scholarly journals A Kalirin missense mutation enhances dendritic RhoA signaling and leads to regression of cortical dendritic arbors across development

2021 ◽  
Vol 118 (49) ◽  
pp. e2022546118
Author(s):  
Melanie J. Grubisha ◽  
Tao Sun ◽  
Leanna Eisenman ◽  
Susan L. Erickson ◽  
Shinny-yi Chou ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Missense Mutation ◽  
Clinical Symptoms ◽  
Unit Length ◽  
Gray Matter Volume ◽  
Primary Auditory Cortex ◽  
Spine Density ◽  
Nucleotide Exchange ◽  
Major Pathway ◽  
Dendritic Length

Normally, dendritic size is established prior to adolescence and then remains relatively constant into adulthood due to a homeostatic balance between growth and retraction pathways. However, schizophrenia is characterized by accelerated reductions of cerebral cortex gray matter volume and onset of clinical symptoms during adolescence, with reductions in layer 3 pyramidal neuron dendritic length, complexity, and spine density identified in multiple cortical regions postmortem. Nogo receptor 1 (NGR1) activation of the GTPase RhoA is a major pathway restricting dendritic growth in the cerebral cortex. We show that the NGR1 pathway is stimulated by OMGp and requires the Rho guanine nucleotide exchange factor Kalirin-9 (KAL9). Using a genetically encoded RhoA sensor, we demonstrate that a naturally occurring missense mutation in Kalrn, KAL-PT, that was identified in a schizophrenia cohort, confers enhanced RhoA activitation in neuronal dendrites compared to wild-type KAL. In mice containing this missense mutation at the endogenous locus, there is an adolescent-onset reduction in dendritic length and complexity of layer 3 pyramidal neurons in the primary auditory cortex. Spine density per unit length of dendrite is unaffected. Early adult mice with these structural deficits exhibited impaired detection of short gap durations. These findings provide a neuropsychiatric model of disease capturing how a mild genetic vulnerability may interact with normal developmental processes such that pathology only emerges around adolescence. This interplay between genetic susceptibility and normal adolescent development, both of which possess inherent individual variability, may contribute to heterogeneity seen in phenotypes in human neuropsychiatric disease.

scholarly journals A Kalirin Missense Mutation Enhances Dendritic RhoA Signaling and Leads to Regression of Cortical Dendritic Arbors Across Development

2021 ◽  
Author(s):  
MJ Grubisha ◽  
T Sun ◽  
SL Erickson ◽  
L Eisenman ◽  
S Chou ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Missense Mutation ◽  
Gray Matter ◽  
Clinical Symptoms ◽  
Gray Matter Volume ◽  
Spine Density ◽  
Major Pathway ◽  
Genetic Vulnerability ◽  
Matter Volume ◽  
Dendritic Length

ABSTRACTNormally, dendritic size is established prior to adolescence then remains relatively constant into adulthood due to a homeostatic balance between growth and retraction pathways. However, schizophrenia is characterized by accelerated reductions of cerebral cortex gray matter volume and onset of clinical symptoms during adolescence, with reductions in layer 3 pyramidal neuron dendritic length, complexity, and spine density identified in multiple cortical regions postmortem. Nogo receptor 1 (NGR1) activation of the GTPase RhoA is a major pathway restricting dendritic growth in the cerebral cortex. We show that the NGR1 pathway is stimulated by OMGp and requires the Rho guanine nucleotide exchange factor, Kalirin-9 (KAL9). Using a genetically encoded RhoA sensor, we demonstrate that a naturally occurring missense mutation in Kalrn, KAL-PT, that was identified in a schizophrenia cohort, confers enhanced RhoA activitation in neuronal dendrites compared to wildtype KAL. In mice containing this missense mutation at the endogenous locus there is an adolescent-onset reduction in dendritic length and complexity of layer 3 pyramidal neurons in the primary auditory cortex. Tissue density of dendritic spines was also reduced. Early adult mice with these structural deficts exhibited impaired detection of short gap durations. These findings provide a neuropsychiatric model of disease capturing how a mild genetic vulnerability may interact with normal developmental processes such that pathology only emerges around adolescence. This interplay between genetic susceptibility and normal adolescent development, both of which possess inherent individual variability, may contribute to heterogeneity seen in phenotypes in human neuropsychiatric disease.SIGNIFICANCE STATEMENTDendrites are long branching processes on neurons that contain small processes called spines that are the site of connections with other neurons, establishing cortical circuitry. Dendrites have long been considered stable structures, with rapid growth prior to adolescence followed by maintenance of size into adulthood. However, schizophrenia is characterized by accelerated reductions of cortical gray matter volume and onset of clinical symptoms during adolescence, with reductions in dendritic length present when examined after death. We show that dendrites retain the capacity for regression, and that a mild genetic vulnerability in a regression pathway leads to onset of structural impairments in previously formed dendrites across adolescence. This suggests that targeting specific regression pathways could potentially lead to new therapeutics for schizophrenia.

