A5077819675- Epigenetics and DNA Methylation
- Genetics and Neurodevelopmental Disorders
- Sleep and Wakefulness Research
- Neuroscience and Neuropharmacology Research
- Epilepsy research and treatment
- Sleep and related disorders
- Circadian rhythm and melatonin
- Ion channel regulation and function
- Stress Responses and Cortisol
- Folate and B Vitamins Research
- Birth, Development, and Health
- RNA modifications and cancer
- Neurogenesis and neuroplasticity mechanisms
- Tryptophan and brain disorders
- Dementia and Cognitive Impairment Research
- Genetic Syndromes and Imprinting
- Neurotransmitter Receptor Influence on Behavior
- Neuroendocrine regulation and behavior
- Identity, Memory, and Therapy
- Autism Spectrum Disorder Research
- Diet and metabolism studies
- Telomeres, Telomerase, and Senescence
- Nerve injury and regeneration
- Genetics, Aging, and Longevity in Model Organisms
- Dietary Effects on Health
University of Wisconsin–Madison
2016-2025
Neurological Surgery
2019-2025
Emory University
2009-2017
Universidade Federal de São Paulo
2003-2013
Zero to Three
2013
Stanford Medicine
2007
Istituto di Sessuologia Clinica
1997
University of Catania
1996
Voltage-gated sodium channels are required for the initiation and propagation of action potentials. Mutations in neuronal voltage-gated channel SCN1A associated with a growing number disorders including generalized epilepsy febrile seizures plus (GEFS+),(7) severe myoclonic infancy, familial hemiplegic migraine. To gain insight into effect mutations on excitability, we introduced human GEFS+ mutation SCN1A-R1648H orthologous mouse gene. Scn1a(RH/RH) mice homozygous R1648H exhibit spontaneous...
The mammalian genome contains four voltage-gated sodium channel genes that are primarily expressed in the central nervous system: SCN1A, SCN2A, SCN3A and SCN8A. Mutations SCN1A SCN2A responsible for several dominant idiopathic epilepsy disorders, including generalized with febrile seizures plus (GEFS+) severe myoclonic of infancy (SMEI). SCN8A associated cognitive deficits neuropsychiatric illness humans movement disorders mice; however, a role (Nav1.6) has not been investigated. To...
In a chemical mutagenesis screen, we identified the novel Scn8a8J allele of gene encoding neuronal voltage-gated sodium channel Na v 1.6. The missense mutation V929F in this alters an evolutionarily conserved residue pore loop domain 2 Electroencephalography (EEG) revealed well-defined spike-wave discharges (SWD), hallmark absence epilepsy, heterozygotes and for two classical Scn8a alleles, Scn8amed (null) Scn8amed-jo (missense). Mouse strain background had significant effect on SWD, with...
Abstract Chronic and severe stress exposure in early childhood is associated with the development of psychiatric disorders. Yet, molecular mechanisms underlying this relationship remain poorly understood. Here, we profile marks (DNA methylation gene expression) throughout human genome to determine associations between regulation. To do so, collected saliva tissue from prepubertal girls (mean age 10.9 ± 1.26 years) who had experienced different levels adversity, ranging mild severe. We found...
Orofacial clefts of the lip and palate are widely recognized to result from complex gene–environment interactions, but inadequate understanding environmental risk factors has stymied development prevention strategies. We interrogated role DNA methylation, an environmentally malleable epigenetic mechanism, in orofacial development. Expression key methyltransferase enzyme DNMT1 was detected throughout morphogenesis epithelium underlying cranial neural crest cell (cNCC) mesenchyme, a highly...
Differentially methylated positions (DMPs) between persons with and without late-onset Alzheimer’s disease (LOAD) were observed at 477 of 769,190 loci in a plurality genes. Of these, 17 shared DMPs identified using clinical LOAD markers analyzed independently as continuous variables comprising Rey Auditory Verbal Learning Test scores, cerebrospinal fluid total tau (t-tau) phosphorylated 181 (p-tau ) levels, t-tau/Aβ1–42 (Aβ 42 ), p-tau /Aβ , Aβ /Aβ1–40 40 ratios. In patients LOAD, 12 the...
Abstract INTRODUCTION Whole genome methylation sequencing (WGMS) in blood identifies differential DNA persons with late‐onset dementia due to Alzheimer's disease (AD) but has not been tested mild cognitive impairment (MCI). METHODS We used WGMS compare levels at 25,244,219 CpG loci 382 samples from 99 MCI, 109 AD, and 174 who are cognitively unimpaired (CU). RESULTS identified 9756 differentially methylated positions (DMPs) including 1743 genes encoding proteins biological pathways related...
