scholarly journals Compensatory Mechanisms Modulate the Neuronal Excitability in a Kainic Acid-Induced Epilepsy Mouse Model

2018 ◽  
Vol 12 ◽  
Author(s):  
Gaojie Pan ◽  
Zhicai Chen ◽  
Honghua Zheng ◽  
Yunwu Zhang ◽  
Huaxi Xu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Kainic Acid ◽  
Neuronal Excitability ◽  
Compensatory Mechanisms

scholarly journals Anticonvulsant effect of dipropofol by enhancing native GABA currents in cortical neurons in mice

2018 ◽  
Vol 120 (3) ◽  
pp. 1404-1414 ◽  
Author(s):  
Jingliang Zhang ◽  
Xiaoling Chen ◽  
Matti Kårbø ◽  
Yi Zhao ◽  
Long An ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Mouse Model ◽  
Kainic Acid ◽  
Neuronal Excitability ◽  
Brain Slices ◽  
Anticonvulsant Effect ◽  
Dependent Manner ◽  
Whole Cell ◽  
Whole Cell Patch Clamp ◽  
Dose Dependent

Temporal lobe epilepsy (TLE), the most common pharmacoresistant focal epilepsy disorder, remains a major unmet medical need. Propofol is used as a short-acting medication for general anesthesia and refractory status epilepticus with issues of decreased consciousness and memory loss. Dipropofol, a derivative of propofol, has been reported to exert antioxidative and antibacterial activities. Here we report that dipropofol exerted anticonvulsant activity in a mouse model of kainic acid-induced seizures. Whole cell patch-clamp recordings of brain slices from the medial entorhinal cortex (mEC) revealed that dipropofol hyperpolarized the resting membrane potential and reduced the number of action potential firings, resulting in suppression of cortical neuronal excitability. Furthermore, dipropofol activated native tonic GABAA currents of mEC layer II stellate neurons in a dose-dependent manner with an EC50 value of 9.3 ± 1.6 μM (mean ± SE). Taken together, our findings show that dipropofol activated GABAA currents and exerted anticonvulsant activities in mice, thus possessing developmental potential for new anticonvulsant therapy. NEW & NOTEWORTHY The anticonvulsant effect of dipropofol was shown in a mouse model of kainic acid-induced seizures. Whole cell patch-clamp recordings of brain slices showed suppression of cortical neuronal excitability by dipropofol. Dipropofol activated the native tonic GABAA currents in a dose-dependent manner.

scholarly journals Astrocyte Glutamate Uptake and Water Homeostasis Are Dysregulated in the Hippocampus of Multiple Sclerosis Patients With Seizures

ASN NEURO ◽  
2020 ◽  
Vol 12 ◽  
pp. 175909142097960
Author(s):  
Andrew S. Lapato ◽  
Sarah M. Thompson ◽  
Karen Parra ◽  
Seema K. Tiwari-Woodruff
Keyword(s):  
Multiple Sclerosis ◽  
Mouse Model ◽  
Regional Differences ◽  
Neuronal Excitability ◽  
Demyelinating Disease ◽  
Glutamate Uptake ◽  
Cx43 Expression ◽  
Water Homeostasis ◽  
Hippocampal Astrocytes ◽  
Multiple Sclerosis Patients

While seizure disorders are more prevalent among multiple sclerosis (MS) patients than the population overall and prognosticate earlier death & disability, their etiology remains unclear. Translational data indicate perturbed expression of astrocytic molecules contributing to homeostatic neuronal excitability, including water channels (AQP4) and synaptic glutamate transporters (EAAT2), in a mouse model of MS with seizures (MS+S). However, astrocytes in MS+S have not been examined. To assess the translational relevance of astrocyte dysfunction observed in a mouse model of MS+S, demyelinated lesion burden, astrogliosis, and astrocytic biomarkers (AQP4/EAAT2/ connexin-CX43) were evaluated by immunohistochemistry in postmortem hippocampi from MS & MS+S donors. Lesion burden was comparable in MS & MS+S cohorts, but astrogliosis was elevated in MS+S CA1 with a concomitant decrease in EAAT2 signal intensity. AQP4 signal declined in MS+S CA1 & CA3 with a loss of perivascular AQP4 in CA1. CX43 expression was increased in CA3. Together, these data suggest that hippocampal astrocytes from MS+S patients display regional differences in expression of molecules associated with glutamate buffering and water homeostasis that could exacerbate neuronal hyperexcitability. Importantly, mislocalization of CA1 perivascular AQP4 seen in MS+S is analogous to epileptic hippocampi without a history of MS, suggesting convergent pathophysiology. Furthermore, as neuropathology was concentrated in MS+S CA1, future study is warranted to determine the pathophysiology driving regional differences in glial function in the context of seizures during demyelinating disease.