A joint study of whole exome sequencing and structural MRI analysis in major depressive disorder

2019 ◽  
Vol 50 (3) ◽  
pp. 384-395 ◽  
Author(s):  
Yamin Zhang ◽  
Mingli Li ◽  
Qiang Wang ◽  
Jacob Shujui Hsu ◽  
Wei Deng ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Rare Variants ◽  
Clinical Symptoms ◽  
Gray Matter Volume ◽  
Structural Mri ◽  
Genetic Component ◽  
Major Depressive ◽  
Genetic Components ◽  
Burden Test

AbstractBackgroundMajor depressive disorder (MDD) is a leading cause of disability worldwide and influenced by both environmental and genetic factors. Genetic studies of MDD have focused on common variants and have been constrained by the heterogeneity of clinical symptoms.MethodsWe sequenced the exome of 77 cases and 245 controls of Han Chinese ancestry and scanned their brain. Burden tests of rare variants were performed first to explore the association between genes/pathways and MDD. Secondly, parallel Independent Component Analysis was conducted to investigate genetic underpinnings of gray matter volume (GMV) changes of MDD.ResultsTwo genes (CSMD1, p = 5.32×10−6; CNTNAP5, p = 1.32×10−6) and one pathway (Neuroactive Ligand Receptor Interactive, p = 1.29×10−5) achieved significance in burden test. In addition, we identified one pair of imaging-genetic components of significant correlation (r = 0.38, p = 9.92×10−6). The imaging component reflected decreased GMV in cases and correlated with intelligence quotient (IQ). IQ mediated the effects of GMV on MDD. The genetic component enriched in two gene sets, namely Singling by G-protein coupled receptors [false discovery rate (FDR) q = 3.23×10−4) and Alzheimer Disease Up (FDR q = 6.12×10−4).ConclusionsBoth rare variants analysis and imaging–genetic analysis found evidence corresponding with the neuroinflammation and synaptic plasticity hypotheses of MDD. The mediation of IQ indicates that genetic component may act on MDD through GMV alteration and cognitive impairment.

Prenatal stress alters spine density and dendritic length of nucleus accumbens and hippocampus neurons in rat offspring

Synapse ◽  
2009 ◽  
Vol 63 (9) ◽  
pp. 794-804 ◽  
Author(s):  
Rubelia Isaura Martínez-Téllez ◽  
Elizabeth Hernández-Torres ◽  
Citlalli Gamboa ◽  
Gonzalo Flores
Keyword(s):  
Nucleus Accumbens ◽  
Prenatal Stress ◽  
Spine Density ◽  
Rat Offspring ◽  
Dendritic Length

scholarly journals Sex-Dependent Cortical Volume Changes in Patients with Degenerative Cervical Myelopathy

2021 ◽  
Vol 10 (17) ◽  
pp. 3965
Author(s):  
Talia C. Oughourlian ◽  
Chencai Wang ◽  
Noriko Salamon ◽  
Langston T. Holly ◽  
Benjamin M. Ellingson
Keyword(s):  
Cervical Myelopathy ◽  
Clinical Symptoms ◽  
Gray Matter Volume ◽  
Brain Regions ◽  
Cortical Volume ◽  
Female Patients ◽  
Asymptomatic Patients ◽  
Compensation Mechanisms ◽  
Male Patients ◽  
Degenerative Cervical Myelopathy

