increased neuronal engulfment by microglia in both mouse and zebrafish and restricted the accumulation of DNA-damaged neurons. Finally, IFN-I deficiency resulted in excess cortical excitatory neurons and tactile hypersensitivity. These data define a role for neuron-engulfing microglia during a critical window of brain development and reveal homeostatic functions of a canonical antiviral signaling pathway in the brain.

ß-Adrenergic Signaling Promotes Morphological Maturation of Astrocytes in Female Mice.

Astrocytes play essential roles in the developing nervous system, including supporting synapse function. These astrocyte support functions emerge coincident with brain maturation and may be tailored in a region-specific manner. For example, gray matter astrocytes have elaborate synapse-associated processes and are morphologically and molecularly distinct from white matter astrocytes. This raises the question of whether there are unique environmental cues that promote gray matter astrocyte identity and synaptogenic function. We previously identified adrenergic receptors as preferentially enriched in developing gray versus white matter astrocytes, suggesting that noradrenergic signaling could be a cue that promotes the functional maturation of gray matter astrocytes. We first characterized noradrenergic projections during postnatal brain development in mouse and human, finding that process density was higher in the gray matter and increased concurrently with astrocyte maturation. RNA sequencing revealed that astrocytes in both species expressed α- and ß-adrenergic receptors. We found that stimulation of ß-adrenergic receptors increased primary branching of rodent astrocytes in vitro Conversely, astrocyte-conditional knockout of the ß1-adrenergic receptor reduced the size of gray matter astrocytes and led to dysregulated sensorimotor integration in female mice. These studies suggest that adrenergic signaling to developing astrocytes impacts their morphology and has implications for adult behavior, particularly in female animals. More broadly, they demonstrate a mechanism through which environmental cues impact astrocyte development. Given the key roles of norepinephrine in brain states, such as arousal, stress, and learning, these findings could prompt further inquiry into how developmental stressors impact astrocyte development and adult brain function.SIGNIFICANCE STATEMENT This study demonstrates a role for noradrenergic signaling in the development of gray matter astrocytes. We provide new evidence that the ß1-adrenergic receptor is robustly expressed by both mouse and human astrocytes, and that conditional KO of the ß1-adrenergic receptor from female mouse astrocytes impairs gray matter astrocyte maturation. Moreover, female conditional KO mice exhibit behavioral deficits in two paradigms that test sensorimotor function. Given the emerging interest in moving beyond RNA sequencing to probe specific pathways that underlie astrocyte heterogeneity, this study provides a foundation for future investigation into the effect of noradrenergic signaling on astrocyte functions in conditions where noradrenergic signaling is altered, such as stress, arousal, and learning.

HSE National Clinical Programme for Eating Disorders in Ireland: COVID-19 pandemic and eating disorder care in a new national eating disorder service.

BACKGROUND: The COVID-19 pandemic experience was different in each country (e.g., prevalence, societal restrictions). There is limited data on eating disorder (ED) diagnosis and service activity trends within Ireland. The aim of this study is to describe the ED referral and hospitalization trends during COVID-19 in Ireland. METHOD: Monthly data (2019-2021) from three regional community ED services (two-child and one-adult) were collected. National psychiatric and medical hospitalization data were analyzed. A descriptive and trend analysis was performed. RESULTS: There was a trend of referrals to community ED services during the COVID-19 pandemic for children (p < .0001) and adults (p = .0019). Albeit the increase in child referrals was evident at an earlier point before adult referrals. There was a trend of a diagnosis for children and adults of anorexia nervosa (p < .0001; p = .0257) and other-specified-feeding-or-eating-disorder (OSFED) respectively (p = .0037; p = .0458). There was no trend in psychiatric co-morbidity. There was a trend of child (p = .0003) not adult (n = 0.1669) psychiatric hospitalization. There was a trend of medical hospitalization for child and adult combined (p < .0001). CONCLUSION: This study adds to the growing literature on the association of the COVID-19 pandemic on ED trends and the need for future public health and service provision funding to be allocated for mental health services during periods of international crisis. PUBLIC SIGNIFICANCE: This study illustrates the referral and hospitalization trend in young persons and adults with an ED in Ireland during the COVID-19 pandemic. This study highlights that there was a trend of Anorexia Nervosa and OSFED presentations during the COVID-19 pandemic.

The L1 cell adhesion molecule constrains dendritic spine density in pyramidal neurons of the mouse cerebral cortex.

