Serum Chemistry Values in Wild Black Vultures in Mississippi, USA

Vultures (Cathartidae and Accipitridae) play an important role in ecosystem balance by rapidly disposing animal carcasses and thus preventing the potential spread of pathogens. Blood chemistry values provide a means of assessing the health of wildlife and wild animal populations; however, there are significant differences in chemistries among species and when comparing captive and free-living New and Old World vultures. In 2007, we collected blood serum from 30 female and 14 male wild, healthy black vultures (Coragyps atratus) live-trapped by the U.S. Department of Agriculture, Animal and Plant Health Inspection Service, Wildlife Services from a power substation in Lowndes County, Mississippi, USA. We analyzed the blood serum to provide serum chemistry base values for use in clinical pathology. The chemical analytes we measured included sodium, chloride, potassium, carbon dioxide, anion gap, glucose, creatinine, calcium, phosphorus, total protein, albumin, globulin, and aspartate aminotransferase. In general, blood chemistry values of black vultures were similar to those found in New and Old World vultures and raptor species. Average chemistry values for males were lower than females for sodium, chloride, creatinine, calcium, total protein, albumin, and globulin. The serum chemistry values we describe in this paper can be important indicators of avian health by gender for the black vulture. Our study provided important blood chemistry values from a large sample size, which is rarely available in free-ranging black vultures. These values could be used by scientists, veterinary pathologists, wildlife rehabilitation centers, and other researchers for baseline data for wild and free-ranging birds. Furthermore, the use of such parameters in assessing population health may enable conservationists to further research environmental conditions affecting species reproduction and survival

Biallelic inherited SCN8A variants, a rare cause of SCN8A‐related developmental and epileptic encephalopathy

ObjectiveMonoallelic de novo gain‐of‐function variants in the voltage‐gated sodium channel SCN8A are one of the recurrent causes of severe developmental and epileptic encephalopathy (DEE). In addition, a small number of de novo or inherited monoallelic loss‐of‐function variants have been found in patients with intellectual disability, autism spectrum disorder, or movement disorders. Inherited monoallelic variants causing either gain or loss‐of‐function are also associated with less severe conditions such as benign familial infantile seizures and isolated movement disorders. In all three categories, the affected individuals are heterozygous for a SCN8A variant in combination with a wild‐type allele. In the present study, we describe two unusual families with severely affected individuals who inherited biallelic variants of SCN8A.MethodsWe identified two families with biallelic SCN8A variants by diagnostic gene panel sequencing. Functional analysis of the variants was performed using voltage clamp recordings from transfected ND7/23 cells.ResultsWe identified three probands from two unrelated families with DEE due to biallelic SCN8A variants. Each parent of an affected individual carried a single heterozygous SCN8A variant and exhibited mild cognitive impairment without seizures. In both families, functional analysis demonstrated segregation of one allele with complete loss‐of‐function, and one allele with altered biophysical properties consistent with partial loss‐of‐function.SignificanceThese studies demonstrate that SCN8A DEE may, in rare cases, result from inheritance of two variants, both of which exhibit reduced channel activity. In these families, heterozygosity for the dominant variants results in less severe disease than biallelic inheritance of two variant alleles. The clinical consequences of variants with partial and complete loss of SCN8A function are variable and likely to be influenced by genetic background.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153117/1/epi16371_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153117/2/epi16371.pd

The novel sodium channel modulator GS‐458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144249/1/epi14196.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144249/2/epi14196-sup-0001-SupInfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144249/3/epi14196_am.pd

Developmentally regulated impairment of parvalbumin interneuron synaptic transmission in an experimental model of Dravet syndrome

Dravet syndrome is a neurodevelopmental disorder characterized by epilepsy, intellectual disability, and sudden death due to pathogenic variants in SCN1A with loss of function of the sodium channel subunit Nav1.1. Nav1.1-expressing parvalbumin GABAergic interneurons (PV-INs) from young Scn1a+/− mice show impaired action potential generation. An approach assessing PV-IN function in the same mice at two time points shows impaired spike generation in all Scn1a+/− mice at postnatal days (P) 16–21, whether deceased prior or surviving to P35, with normalization by P35 in surviving mice. However, PV-IN synaptic transmission is dysfunctional in young Scn1a+/− mice that did not survive and in Scn1a+/− mice ≥ P35. Modeling confirms that PV-IN axonal propagation is more sensitive to decreased sodium conductance than spike generation. These results demonstrate dynamic dysfunction in Dravet syndrome: combined abnormalities of PV-IN spike generation and propagation drives early disease severity, while ongoing dysfunction of synaptic transmission contributes to chronic pathology