Degenerative cervical myelopathy (DCM) is a progressive condition characterized by degeneration of osseocartilaginous structures within the cervical spine resulting in compression of the spinal cord and presentation of clinical symptoms. Compared to healthy controls (HCs), studies have shown DCM patients experience structural and functional reorganization in the brain; however, sex-dependent cortical differences in DCM patients remains largely unexplored. In the present study, we investigate the role of sex differences on the structure of the cerebral cortex in DCM and determine how structural differences may relate to clinical measures of neurological function. T1-weighted structural MRI scans were acquired in 85 symptomatic and asymptomatic patients with DCM and 90 age-matched HCs. Modified Japanese Orthopedic Association (mJOA) scores were obtained for patients. A general linear model was used to determine vertex-level significant differences in gray matter volume (GMV) between the following groups (1) male HCs and female HCs, (2) male patients and female patients, (3) male patients and male HCs, and (4) female patients and female HCs. Within patients, males exhibited larger GMV in motor, language, and vision related brain regions compared to female DCM patients. Males demonstrated a significant positive correlation between GMV and mJOA score, in which patients with worsening neurological symptoms exhibited decreasing GMV primarily across somatosensory and motor related cortical regions. Females exhibited a similar association, albeit across a broader range of cortical areas including those involved in pain processing. In sensorimotor regions, female patients consistently showed smaller GMV compared with male patients, independent of mJOA score. Results from the current study suggest strong sex-related differences in cortical volume in patients with DCM, which may reflect hormonal influence or differing compensation mechanisms.

scholarly journals Rac GEF Dock4 interacts with cortactin to regulate dendritic spine formation

2013 ◽  
Vol 24 (10) ◽  
pp. 1602-1613 ◽  
Author(s):  
Shuhei Ueda ◽  
Manabu Negishi ◽  
Hironori Katoh
Keyword(s):  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Actin Binding ◽  
Spine Density ◽  
Nucleotide Exchange ◽  
Spine Formation ◽  
Nucleotide Exchange Factor ◽  
Important Interaction

In neuronal development, dendritic spine formation is important for the establishment of excitatory synaptic connectivity and functional neural circuits. Developmental deficiency in spine formation results in multiple neuropsychiatric disorders. Dock4, a guanine nucleotide exchange factor (GEF) for Rac, has been reported as a candidate genetic risk factor for autism, dyslexia, and schizophrenia. We previously showed that Dock4 is expressed in hippocampal neurons. However, the functions of Dock4 in hippocampal neurons and the underlying molecular mechanisms are poorly understood. Here we show that Dock4 is highly concentrated in dendritic spines and implicated in spine formation via interaction with the actin-binding protein cortactin. In cultured neurons, short hairpin RNA (shRNA)–mediated knockdown of Dock4 reduces dendritic spine density, which is rescued by coexpression of shRNA-resistant wild-type Dock4 but not by a GEF-deficient mutant of Dock4 or a truncated mutant lacking the cortactin-binding region. On the other hand, knockdown of cortactin suppresses Dock4-mediated spine formation. Taken together, the results show a novel and functionally important interaction between Dock4 and cortactin for regulating dendritic spine formation via activation of Rac.

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

2019 ◽  
Vol 39 (32) ◽  
pp. 6233-6250 ◽  
Author(s):  
Vishwa Mohan ◽  
Sarah D. Wade ◽  
Chelsea S. Sullivan ◽  
Michael R Kasten ◽  
Cassandra Sweetman ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Dendritic Spine ◽  
Spine Density ◽  
Dendritic Spine Density ◽  
Mouse Cerebral Cortex ◽  
Close Homolog

scholarly journals Volumetric Deficit Within the Fronto-Limbic-Striatal Circuit in First-Episode Drug Naïve Patients With Major Depression Disorder