A novel function for the L1 cell adhesion molecule, which binds the actin adaptor protein Ankyrin was identified in constraining dendritic spine density on pyramidal neurons in the mouse neocortex. In an L1-null mouse mutant increased spine density was observed on apical but not basal dendrites of pyramidal neurons in diverse cortical areas (prefrontal cortex layer 2/3, motor cortex layer 5, visual cortex layer 4. The Ankyrin binding motif (FIGQY) in the L1 cytoplasmic domain was critical for spine regulation, as demonstrated by increased spine density and altered spine morphology in the prefrontal cortex of a mouse knock-in mutant (L1YH) harboring a tyrosine (Y) to histidine (H) mutation in the FIGQY motif, which disrupted L1-Ankyrin association. This mutation is a known variant in the human L1 syndrome of intellectual disability. L1 was localized by immunofluorescence staining to spine heads and dendrites of cortical pyramidal neurons. L1 coimmunoprecipitated with Ankyrin B (220 kDa isoform) from lysates of wild type but not L1YH forebrain. This study provides insight into the molecular mechanism of spine regulation and underscores the potential for this adhesion molecule to regulate cognitive and other L1-related functions that are abnormal in the L1 syndrome.

The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration.

Complement overactivation mediates microglial synapse elimination in neurological diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), but how complement activity is regulated in the brain remains largely unknown. We identified that the secreted neuronal pentraxin Nptx2 binds complement C1q and thereby regulates its activity in the brain. Nptx2-deficient mice show increased complement activity, C1q-dependent microglial synapse engulfment, and loss of excitatory synapses. In a neuroinflammation culture model and in aged TauP301S mice, adeno-associated virus (AAV)-mediated neuronal overexpression of Nptx2 was sufficient to restrain complement activity and ameliorate microglia-mediated synapse loss. Analysis of human cerebrospinal fluid (CSF) samples from a genetic FTD cohort revealed reduced concentrations of Nptx2 and Nptx2-C1q protein complexes in symptomatic patients, which correlated with elevated C1q and activated C3. Together, these results show that Nptx2 regulates complement activity and microglial synapse elimination in the brain and that diminished Nptx2 concentrations might exacerbate complement-mediated neurodegeneration in patients with FTD.

Exploring the Use of Common Strict Search Criteria in Nursing Literature Searches.

BACKGROUND: Health sciences librarians and nursing journal contributors have expressed concern about the impact of using strict parameters when searching the literature. PURPOSE: The purpose of this study was to explore the use of strict search criteria (eg, 5-year rule, "nurse as author") by direct care nurses and nursing students. METHODS: Fourteen online focus groups were conducted with 54 participants: direct care nurses, health sciences librarians, nursing faculty, and nursing students. Nursing faculty and health sciences librarians were included as participants to add perspective to the origins and effects of the use of stringent search criteria. RESULTS: The majority of the nurses viewed the 5-year rule and nurse as author search limits favorably, while noting that a strict date range may hamper successful searching. Librarians viewed these search criteria more unfavorably but recognized the value of topic-appropriate search limits. CONCLUSION: Reliance on strict limits can be detrimental to pertinent results; however, appropriate use is essential for relevant results. Pedagogy focused on searching the nursing literature needs to emphasize that limits are tools to be used judiciously.

National Clinical Programme for Eating Disorders: a pragmatic review of a new national eating disorder service in Ireland.

OBJECTIVE: The Health Service Executive National Clinical Programme for Eating Disorders (NCPED) launched a Model of Care for Eating Disorder Services in Ireland in 2018. Currently, one adult and two child and adolescent eating disorder services are operational out of a total of sixteen recommended. The three objectives of this paper are to describe the early (1) referral pattern, (2) level of service activity and (3) the level of service user satisfaction. METHOD: Monthly submitted service activity data from each service to the NCPED between March 2018 and October 2020 were retrospectively analysed. One hundred and fifty-nine carers and service users completed an experience of service questionnaire (ESQ). A descriptive analysis of referral pattern, level of service activity and ESQ was performed. A thematic analysis was performed on three qualitative questions on the ESQ. RESULTS: There was substantial referral numbers to eating disorder services by 18 months (n = 258). The main referral source was community mental health teams. The majority (n = 222, 86%) of referrals were offered an assessment. The most common age profile was 10-17 years of age (n = 120, 54.1%), and anorexia nervosa was the most common disorder (n = 96, 43.2%). ESQ results demonstrate that most service users were satisfied with their service, and the main themes were carer involvement, staff expertise, therapeutic alliance and service access. CONCLUSIONS: This preliminary service activity and service user satisfaction data highlight several issues, including trends when setting up a regional eating disorder service, potential pitfalls of pragmatic data collection and the need for adequate information-technology infrastructure.

