Karoly Mirnics

Karoly Mirnics
University of Nebraska Medical Center | UNMC · Department of Developmental Neuroscience

MD, PhD

About

242
Publications
30,644
Reads
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13,084
Citations
Citations since 2016
47 Research Items
4822 Citations
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20162017201820192020202120220200400600800
Introduction
Research Interests and Projects: - Transcriptome changes across human brain disorders - Animal models of neurodevelopmental and psychiatric disorders - Effects of Gene*Environment interaction on the developing brain - Effects of Environment*Environment interaction on the developing brain - Peripheral biomarkers of neurodevelopmental and neuropsychiatric disorders - Neuroprotection by activity
Additional affiliations
July 2016 - present
Munroe-Meyer Institute for Genetics and Rehabilitation
Position
  • Managing Director
Description
  • Two NIH-funded projects as PI: • R01 MH110636 ‘Effects Of Environmental Challenges On Genetically Modified Interneuronal Subpopulations’ • R01 MH110636 "Vulnerability of DHCR7+/- mutation carriers to aripiprazole and trazodone treatment."
June 2006 - July 2016
Vanderbilt University
Position
  • Understanding and modeling gene expression changes discovered in human brain disorders
Description
  • From associate professor with tenure to full professor and James G. Blakemore endowed chair. For latest update on our research projects see lab website at www.mirnicslab.org.
January 2001 - June 2006
University of Pittsburgh
Position
  • Molecular pathobiology of schizophrenia
Description
  • Established independent laboratory as a tenure-track assistant professor and rose in ranks to associate professor.
Education
October 2009 - October 2010
Semmelweis University
Field of study
  • Biological Psychiatry
September 1980 - September 1986
University of Novi Sad, Novi Sad, Serbia
Field of study
  • Medicine

Publications

Publications (242)
Article
Cholesterol is ubiquitous in cells; it plays a critical role in membrane structure and transport as well as in intracellular trafficking processes. There are suggestions that cholesterol metabolism is linked to innate immunity with inhibitors of DHCR7, the last enzyme in the cholesterol pathway, suggested to have potential as viral therapeutics nea...
Article
Full-text available
Polypharmacy is commonly used to treat psychiatric disorders. These combinations often include drugs with sterol biosynthesis inhibiting side effects, including the antipsychotic aripiprazole (ARI), and antidepressant trazodone (TRZ). As the effects of psychotropic medications are poorly understood across the various tissue types to date, we invest...
Article
Background Somatostatin (SST) and Cholecystokinin (CCK) are peptide hormones that regulate the endocrine system, cell proliferation and neurotransmission. New Method We utilized the novel Easi-CRISPR system to generate two knock-in mouse strains with Cre recombinase in SST- and CCK-expressing cells and validated their utility in the developing and...
Article
Full-text available
De novo sterol synthesis is a critical homeostatic mechanism in the brain that begins during early embryonic development and continues throughout life. Multiple medications have sterol-biosynthesis-inhibiting side effects, with potentially detrimental effects on brain health. Using LC-MS/MS, we investigated the effects of six commonly used beta-blo...
Article
Full-text available
Polypharmacy, or the simultaneous use of multiple drugs to treat a single patient, is a common practice in psychiatry. Unfortunately, data on the health effects of commonly used combinations of medications are very limited. In this study, we therefore investigated the effects and interactions between two commonly prescribed psychotropic medications...
Preprint
Full-text available
Somatostatin (SST) and Cholecystokinin (CCK) are peptide hormones that regulate the endocrine system, cell proliferation and neurotransmission. Knock-in mouse models to study cell types that produce these critically important molecules are limited to date. To address this, we utilized the novel Easi- CRISPR system to generate two knock-in mouse str...
Article
Full-text available
Pancreatic cancer (PC) is characterized by metabolic deregulations that often manifest as deviations in metabolite levels and aberrations in their corresponding metabolic genes across the clinical specimens and preclinical PC models. Cholesterol is one of the critical metabolites supporting PC, synthesized or acquired by PC cells. Nevertheless, the...