2021 ◽  
Vol 11 ◽  
Author(s):  
Yiran Zhang ◽  
Yun Yang ◽  
Licheng Zhu ◽  
Qing Zhu ◽  
Yuxi Jia ◽  
...  
Keyword(s):  
Gray Matter ◽  
Clinical Symptoms ◽  
Gray Matter Volume ◽  
First Episode ◽  
Major Depression Disorder ◽  
Lingual Gyrus ◽  
Drug Naïve ◽  
The Right ◽  
The Brain ◽  
Depression Disorder

Background: Depression is a major psychiatric disorder and the leading cause of disability worldwide. Previous evidence suggested certain pattern of structural alterations were induced by major depression disorder (MDD) with heterogeneity due to patients' clinical characteristics and proposed that early impairment of fronto-limbic-striatal circuit was involved. Yet the hypothesis couldn't be replicated fully. Accordingly, this study aimed to validate this hypothesis in a new set of first-episode, drug naïve MDD patients and further explore the neuroimaging biomarker of illness severity using whole-brain voxel-based morphometry (VBM).Materials and Methods: A total of 93 participants, 30 patients with first-episode medication-naïve MDD, and 63 healthy controls were enrolled in the study. VBM was applied to analyze differences in the gray matter volume (GMV) between these two groups. The correlation between the GMV of the identified brain regions and the severity of clinical symptoms quantified by the Hamilton Depression Scale (HAMD) was further conducted in the post-hoc analysis to confirm the role of GMV structural alteration in clinical symptoms.Results: Our results revealed that the brain gray matter volume of the prefrontal lobe, limbic system, striatum, cerebellum, temporal lobe, and bilateral lingual gyri were significantly decreased in MDD patients compared with healthy controls. Besides, the HAMD scores were negatively correlated with GMV of the right insula and positively correlated with that of the right lingual gyrus.Conclusions: Our findings provide robust evidence that gray matter structural abnormalities within the prefronto-limbic-striatal circuit are implicated in the pathophysiology of MDD at an early stage without confounding influence of medication status. Besides, our data suggest that the cerebellum, lingual gyrus, and fusiform gyrus should also be integrated into the brain alterations in MDD. Future synthesis of individual neuroimaging studies and more advanced statistical analysis comparing subfields of the aforementioned regions are warranted to further shed light on the neurobiology of the disease and assist in the diagnosis of this burdensome disorder.

scholarly journals Volumetric Alterations of the Cerebral Cortex in Eating Disorders

2021 ◽  
Vol 10 (23) ◽  
pp. 5480
Author(s):  
Laura Vidal ◽  
Miguel A Ortega ◽  
Miguel Angel Alvarez-Mon ◽  
Melchor Álvarez-Mon ◽  
Guillermo Lahera
Keyword(s):  
Eating Disorders ◽  
Cerebral Cortex ◽  
Eating Disorder ◽  
Binge Eating ◽  
Cortical Thickness ◽  
Gray Matter ◽  
Binge Eating Disorder ◽  
Gray Matter Volume ◽  
The Right ◽  
The Brain