Distinct stromal and immune cell interactions shape the pathogenesis of rheumatoid and psoriatic arthritis.

OBJECTIVES: Immune and stromal cell communication is central in the pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), however, the nature of these interactions in the synovial pathology of the two pathotypes can differ. Identifying immune-stromal cell crosstalk at the site of inflammation in RA and PsA is challenging. This study creates the first global transcriptomic analysis of the RA and PsA inflamed joint and investigates immune-stromal cell interactions in the pathogenesis of synovial inflammation. METHODS: Single cell transcriptomic profiling of 178 000 synovial tissue cells from five patients with PsA and four patients with RA, importantly, without prior sorting of immune and stromal cells. This approach enabled the transcriptomic analysis of the intact synovial tissue and identification of immune and stromal cell interactions. State of the art data integration and annotation techniques identified and characterised 18 stromal and 14 immune cell clusters. RESULTS: Global transcriptomic analysis of synovial cell subsets identifies actively proliferating synovial T cells and indicates that due to differential λ and κ immunoglobulin light chain usage, synovial plasma cells are potentially not derived from the local memory B cell pool. Importantly, we report distinct fibroblast and endothelial cell transcriptomes indicating abundant subpopulations in RA and PsA characterised by differential transcription factor usage. Using receptor-ligand interactions and downstream target characterisation, we identify RA-specific synovial T cell-derived transforming growth factor (TGF)-ß and macrophage interleukin (IL)-1ß synergy in driving the transcriptional profile of FAPα+THY1+ invasive synovial fibroblasts, expanded in RA compared with PsA. In vitro characterisation of patient with RA synovial fibroblasts showed metabolic switch to glycolysis, increased adhesion intercellular adhesion molecules 1 expression and IL-6 secretion in response to combined TGF-ß and IL-1ß treatment. Disrupting specific immune and stromal cell interactions offers novel opportunities for targeted therapeutic intervention in RA and PsA.

Chemically Modified mocRNAs for Highly Efficient Protein Expression in Mammalian Cells.

mRNA has recently been established as a new class of therapeutics, due to its programmability and ability to produce proteins of interest rapidly in vivo. Despite its demonstrated utility, mRNA as a protein expression platform remains limited by its translational capacity and RNA stability. Here, we introduce messenger-oligonucleotide conjugated RNAs (mocRNAs) to enable site-specific, robust, and modularized encoding of chemical modifications for highly efficient and stable protein expression. In mocRNA constructs, chemically synthesized oligonucleotides are ligated to the 3' terminus of mRNA substrates to protect poly(A) tails from degradation, without compromising their potency in stimulating translation. As a proof-of-concept, mocRNAs modified by deadenylase-resistant oligonucleotides result in augmented protein production by factors of 2-4 in human HeLa cells and by 10-fold in primary rat cortical neuronal cultures. By directly linking enzymatic and organic synthesis of mRNA, we envision that the mocRNA design will open new avenues to expand the chemical space and translational capacity of RNA-based vectors in basic research and therapeutic applications.

Variability in Thyroid Cancer Multidisciplinary Team Meeting Recommendations Is Not Explained by Standard Variables: Outcomes of a Single Centre Review.

Multidisciplinary team (MDT) meetings are the mainstay of the decision-making process for patients presenting with complex clinical problems such as papillary thyroid carcinoma (PTC). Adherence to guidelines by MDTs has been extensively investigated; however, scarce evidence exists on MDT performance and variability where guidelines are less prescriptive. We evaluated the consistency of MDT management recommendations for T1 and T2 PTC patients and explored key variables that may influence therapeutic decision making. A retrospective review of the prospective database of all T1 and T2 PTC patients discussed by the MDT was conducted between January 2016 and May 2021. Univariate analysis (with Bonferroni correction significance calculated at p < 0.006) was performed to establish clinical variables linked to completion thyroidectomy and Radioactive iodine (RAI) recommendations. Of 468 patients presented at thyroid MDT, 144 pT1 PTC and 118 pT2 PTC met the selection criteria. Only 18% (n = 12) of pT1 PTC patients initially managed with hemithyroidectomy were recommended completion thyroidectomy. Mean tumour diameter was the only variable differing between groups (p = 0.003). pT2 patients were recommended completion thyroidectomy in 66% (n = 16) of instances. No measured variable explained the difference in recommendation. pT1 patients initially managed with total thyroidectomy were not recommended RAI in 71% (n = 55) of cases with T1a status (p = 0.001) and diameter (p = 0.001) as statistically different variables. For pT2 patients, 60% (n = 41) were recommended RAI post-total thyroidectomy, with no differences observed among groups. The majority of MDT recommendations were concordant for patients with similar measurable characteristics. Discordant recommendations for a small group of patients were not explained by measured variables and may have been accounted for by individual patient factors. Further research into the MDT decision-making process is warranted.