Astrocyte reactivity in a mouse model of SCN8A epileptic encephalopathy

ObjectiveSCN8A epileptic encephalopathy is caused predominantly by de novo gain-of-function mutations in the voltage-gated sodium channel Nav1.6. The disorder is characterized by early onset of seizures and developmental delay. Most patients with SCN8A epileptic encephalopathy are refractory to current anti-seizure medications. Previous studies determining the mechanisms of this disease have focused on neuronal dysfunction as Nav1.6 is expressed by neurons and plays a critical role in controlling neuronal excitability. However, glial dysfunction has been implicated in epilepsy and alterations in glial physiology could contribute to the pathology of SCN8A encephalopathy. In the current study, we examined alterations in astrocyte and microglia physiology in the development of seizures in a mouse model of SCN8A epileptic encephalopathy.MethodsUsing immunohistochemistry, we assessed microglia and astrocyte reactivity before and after the onset of spontaneous seizures. Expression of glutamine synthetase and Nav1.6, and Kir4.1 channel currents were assessed in astrocytes in wild-type (WT) mice and mice carrying the N1768D SCN8A mutation (D/+).ResultsAstrocytes in spontaneously seizing D/+ mice become reactive and increase expression of glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivity. These same astrocytes exhibited reduced barium-sensitive Kir4.1 currents compared to age-matched WT mice and decreased expression of glutamine synthetase. These alterations were only observed in spontaneously seizing mice and not before the onset of seizures. In contrast, microglial morphology remained unchanged before and after the onset of seizures.SignificanceAstrocytes, but not microglia, become reactive only after the onset of spontaneous seizures in a mouse model of SCN8A encephalopathy. Reactive astrocytes have reduced Kir4.1-mediated currents, which would impair their ability to buffer potassium. Reduced expression of glutamine synthetase would modulate the availability of neurotransmitters to excitatory and inhibitory neurons. These deficits in potassium and glutamate handling by astrocytes could exacerbate seizures in SCN8A epileptic encephalopathy. Targeting astrocytes may provide a new therapeutic approach to seizure suppression.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/172811/1/epi412564_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/172811/2/epi412564.pd

KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome.

Rett syndrome is a severe form of autism spectrum disorder, mainly caused by mutations of a single gene methyl CpG binding protein 2 (MeCP2) on the X chromosome. Patients with Rett syndrome exhibit a period of normal development followed by regression of brain function and the emergence of autistic behaviors. However, the mechanism behind the delayed onset of symptoms is largely unknown. Here we demonstrate that neuron-specific K(+)-Cl(-) cotransporter2 (KCC2) is a critical downstream gene target of MeCP2. We found that human neurons differentiated from induced pluripotent stem cells from patients with Rett syndrome showed a significant deficit in KCC2 expression and consequently a delayed GABA functional switch from excitation to inhibition. Interestingly, overexpression of KCC2 in MeCP2-deficient neurons rescued GABA functional deficits, suggesting an important role of KCC2 in Rett syndrome. We further identified that RE1-silencing transcriptional factor, REST, a neuronal gene repressor, mediates the MeCP2 regulation of KCC2. Because KCC2 is a slow onset molecule with expression level reaching maximum later in development, the functional deficit of KCC2 may offer an explanation for the delayed onset of Rett symptoms. Our studies suggest that restoring KCC2 function in Rett neurons may lead to a potential treatment for Rett syndrome

KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome

Rett syndrome is a severe form of autism spectrum disorder, mainly caused by mutations of a single gene methyl CpG binding protein 2 (MeCP2) on the X chromosome. Patients with Rett syndrome exhibit a period of normal development followed by regression of brain function and the emergence of autistic behaviors. However, the mechanism behind the delayed onset of symptoms is largely unknown. Here we demonstrate that neuron-specific K(+)-Cl(−) cotransporter2 (KCC2) is a critical downstream gene target of MeCP2. We found that human neurons differentiated from induced pluripotent stem cells from patients with Rett syndrome showed a significant deficit in KCC2 expression and consequently a delayed GABA functional switch from excitation to inhibition. Interestingly, overexpression of KCC2 in MeCP2-deficient neurons rescued GABA functional deficits, suggesting an important role of KCC2 in Rett syndrome. We further identified that RE1-silencing transcriptional factor, REST, a neuronal gene repressor, mediates the MeCP2 regulation of KCC2. Because KCC2 is a slow onset molecule with expression level reaching maximum later in development, the functional deficit of KCC2 may offer an explanation for the delayed onset of Rett symptoms. Our studies suggest that restoring KCC2 function in Rett neurons may lead to a potential treatment for Rett syndrome

Postictal Death Is Associated with Tonic Phase Apnea in a Mouse Model of Sudden Unexpected Death in Epilepsy

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167472/1/ana26053_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167472/2/ana26053.pd