Eating disorders are relatively frequent psychiatric disorders that can produce serious consequences at the brain level. In an effort to clarify the neurobiological mechanisms of their pathogenesis, some studies have suggested the existence of modifications of the cortical architecture in eating disorders, but it is unknown whether the alterations described are a cause or consequence of eating disorders. The main objective of this systematic review is to collect the evidence available about the volumetric alterations of the cerebral cortex in eating disorders in adults and their apparent relationship with the pathogenesis of the disease. Initially, 91 articles were found by a search that included the terms anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder, gray matter, cortical thickness (CT), and brain volume. To pare down the articles, the following inclusion criteria were applied: (1) cortical thickness and/or gray matter volume (GMV) in patients with anorexia, bulimia nervosa, or binge-eating disorder was the main measure of the study; and (2) the sample was adult patients aged 18–65. The exclusion criteria were as follows: (1) articles that did not analyze cortical thickness or gray matter volume; (2) studies with patients with comorbidities; and (3) studies in patients who did not meet the DSM-IV/DSM-V criteria. In the first phase of selection, we proceeded to read the titles and abstracts as a first screen, thereby excluding 62 studies, followed by a complete critical reading of the 29 remaining articles. In this last phase, nine studies were excluded because they did not specify the eating disorder subtype, they included adolescents, or they did not measure GMV or CT. Finally, after the above systematic selection process, 20 articles were included in this review. Despite the methodological heterogeneity of the studies, there was some agreement between them. They showed an overall reduction in GMV in eating disorders, as well as alterations in certain regions of the cerebral cortex. Some of the most often mentioned cortical areas were the frontal, cingulate, and right orbitofrontal cortices, the precuneus, the right insula, and some temporoparietal gyri in cases of AN, with greater cortical involvement in frontotemporal and medial orbitofrontal regions in BN and binge eating disorder. Likewise, certain cortical regions, such as the left inferior frontal gyrus, the precuneus, the right superior motor area, the cingulate cortex, the insula, and the medial orbitofrontal sulcus, often remained altered after recovery from AN, making them potential cortical areas involved in the etiopathogenesis of AN. A reduction in GMV in specific areas of the CNS can inform us about the neurobiological mechanisms that underlie eating disorders as well as give us a better understanding of their possible consequences at the brain level.

scholarly journals Critical Role of TLR4 on the Microglia Activation Induced by Maternal LPS Exposure Leading to ASD-Like Behavior of Offspring

2021 ◽  
Vol 9 ◽  
Author(s):  
Lu Xiao ◽  
Junyan Yan ◽  
Di Feng ◽  
Shasha Ye ◽  
Ting Yang ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Frontal Cortex ◽  
Litter Size ◽  
Fetal Brain ◽  
Spine Density ◽  
Dendritic Length ◽  
Related Proteins ◽  
Lps Treatment ◽  
Synaptic Pruning

Objective: To investigate the role of TLR4 on the microglia activation in the pre-frontal cortex, which leads to autism-like behavior of the offspring induced by maternal lipopolysaccharide (LPS) exposure.Methods: Pregnant TLR4−/− (knockout, KO) and WT (wild type, WT) dams were intraperitoneally injected with LPS or PBS, respectively. The levels of TNFα, IL-1β, and IL-6 in the maternal serum and fetal brain were assessed with ELISA following LPS exposure. The gestation period, litter size and weight of the offspring were evaluated. Three-chamber sociability test, open field test and olfactory habituation/dishabituation test were used to assess the offspring's autism-like behavior at 7 weeks of age. Western blotting was performed to examine the levels of TLR4, Phospho-NFκB p65, IKKα, IBA-1, iNOS, Arg-1, C3, CR3A, NMDAR2A, and Syn-1 expression in the pre-frontal cortex. The morphological changes in the microglia, the distribution and expression of TLR4 were observed by immunofluorescence staining. Golgi-Cox staining was conducted to evaluate the dendritic length and spine density of the neurons in 2-week-old offspring.Results: Maternal LPS stimulation increased serum TNFα and IL-6, as well as fetal brain TNFα in the WT mice. The litter size and the weight of the WT offspring were significantly reduced following maternal LPS treatment. LPS-treated WT offspring had lower social and self-exploration behavior, and greater anxiety and repetitive behaviors. The protein expression levels of TLR4 signaling pathways, including TLR4, Phospho-NFκB p65, IKKα, and IBA-1, iNOS expression were increased in the LPS-treated WT offspring, whereas Arg-1 was decreased. Maternal LPS treatment resulted in the significant reduction in the levels of the synaptic pruning-related proteins, C3 and CR3A. Moreover, the neuronal dendritic length and spine density, as well as the expression levels of the synaptic plasticity-related proteins, NMDAR2A and Syn-1 were reduced in the WT offspring; however, gestational LPS exposure had no effect on the TLR4−/− offspring.Conclusion: Activation of TLR4 signaling pathway following maternal LPS exposure induced the abnormal activation of microglia, which in turn was involved in excessive synaptic pruning to decrease synaptic plasticity in the offspring. This may be one of the reasons for the autism-like behavior in the offspring mice.

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