Semaphorin3F Drives Dendritic Spine Pruning Through Rho-GTPase Signaling.

Dendritic spines of cortical pyramidal neurons are initially overproduced then remodeled substantially in the adolescent brain to achieve appropriate excitatory balance in mature circuits. Here we investigated the molecular mechanism of developmental spine pruning by Semaphorin 3F (Sema3F) and its holoreceptor complex, which consists of immunoglobulin-class adhesion molecule NrCAM, Neuropilin-2 (Npn2), and PlexinA3 (PlexA3) signaling subunits. Structure-function studies of the NrCAM-Npn2 interface showed that NrCAM stabilizes binding between Npn2 and PlexA3 necessary for Sema3F-induced spine pruning. Using a mouse neuronal culture system, we identified a dual signaling pathway for Sema3F-induced pruning, which involves activation of Tiam1-Rac1-PAK1-3 -LIMK1/2-Cofilin1 and RhoA-ROCK1/2-Myosin II in dendritic spines. Inhibitors of actin remodeling impaired spine collapse in the cortical neurons. Elucidation of these pathways expands our understanding of critical events that sculpt neuronal networks and may provide insight into how interruptions to these pathways could lead to spine dysgenesis in diseases such as autism, bipolar disorder, and schizophrenia.

Serum miRNA Signature in Rheumatoid Arthritis and "At-Risk Individuals".

Background: MicroRNAs (miRNAs) are small non-coding RNAs which have been implicated as potential biomarkers or therapeutic targets in autoimmune diseases. This study examines circulatory miRNAs in RA patients and further investigates if a serum miRNA signature precedes clinical manifestations of disease in arthralgia or "at-risk individuals". Methods: Serum was collected from HC subjects (N = 20), RA patients (N = 50), and arthralgia subjects (N = 10), in addition to a subgroup of the RA patients post-methotrexate (MTX) (N = 18). The FirePlex miRNA Immunology-V2 panel was selected for multiplex analysis of 68 miRNAs in each sample. DNA intelligent analysis (DIANA)-mirPath and Ingenuity Pathway Analysis (IPA) software were used to predict pathways targeted by the dysregulated miRNAs. Results: 8 miRNA (miR-126-3p, let-7d-5p, miR-431-3p, miR-221-3p, miR-24-3p, miR-130a-3p, miR-339-5p, let-7i-5p) were significantly elevated in RA serum compared to HC (all p < 0.01) and 1 miRNA (miR-17-5p) was significantly lower in RA (p < 0.01). High specificity and sensitivity were determined by receiver operating characteristic (ROC) curve analysis. Both miR-339-5p and let-7i-5p were significantly reduced post-MTX (both p < 0.01). MiR-126-3p, let-7d-5p, miR-431-3p, miR-221-3p, miR-24-3p, miR-130a-3p were also significantly elevated in subjects "at risk" of developing RA (all p < 0.05) compared to HC. IPA analysis of this miRNA signature identified downstream targets including key transcription factors NF-κB, STAT-1, STAT-3, cytokines IL-1ß, TNF-α, and matrix-metalloproteases all importantly associated with RA pathogenesis. Conclusion: This study identified six miRNAs that are altered in both RA and "at-risk individuals," which potentially regulate key downstream pathways involved in regulating inflammation. These may have potential as predictive signature for disease onset and early progression.

Pilot Randomized Controlled Trial of a Standard Versus a Modified Low-Phosphorus Diet in Hemodialysis Patients.