Summary Purpose Mutations in the voltage‐gated sodium channel (VGSC) gene SCN1A are responsible for a number of epilepsy disorders, including genetic with febrile seizures plus ( GEFS +) and D ravet syndrome. In addition to seizures, patients mutations often experience sleep abnormalities, suggesting that may also play role neuronal pathways involved regulation sleep. However, date, architecture has not been directly examined. To fill this gap, we tested hypothesis contributes architecture,...
The autism spectrum disorders (ASD) comprise a broad group of behaviorally related neurodevelopmental affecting as many 1 in 68 children. hallmarks ASD consist impaired social and communication interactions, pronounced repetitive behaviors restricted patterns interests. Family, twin epidemiological studies suggest polygenetic epistatic susceptibility model involving the interaction genes; however, etiology is likely to be complex include both epigenetic environmental factors....
Methylation on the fifth position of cytosine (5-mC) is an essential epigenetic mark that linked to both normal neurodevelopment and neurological diseases. The recent identification another modified form cytosine, 5-hydroxymethylcytosine (5-hmC), in stem cells post-mitotic neurons, raises new questions as role this base mediating effects. Genomic studies these marks using model systems are limited, particularly with array-based tools, because standard method detecting DNA methylation cannot...
Environmental stress contributes to the development of psychiatric disorders, including posttraumatic disorder and anxiety. While even acute alters gene expression, molecular mechanisms underlying these changes remain largely unknown. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive DNA modification that highly enriched in brain associated with active transcription neuronal genes. Here we examined behavioral alterations adult mice experienced an early-life before weaning...
Abstract While embryonic mammalian central nervous system (CNS) axons readily grow and differentiate, only a minority of fully differentiated mature CNS neurons are able to regenerate injured axons, leading stunted functional recovery after injury disease. To delineate DNA methylation changes specifically associated with axon regeneration, we used Fluorescent-Activated Cell Sorting (FACS)-based methodology in rat optic nerve transection model segregate the retinal ganglion cells (RGCs) into...
It is a common clinical observation that stress accompanied by dysfunction of the hypothalamic-pituitary-ovarian axis, and there mounting experimental evidence CRH, principal regulator ACTH release central coordinator response, able to suppress gonadal function inhibiting hypothalamic GnRH release. Recently, it has been shown immunoreactive CRH messenger RNA, receptors are also present in ovary. This prompted us examine role on ovarian function. To accomplish this, we studied effects this...
Voltage-gated sodium channels (VGSCs) are responsible for the initiation and propagation of transient depolarizing currents play a critical role in electrical signaling between neurons. A null mutation VGSC gene SCN8A, which encodes transmembrane protein Nav1.6, was identified previously human family. Heterozygous carriers displayed range phenotypes, including ataxia, cognitive deficits, emotional instability. possible SCN8A also proposed studies examining genetic basis attempted suicide...
Summary Purpose Epilepsy is a complex disease characterized by predisposition toward seizures. There are numerous barriers to the successful treatment of epilepsy. For instance, current antiepileptic drugs have adverse side effects and variable efficacies. Furthermore, pathophysiologic basis epilepsy remains largely elusive. Therefore, investigating novel genes biologic processes underlying may provide valuable insight enable development new therapeutic agents. We previously identified...
Abstract INTRODUCTION DNA microarray‐based studies report differentially methylated positions (DMPs) in blood between late‐onset dementia due to Alzheimer's disease (AD) and cognitively unimpaired individuals, but interrogate < 4% of the genome. METHODS We used whole genome methylation sequencing (WGMS) quantify levels at 25,409,826 CpG loci 281 samples from 108 AD 173 individuals. RESULTS WGMS identified 28,038 DMPs throughout human methylome, including 2707 genes (e.g., SORCS3 , GABA...
Environmental stress is among the most important contributors to increased susceptibility develop psychiatric disorders. While it well known that acute environmental alters gene expression, molecular mechanisms underlying these changes remain largely unknown. 5-hydroxymethylcytosine (5hmC) a novel environmentally sensitive epigenetic modification highly enriched in neurons and associated with active neuronal transcription. Recently, we reported genome-wide disruption of hippocampal 5hmC male...