A5068836840- Neuroscience and Neuropharmacology Research
- Ion channel regulation and function
- Genetics and Neurodevelopmental Disorders
- Cellular transport and secretion
- Neuroscience and Neural Engineering
- Epilepsy research and treatment
- Neural dynamics and brain function
- RNA and protein synthesis mechanisms
- CRISPR and Genetic Engineering
- Genomics and Chromatin Dynamics
- Nicotinic Acetylcholine Receptors Study
- Cardiac electrophysiology and arrhythmias
- Chromosomal and Genetic Variations
- RNA Research and Splicing
- Mitochondrial Function and Pathology
- Photoreceptor and optogenetics research
- Receptor Mechanisms and Signaling
- Amyotrophic Lateral Sclerosis Research
- Monoclonal and Polyclonal Antibodies Research
- Immune Cell Function and Interaction
- Lipid Membrane Structure and Behavior
- T-cell and Retrovirus Studies
- RNA modifications and cancer
- Advanced Memory and Neural Computing
- Diet and metabolism studies
Columbia University Irving Medical Center
2016-2025
Columbia University
2015-2024
Center for Genomic Science
2024
Jackson Laboratory
2001-2015
The University of Melbourne
2015
The Royal Melbourne Hospital
2015
Duke University
2015
Austin Health
2015
Florey Institute of Neuroscience and Mental Health
2015
Charing Cross Hospital
2015
We describe a hypothalamus-specific mRNA that encodes preprohypocretin, the putative precursor of pair peptides share substantial amino acid identities with gut hormone secretin. The hypocretin (Hcrt) protein products are restricted to neuronal cell bodies dorsal and lateral hypothalamic areas. fibers these neurons widespread throughout posterior hypothalamus project multiple targets in other areas, including brainstem thalamus. Hcrt immunoreactivity is associated large granular vesicles at...
The mouse mutant ducky, a model for absence epilepsy, is characterized by spike-wave seizures and ataxia. ducky gene was mapped previously to distal chromosome 9. High-resolution genetic physical mapping has resulted in the identification of the<i>Cacna2d2</i> encoding α2δ2 voltage-dependent calcium channel subunit. Mutations <i>Cacna2d2</i> were found underlie phenotype original (<i>du</i>) strain newly identified (<i>du</i><sup><i>2J</i></sup>). Both mutations are predicted result loss...
The "housekeeping" sodium/hydrogen exchanger, NHE1, mediates the electroneutral 1:1 exchange of Na+ and H+ across plasma membrane. NHE1 is ubiquitous studied extensively for regulation pH i, cell volume, response to growth factors. We describe a spontaneous mouse mutant, s low-w ave e pilepsy, (swe), with neurological syndrome including ataxia unique epilepsy phenotype consisting 3/sec absence tonic-clonic seizures. swe was fine-mapped on Chromosome 4 identified as null allele Nhe1. Mutants...
The neurological mutant mouse strain El is a model for complex partial seizures in humans. inheritance of epileptic with seven conventional chromosomal markers and over 60 endogenous proviral was studied by means backcrosses two seizure-resistant strains, DBA/2J ABP/LeJ. major gene responsible this phenotype ( El-1 ) localized to region distal respect the centromere on chromosome 9. At least one other gene, El-2 , linked 2, also influences seizure phenotype. In addition, potential modifier...
NMDA receptors play crucial roles in excitatory synaptic transmission. Rare variants GRIN2A encoding the GluN2A subunit are associated with a spectrum of disorders, ranging from mild speech and language delay to intractable neurodevelopmental including but not limited developmental epileptic encephalopathy. A de novo missense variant, p.Ser644Gly, was identified child this disorder, Grin2a knock-in mice were generated model extend understanding childhood disease. Homozygous heterozygous...
Gain-of-function (GOF) variants in K+ channels cause severe childhood epilepsies, but there are no mechanisms to explain how increased currents lead network hyperexcitability. Here, we introduce a human Na+-activated (KNa) channel variant (KCNT1-Y796H) into mice and, using multiplatform approach, find motor cortex hyperexcitability and early-onset seizures, phenotypes strikingly similar those of patients. Although the increases KNa cortical excitatory inhibitory neurons, is an increase...
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...
Summary Objective Evidence from basic neurophysiology and molecular genetics has implicated persistent sodium current conducted by voltage‐gated (Na V ) channels as a contributor to the pathogenesis of epilepsy. Many antiepileptic drugs target Na modulate neuronal excitability, mainly use‐dependent block transient current, although suppression may also contribute efficacy these drugs. We hypothesized that drug or compound capable preferential inhibition would have activity. Methods examined...
Excessive excitation is hypothesized to cause motoneuron (MN) degeneration in amyotrophic lateral sclerosis (ALS), but actual proof of hyperexcitation vivo missing, and trials based on this concept have failed. We demonstrate, by single-MN electrophysiology, that, contrary expectations, excitatory responses evoked sensory brainstem inputs are reduced MNs presymptomatic mutSOD1 mice. This impairment correlates with disrupted postsynaptic clustering Homer1b, Shank, AMPAR subunits. Synaptic...
Effective gene therapy for gain-of-function or dominant-negative disease mutations may require eliminating expression of the mutant copy together with wild-type replacement. We evaluated such a knockdown-replace strategy in mouse model DNM1 disease, debilitating and intractable neurodevelopmental epilepsy. To challenge approach robustly, we expressed patient-based variant GABAergic neurons-which resulted growth delay lethal seizures evident by postnatal week three-and delivered to newborn...
A novel gene (<i>Cacng2</i>;<i>γ<sub>2</sub></i>) encoding a protein similar to the voltage-activated Ca<sup>2+</sup> channel γ<sub>1</sub> subunit was identified as defective in epileptic and ataxic mouse, stargazer. In this study, we analyzed association of neuronal γ<sub>2</sub> with channels rabbit brain, function recombinant expressed in<i>Xenopus</i> oocytes. Our results showed that closely related (called γ<sub>3</sub>) co-sedimented co-immunoprecipitated subunits <i>in vivo</i>....
Absence epilepsy, characterized by spike–wave discharges (SWD) in the electroencephalogram, arises from aberrations within circuitry of cerebral cortex and thalamus that regulates awareness. The inbred mouse strain C3H/HeJ is prone to absence seizures, with a major susceptibility locus, spkw1, accounting for most phenotype. Here we find spkw1 associated hypomorphic retroviral-like insertion mutation Gria4 gene, encoding one four amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA)...
To elucidate the functional consequences of epileptic encephalopathy-causing de novo mutations in DNM1 (A177P, K206N, G359A), which encodes a large mechanochemical GTPase essential for neuronal synaptic vesicle endocytosis.HeLa and COS-7 cells transfected with wild-type mutant constructs were used transferrin assays, high-content imaging, colocalization studies, Western blotting, electron microscopy (EM). EM was also conducted on brain sections mice harboring middle-domain Dnm1 mutation...
Highlights•Tsc1-null late embryonic RGCs generate cytomegalic pyramidal neurons (CPNs)•CPNs are synaptically hyperexcitable and susceptible to seizure-like activities•Enhanced synaptic excitation in CPNs contributes epileptogenesis•Astrocyte gliosis evolves secondary recurrent seizuresSummaryTuberous sclerosis complex (TSC) is a developmental disorder associated with epilepsy, autism, cognitive impairment. Despite inactivating mutations the TSC1 or TSC2 genes hyperactive mechanistic target...