INTRODUCTION: The standard low-phosphorus diet restricts pulses, nuts, and whole grains and other high phosphorus foods to control hyperphosphatemia. We conducted a randomized controlled trial to evaluate the effectiveness, safety, and tolerability of the modified diet, which introduced some pulses and nuts, increased the use of whole grains, increased focus on the avoidance of phosphate additives, and introduced the prescription of low-biological-value protein such as bread. METHODS: We conducted a multicenter, pragmatic, parallel-arm, open-label, randomized controlled trial of modified versus standard diet in 74 adults on hemodialysis with hyperphosphatemia over 1 month. Biochemistry was assessed using monthly laboratory tests. Dietary intake was assessed using a 2-day record of weighed intake of food, and tolerability was assessed using a patient questionnaire. RESULTS: There was no significant difference in the change in serum phosphate between the standard and modified diets. Although total dietary phosphorus intake was similar, phytate-bound phosphorus, found in pulses, nuts, and whole grains, was significantly higher in the modified diet (P < 0.001). Dietary fiber intake was also significantly higher (P < 0.003), as was the percentage of patients reporting an increase in bowel movements while following the modified diet (P = 0.008). There was no significant difference in the change in serum potassium or in reported protein intake between the 2 diets. Both diets were similarly well tolerated. CONCLUSION: The modified low phosphorus diet was well tolerated and was associated with similar phosphate and potassium control but with a wider food choice and greater fiber intake than the standard diet.

The use of intravenous iron in pregnancy: for whom and when? A survey of Australian and New Zealand obstetricians.

BACKGROUND: Iron deficiency anaemia in pregnancy (IDAP) affects 11-18% of Australian pregnancies and is associated with adverse perinatal outcomes. National prescribing data suggests the use of intravenous iron in pregnancy is increasingly common. This study aimed to: 1) Establish the current patterns of intravenous iron use by Fellows of the Royal Australian and New Zealand College of Obstetricians (FRANZCOG) when treating iron deficiency and IDAP including immediately postpartum and; 2) Assess FRANZCOG opinions regarding potential trial of intravenous iron for first-line treatment of IDAP. METHODS: An online survey of RANZCOG Fellows practicing obstetrics was distributed in September 2018. Results were analysed descriptively and responses compared by clinician demographics using Chi-squared testing. RESULTS: Of 484 respondents (21% of FRANZCOG), 457 were currently practicing obstetrics. Most prescribed intravenous iron in pregnancy (96%) and/or postpartum (85%). Most intravenous iron was prescribed for IDAP (98%) rather than iron deficiency without anaemia (53%), and for IDAP most commonly second-line to failed oral iron supplementation and first-line in special circumstances (59%). Intravenous iron prescribing was associated with shorter time since FRANZCOG completion (p = 0.01), public hospital practice (p = 0.008) and higher hospital birth numbers (p = 0.01). Most respondents (90%) would consider a randomised controlled trial of first-line intravenous iron for IDAP, although views on appropriate thresholds differed. CONCLUSIONS: Almost all respondents prescribed intravenous iron for IDAP, and while mostly used for second-line treatment over half sometimes used it first-line. With accelerating intravenous iron use, further research is required into its optimal use in pregnancy, recognizing important clinical outcomes and cost effectiveness.

Serum MicroRNA Signature as a Diagnostic and Therapeutic Marker in Patients with Psoriatic Arthritis.

OBJECTIVE: MicroRNA (miRNA) are small endogenous regulatory RNA molecules that have emerged as potential therapeutic targets and biomarkers in autoimmunity. Here, we investigated serum miRNA levels in patients with psoriatic arthritis (PsA) and further assessed a serum miRNA signature in therapeutic responder versus nonresponder PsA patients. METHODS: Serum samples were collected from healthy controls (HC; n = 20) and PsA patients (n = 31), and clinical demographics were obtained. To examine circulatory miRNA in serum from HC and PsA patients, a focused immunology miRNA panel was analyzed utilizing a miRNA Fireplex assay (FirePlex Bioworks Inc.). MiRNA expression was further assessed in responders versus nonresponders according to the European League Against Rheumatism response criteria. RESULTS: Six miRNA (miR-221-3p, miR-130a-3p, miR-146a-5p, miR-151-5p, miR-26a-5p, and miR-21-5p) were significantly higher in PsA compared to HC (all P < 0.05), with high specificity and sensitivity determined by receiver-operating characteristic curve analysis. Analysis of responder versus nonresponders demonstrated higher baseline levels of miR-221-3p, miR-130a-3p, miR-146a-5p, miR-151-5p, and miR-26a-5p were associated with therapeutic response. CONCLUSION: This study identified a 6-serum microRNA signature that could be attractive candidates as noninvasive markers for PsA and may help to elucidate the disease pathogenesis.

Dysregulated miR-125a promotes angiogenesis through enhanced glycolysis.