Preprint
Full-text available
Ferroptosis is a form of cell death that has received considerable attention not only as a means to eradicate defined tumour entities but also because it provides unforeseen insights into the metabolic adaptation exploited by tumours to counteract phospholipid oxidation. Here, we identify a pro-ferroptotic activity of 7-dehydrocholesterol reductase...
Article
Full-text available
Smith-Lemli-Opitz syndrome (SLOS) is a severe monogenic disorder resulting in low cholesterol and high 7-dehydrocholesterol (7-DHC) levels. 7-DHC-derived oxysterols likely contribute to disease pathophysiology, and thus antioxidant treatment might be beneficial because of high oxidative stress. In a three-year prospective study, we investigated the...
Article
Cholesterol is essential for normal brain function and development. Genetic disruptions of sterol biosynthesis result in intellectual and developmental disabilities. Developing neurons synthesize their own cholesterol, and disruption of this process can occur by both genetic and chemical mechanisms. Many commonly prescribed medications interfere wi...
Article
Full-text available
The last step of cholesterol biosynthesis is the conversion of 7-dehydrocholesterol (7-DHC) into cholesterol, a reaction catalyzed by dehydrocholesterol reductase 7 (DHCR7). Investigation of the effect of Dhcr7 single-allele mutations on the metabolism of aripiprazole (ARI) and cariprazine (CAR) in maternally exposed transgenic pups revealed that A...
Article
Sterol biosynthesis is a critical homeostatic mechanism of the body. Sterol biosynthesis begins during early embryonic life and continues throughout life. Many commonly used medications, prescribed >200 million times in the United States annually, have a sterol biosynthesis inhibition side effect. Using our high-throughput LC-MS/MS method, we asses...
Article
Full-text available
Mouse brain contains over 100 million neuronal, glial, and other support cells. Developing neurons and astrocytes synthesize their own cholesterol, and disruption of this process can occur by both genetic and chemical mechanisms. In this study we have exposed cultured murine neurons and astrocytes to six different prescription medications that cros...
Article
Full-text available
Trazodone (TRZ) is a commonly prescribed antidepressant with significant off-label use for insomnia. A recent drug screening revealed that TRZ interferes with sterol biosynthesis, causing elevated levels of sterol precursor 7-dehydrocholesterol (7-DHC). Recognizing the well-documented, disruptive effect of 7-DHC on brain development, we designed a...
Article
Genes and environment interact during intrauterine life, and potentially alter the developmental trajectory of the brain. This can result in life-long consequences on brain function. We have previously developed two transgenic mouse lines that suppress Gad1 expression in parvalbumin (PVALB) and neuropeptide Y (NPY) expressing interneuron population...
Article
Full-text available
Cariprazine (CAR) is a strong inhibitor of the Dhcr7 enzyme, the last enzyme in the cholesterol biosynthesis pathway. We assessed the effects of CAR on maternally exposed Dhcr7+/− and wild-type mouse offspring, and tested the biochemical effects of CAR in human serum samples. Dhcr7+/− and wild-type time-pregnant mice were exposed to vehicle or 0.2...
Article
Amiodarone is prescribed for the treatment and prevention of irregular heartbeats. Although effective in clinical practice, the long-term use of amiodarone has many unwanted side effects, including cardiac, pulmonary, hepatic and neurological toxicities. Our objective was to elucidate effects of amiodarone exposure on the cholesterol metabolism in...
Article
Full-text available
Brain cholesterol biosynthesis, a separate and distinct process from whole-body cholesterol homeostasis, starts during embryonic development. To gain a better understanding of the neuronal and glial contributions to the brain cholesterol pool, we studied this process in control, Dhcr7 -/- , and Dhcr24 -/- cell cultures. Our LC-MS/MS method allowed...
Article
Full-text available
Mutations in both copies in the gene encoding 7-dehydrocholesterol reductase (DHCR7) cause Smith–Lemli–Opitz Syndrome (SLOS), which is characterized by a toxic elevation in 7-dehydrocholesterol (7-DHC). Aripiprazole (ARI) exposure, independent of genetic mutations, also leads to elevation of 7-DHC. We investigated the combined effect of a single-co...
