Biology subjects

Khlghatyan, J.

Publications and source records attributed to Khlghatyan, J..

5 recordsLinked to original sources

bioRxiv2021

Patient brain organoids identify a link between the 16p11.2 copy number variant and the RBFOX1 gene.

Copy number variants (CNVs) that delete or duplicate 30 genes within the 16p11.2 genomic region give rise to a range of neurodevelopmental phenotypes with high penetrance in humans. Despite the identification of this small region, the mechanisms by which 16p11.2 CNVs lead to disease are unclear. Relevant models, like human cortical organoids (hCOs), are needed to understand the human-specific mechanisms of neurodevelopmental disease. We generated hCOs from 18 patients and controls, profiling 167,958 cells with single cell (sc)RNA-seq. Analysis revealed neuronal-specific differential expression of genes outside of the 16p11.2 region that were related to cell-cell adhesion, neuronal projection growth, and neurodevelopmental disorders. Furthermore, 16p11.2 deletion syndrome organoids exhibited reduced mRNA and protein levels of RBFOX1, a gene which can also harbor CNVs linked to neurodevelopmental phenotypes. We found that many genes previously shown to be regulated by RBFOX1 are also perturbed in organoids from patients with 16p11.2 deletion syndrome, and thus identified a novel link between independent CNVs associated with neuronal development and autism. Overall, this work suggests convergent signaling, which indicates the possibility of a common therapeutic mechanism across multiple rare neuronal diseases.

neuroscience↗

bioRxiv2020

A miR-137-related biological pathway of risk for Schizophrenia is associated with human brain emotion processing

Genome-Wide-Association studies have involved miR-137 in schizophrenia. However, the biology underlying this statistical evidence is unclear. Statistical polygenic risk for schizophrenia is associated with working memory, while other biological evidence involves miR-137 in emotion processing. We investigated the function of miR-137 target schizophrenia risk genes in humans. We identified a prefrontal co-expression pathway of schizophrenia-associated miR-137 targets and validated the association with miR-137 expression in neuroblastoma cells. Alleles predicting greater co-expression of this pathway were associated with greater prefrontal activation during emotion processing in two independent cohorts of healthy volunteers (N1=222; N2=136). Statistical polygenic risk for schizophrenia was instead associated with prefrontal activation during working memory. A co-expression pathway links miR-137 and its target genes to emotion processing and risk for schizophrenia. Low prefrontal miR-137 expression may be related with SCZ risk via increased expression of target risk genes, itself associated with increased prefrontal activation during emotion processing.

neuroscience↗

bioRxiv2019

CRISPR/Cas9 mediated intersectional knockout of GSK3β in D2 receptor expressing mPFC neurons reveals contributions to emotional regulation

BackgroundGlycogen synthase kinase 3{beta} (GSK3{beta}) regulates neurodevelopment, synaptic plasticity as well as mood, cognition, social interaction, and depressive-like behaviors. Inhibition of GSK3{beta} is a shared consequence of treatment by lithium, SSRIs, ketamine and antipsychotics. GSK3{beta} activity is regulated by dopamine D2 receptor signaling and can be inhibited by psychoactive drugs in a D2 receptor dependent manner. Functions of GSK3{beta} in striatal D2 neurons has been studied extensively. However, GSK3{beta} is ubiquitously expressed in the brain and D2 receptor expressing cells are distributed as a mosaic in multiple cortical regions. This complicates the interrogation of GSK3{beta} functions in cortical D2 cells in a circuit defined manner using conventional animal models.\n\nMethodsWe have used a CRISPR/Cas9 mediated intersectional approach to achieve targeted deletion of GSK3{beta} in D2 expressing neurons of the adult medial prefrontal cortex (mPFC).\n\nResultsIsolation and analysis of ribosome associated RNA specifically from mPFC D2 neurons lacking GSK3{beta} demonstrated large scale translatome alterations. Deletion of GSK3{beta} in mPFC D2 neurons revealed its contribution to anxiety-related, cognitive, and social behaviors.\n\nConclusionsOur results underscore the viability of intersectional knockout approach to study functions of a ubiquitous gene in a network defined fashion while uncovering a contribution of GSK3{beta} expressed in mPFC D2 neurons in the regulation of behavioral dimensions related to mood and emotions. This advances our understanding of GSK3{beta} action at a brain circuit level and can potentially lead to the development of circuit selective therapeutics.

neuroscience↗

bioRxiv2019

Fxr1 regulates sleep and synaptic homeostasis

The fragile X autosomal homolog 1 (Fxr1) has been GWAS-associated to schizophrenia and insomnia but its contributions to brain functions are unclear. Homeostatic regulation of synaptic strength is essential for the maintenance of brain functions and engages both global and cell autonomous level processes. We used Crispr/Cas9-mediated somatic knockouts, overexpression, neuronal activity recordings and translatome sequencing, to examine the contribution of Fxr1 to cell-autonomous homeostatic synaptic scaling and global-level sleep homeostasis. Our findings indicate that Fxr1 is downregulated during scaling and sleep deprivation via a Gsk3{beta} dependent mechanism. In both conditions, downregulation of Fxr1 is essential for the homeostatic modulation of synaptic strength. Furthermore, overexpression of Fxr1 during sleep deprivation results in altered EEG signatures and reverts changes of translatome profiles. These findings indicate that Fxr1 represents a shared signaling hub linking cell autonomous homeostatic plasticity and system level sleep homeostasis with potential implications for neuropsychiatric illnesses.

neuroscience↗

bioRxiv2018

High sensitivity mapping of cortical dopamine D2 receptor expressing neurons

Cortical D2 dopamine receptor (Drd2) have mostly been examined in the context of cognitive function regulation and neurotransmission modulation of medial prefrontal cortex by principal neurons and parvalbumin positive, fast-spiking, interneurons in schizophrenia. Early studies suggested the presence of D2 receptors in several cortical areas, albeit with major technical limitations. We used combinations of transgenic reporter systems, recombinase activated viral vectors, quantitative translatome analysis and high sensitivity in situ hybridization to identify D2 receptor expressing cells and establish a map of their respective projections. Our results identified previously uncharacterized clusters of D2 expressing neurons in limbic and sensory regions of the adult mouse brain cortex. Characterization of these clusters by translatome analysis and cell type specific labeling revealed highly heterogeneous expression of D2 receptors in principal neurons and various populations of interneurons across cortical areas. Transcript enrichment analysis also demonstrated variable levels of D2 receptor expression and several orphan G-protein-coupled receptors co-expression in different neuronal clusters, thus suggesting strategies for genetic and therapeutic targeting of D2 expressing neurons in specific cortical areas. These results pave the way for a thorough reexamination of cortical D2 receptor functions, which could provide information about neuronal circuits involved in psychotic and mood disorders.

neuroscience↗