BACKGROUND: Although neoangiogenesis is a hallmark of chronic inflammatory diseases such as inflammatory arthritis and many cancers, therapeutic agents targeting the vasculature remain elusive. Here we identified miR-125a as an important regulator of angiogenesis. METHODS: MiRNA levels were quantified in Psoriatic Arthritis (PsA) synovial-tissue by RT-PCR and compared to macroscopic synovial vascularity. HMVEC were transfected with anti-miR-125a and angiogenic mechanisms quantified using tube formation assays, transwell invasion chambers, wound repair, RT-PCR and western blot. Real-time analysis of EC metabolism was assessed using the XF-24 Extracellular-Flux Analyzer. Synovial expression of metabolic markers was assessed by immunohistochemistry and immunofluorescent staining. MiR-125a CRISPR/Cas9-based knock-out zebrafish were generated and vascular development assessed. Finally, glycolytic blockade using 3PO, which inhibits Phosphofructokinase-fructose-2,6-bisphophatase 3 (PFKFB3), was assessed in miR-125a-/- ECs and zebrafish embryos. FINDINGS: MiR-125a is significantly decreased in PsA synovium and inversely associated with macroscopic vascularity. In-vivo, CRISPR/cas9 miR-125a-/- zebrafish displayed a hyper-branching phenotype. In-vitro, miR-125a inhibition promoted EC tube formation, branching, migration and invasion, effects paralleled by a shift in their metabolic profile towards glycolysis. This metabolic shift was also observed in the PsA synovial vasculature where increased expression of glucose transporter 1 (GLUT1), PFKFB3 and Pyruvate kinase muscle isozyme M2 (PKM2) were demonstrated. Finally, blockade of PFKFB3 significantly inhibited anti-miR-125a-induced angiogenic mechanisms in-vitro, paralleled by normalisation of vascular development of CRISPR/cas9 miR-125a-/- zebrafish embryos. INTEPRETATION: Our results provide evidence that miR-125a deficiency enhances angiogenic processes through metabolic reprogramming of endothelial cells. FUND: Irish Research Council, Arthritis Ireland, EU Seventh Framework Programme (612218/3D-NET).

Close Homolog of L1 Regulates Dendritic Spine Density in the Mouse Cerebral Cortex Through Semaphorin 3B.

Dendritic spines in the developing mammalian neocortex are initially overproduced and then eliminated during adolescence to achieve appropriate levels of excitation in mature networks. We show here that the L1 family cell adhesion molecule Close Homolog of L1 (CHL1) and secreted repellent ligand Semaphorin 3B (Sema3B) function together to induce dendritic spine pruning in developing cortical pyramidal neurons. Loss of CHL1 in null mutant mice in both genders resulted in increased spine density and a greater proportion of immature spines on apical dendrites in the prefrontal and visual cortex. Electron microscopy showed that excitatory spine synapses with postsynaptic densities were increased in the CHL1-null cortex, and electrophysiological recording in prefrontal slices from mutant mice revealed deficiencies in excitatory synaptic transmission. Mechanistically, Sema3B protein induced elimination of spines on apical dendrites of cortical neurons cultured from wild-type but not CHL1-null embryos. Sema3B was secreted by the cortical neuron cultures, and its levels increased when cells were treated with the GABA antagonist gabazine. In vivo CHL1 was coexpressed with Sema3B in pyramidal neuron subpopulations and formed a complex with Sema3B receptor subunits Neuropilin-2 and PlexinA4. CHL1 and NrCAM, a closely related L1 adhesion molecule, localized primarily to distinct spines and promoted spine elimination to Sema3B or Sema3F, respectively. These results support a new concept in which selective spine elimination is achieved through different secreted semaphorins and L1 family adhesion molecules to sculpt functional neural circuits during postnatal maturation.SIGNIFICANCE STATEMENT Dendritic spines in the mammalian neocortex are initially overproduced and then pruned in adolescent life through unclear mechanisms to sculpt maturing cortical circuits. Here, we show that spine and excitatory synapse density of pyramidal neurons in the developing neocortex is regulated by the L1 adhesion molecule, Close Homolog of L1 (CHL1). CHL1 mediated spine pruning in response to the secreted repellent ligand Semaphorin 3B and associated with receptor subunits Neuropilin-2 and PlexinA4. CHL1 and related L1 adhesion molecule NrCAM localized to distinct spines, and promoted spine elimination to Semaphorin 3B and -3F, respectively. These results support a new concept in which selective elimination of individual spines and nascent synapses can be achieved through the action of distinct secreted semaphorins and L1 adhesion molecules.