Article
Cholesterol serves as a building material for cellular membranes and plays an important role in cellular metabolism. The brain relies on its own cholesterol biosynthesis, which starts during embryonic development. Cholesterol is synthesized from two immediate precursors, desmosterol and 7‐DHC. Mutations in the DHCR24 enzyme, which converts desmoste...
Article
Full-text available
Cholesterol synthesis is a complex, coordinated process involving a series of enzymes. As of today, our understanding of subcellular localization of cholesterol biosynthesis enzymes is far from complete. Considering the complexity and intricacies of this pathway and the importance of functions of DHCR7, DHCR24 and EBP enzymes for human health, we u...
Article
Introduction: Metabolic stress (e.g., gestational diabetes mellitus (GDM) and obesity) and infections are common during pregnancy, impacting fetal development and the health of offspring. Such antenatal stresses can differentially impact male and female offspring. We sought to determine how metabolic stress and maternal immune activation (MIA), ei...
Article
Full-text available
Maternal inflammation and diabetes increase the risk for psychiatric disorders in offspring. We hypothesized that these co-occurring risk factors may potentiate each other. To test this, we maternally exposed developing mice in utero to gestational diabetes mellitus (GDM) and/or maternal immune activation (MIA). Fetal mouse brains were exposed to e...
Article
Full-text available
Background: Genetic studies in autism have pinpointed a heterogeneous group of loci and genes. Further, environment may be an additional factor conferring susceptibility to autism. Transcriptome studies investigate quantitative differences in gene expression between patient-derived tissues and control. These studies may pinpoint genes relevant to...
Article
Full-text available
While antipsychotic medications provide important relief from debilitating psychotic symptoms, they also have significant adverse side effects, which might have relevant impact on human health. Several research studies, including ours, have shown that commonly used antipsychotics such as haloperidol and aripiprazole affect cholesterol biosynthesis...
Article
Full-text available
Smith-Lemli-Opitz syndrome is a recessive disorder caused by mutations in 7-dehyrocholesterol reductase (DHCR7) with a heterozygous carrier frequency of 1-3%. A defective DHCR7 causes accumulation of 7-DHC, which is a highly oxidizable and toxic compound. Recent studies suggest that several antipsychotics, including the highly-prescribed pharmaceut...
Article
Early parental loss is associated with social–emotional dysregulation and amygdala physiologic changes. Previously, we examined whole amygdala gene expression in infant monkeys exposed to early maternal deprivation. Here, we focus on an amygdala region with immature neurons at birth: the paralaminar nucleus (PL). We hypothesized that 1) the normal...
Article
Full-text available
Neuronal epigenomes, including chromosomal loopings moving distal cis-regulatory elements into proximity of target genes, could serve as molecular proxy linking present-day-behaviour to past exposures. However, longitudinal assessment of chromatin state is challenging, because conventional chromosome conformation capture assays essentially provide...
Data
Supplementary Figures 1-6, Supplementary Tables 1-2
Data
Top Counts of DamIDseq Normalized Read Counts
Article
A small library of pharmacologically active compounds (the NIH Clinical Collection) was assayed in Neuro2a cells to determine their effect on the last step in the biosynthesis of cholesterol, the transformation of 7-dehydrocholesterol (7-DHC) to cholesterol promoted by 7-dehydrocholesterol reductase, DHCR7. Of some 727 compounds in the NIH Clinical...
Article
In order to decipher the disease etiology, progression and treatment of multifactorial human brain diseases we utilize a host of different experimental models. Recently, patient-derived human dermal fibroblast (HDF) cultures have re-emerged as promising in vitro functional system for examining various cellular, molecular, metabolic and (patho)physi...
Article
Major depressive disorder (MDD) is one of the most prevalent major psychiatric disorders with a lifetime prevalence of 17%. Recent evidence suggests MDD is not only a brain dysfunction, but a systemic disease affecting the whole body. Central and peripheral inflammatory changes seem to be a centerpiece of MDD pathology: a subset of patients show el...
Article
Well-established cell culture models were combined with new analytical methods to assess the effects of small molecules on the cholesterol biosynthesis pathway. The analytical protocol, which is based on sterol derivation with the dienolphile PTAD, was found to be reliable for the analysis of 7-DHC and desmosterol. The PTAD method was applied to th...
Article
Full-text available
The maturation of the brain involves the coordinated expression of thousands of genes, proteins and regulatory elements over time. In sensory pathways, gene expression profiles are modified by age and sensory experience in a manner that differs between brain regions and cell types. In the auditory system of altricial animals, neuronal activity incr...
Data
Supplemental Material 3. Regional distribution of PVALB/dt-Tomato dual staining Micrographs of immunostained sections for dt-Tomato (left column) and PVALB (right column) from a Pvalb/Gad1 Tg mouse. Top panels – hippocampus; middle panels – supragranular cortical layers; bottom panels – nucleus reticularis thalami. Note the interneuronal distributi...
Data
Supplemental Material 6. Coordination, strength, acoustic startle and working memory are unperturbed in Pvalb/Gad1 Tg animals (A) coordination, (B) grip strength, (C) acoustic startle assessed before PPI testing, and (D) Y-maze alternation test. Supplemental Material 7. MOVIE: Wt animals are hesitant investigating the novel object. Supplemental Mat...
Data
Supplemental Material 5. Gad1 mRNA loss does not alter layer V prelimbic prefrontal cortical (PL-PFC) spontaneous excitatory postsynaptic currents (sEPSCs) Neither the (A) frequency nor (B) amplitude of Layer V PL-PFC sEPSCs is significantly different between PL-PFC WT or Pvalb/Gad1 Tg experimental conditions. (Panel A: Frequency: WT 4.28±0.51Hz vs...
Data
Supplemental Material 4. NPY+ and CCK+ interneuron density appears to be unchanged in the Pvalb/Gad1 transgenic (Tg) mice CCK immunostaining was performed using alexa-568 (red) fluorescence, NPY staining was carried out using alexa-488 (green). Representative micrographs denote hippocampus for CCK (top panels) and frontal cortex for NPY staining (b...
Article
Full-text available
Antagonists of the N-methyl-D-aspartate (NMDA)-type glutamate receptor induce psychosis in healthy individuals and exacerbate schizophrenia symptoms in patients. In this study we have produced an animal model of NMDA receptor hypofunction by chronically treating rats with low doses of the NMDA receptor antagonist MK-801. Subsequently, we performed...
Article
Full-text available
The NMDA receptor antagonist phencyclidine (PCP) creates schizophrenia-like symptoms in normal controls. The effect of PCP on non-human primate brain gene expression was examined and compared to changes induced by olanzapine treatment. Experimental studies of PCP and antipsychotic drugs have direct relevance to understanding the patho-physiology an...
Article
Full-text available
Major depressive disorder (MDD) is increasingly viewed as interplay of environmental stressors and genetic predisposition, and recent data suggest that the disease affects not only the brain, but the entire body. As a result, we aimed at determining whether patients with major depression have aberrant molecular responses to stress in peripheral tis...
Article
Full-text available
Reduced expression of the Gad1 gene-encoded 67-kDa protein isoform of glutamic acid decarboxylase (GAD67) is a hallmark of schizophrenia. GAD67 downregulation occurs in multiple interneuronal sub-populations, including the parvalbumin-positive (PVALB+) cells. To investigate the role of the PV-positive GABAergic interneurons in behavioral and molecu...
Article
Full-text available
Background Maternal immune activation and subsequent interleukin-6 (IL-6) induction disrupt normal brain development and predispose the offspring to developing autism and schizophrenia. While several proteins have been identified as having some link to these developmental disorders, their prevalence is still small and their causative role, if any,...
Article
Over the last decade transcriptome studies of postmortem tissue from subjects with schizophrenia revealed that synaptic, mitochondrial, immune system, GABA-ergic and oligodendrocytic changes are all integral parts of the disease process. The combined genetic and transcriptomics studies argue that the molecular underpinnings of the disease are even...