scholarly journals Changes in the Fluorescence Tracking of NaV1.6 Protein Expression in a BTBR T+Itpr3tf/J Autistic Mouse Model

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Musaad A. Alshammari ◽  
Mohammad R. Khan ◽  
Fawaz Alasmari ◽  
Abdulaziz O. Alshehri ◽  
Rizwan Ali ◽  
...  
Keyword(s):  
Mouse Model ◽  
Western Blot ◽  
Neuronal Excitability ◽  
Autism Spectrum ◽  
Wild Type ◽  
Western Blot Assay ◽  
Critical Determinant ◽  
Molecular Features ◽  
Voltage Gated Sodium Channels ◽  
Wild Type Control

The axon initial segment (AIS), the site of action potential initiation in neurons, is a critical determinant of neuronal excitability. Growing evidence indicates that appropriate recruitment of the AIS macrocomplex is essential for synchronized firing. However, disruption of the AIS structure is linked to the etiology of multiple disorders, including autism spectrum disorder (ASD), a condition characterized by deficits in social communication, stereotyped behaviors, and very limited interests. To date, a complete understanding of the molecular components that underlie the AIS in ASD has remained elusive. In this research, we examined the AIS structure in a BTBR T+Itpr3tf/J mouse model (BTBR), a valid model that exhibits behavioral, electrical, and molecular features of autism, and compared this to the C57BL/6J wild-type control mouse. Using Western blot studies and high-resolution confocal microscopy in the prefrontal frontal cortex (PFC), our data indicate disrupted expression of different isoforms of the voltage-gated sodium channels (NaV) at the AIS, whereas other components of AIS such as ankyrin-G and fibroblast growth factor 14 (FGF14) and contactin-associated protein 1 (Caspr) in BTBR were comparable to those in wild-type control mice. A Western blot assay showed that BTBR mice exhibited a marked increase in different sodium channel isoforms in the PFC compared to wild-type mice. Our results provide potential evidence for previously undescribed mechanisms that may play a role in the pathogenesis of autistic-like phenotypes in BTBR mice.

scholarly journals A Mouse Model of Repetitive Blast Traumatic Brain Injury Reveals Post-Trauma Seizures and Increased Neuronal Excitability

2020 ◽  
Vol 37 (2) ◽  
pp. 248-261 ◽  
Author(s):  
Vladislav Bugay ◽  
Eda Bozdemir ◽  
Fabio A. Vigil ◽  
Sang H. Chun ◽  
Deborah M. Holstein ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mouse Model ◽  
Neuronal Excitability ◽  
Blast Traumatic Brain Injury

Activation of mTOR signaling pathway is secondary to neuronal excitability in a mouse model of mesio-temporal lobe epilepsy

2015 ◽  
Vol 41 (7) ◽  
pp. 976-988 ◽  
Author(s):  
Ayako Shima ◽  
Naoki Nitta ◽  
Fumio Suzuki ◽  
Anne-Marie Laharie ◽  
Kazuhiko Nozaki ◽  
...  
Keyword(s):  
Mouse Model ◽  
Temporal Lobe Epilepsy ◽  
Signaling Pathway ◽  
Temporal Lobe ◽  
Neuronal Excitability ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway

scholarly journals Hormonal and Metabolic Defects in a Prader-Willi Syndrome Mouse Model with Neonatal Failure to Thrive

Endocrinology ◽  
2005 ◽  
Vol 146 (10) ◽  
pp. 4377-4385 ◽  
Author(s):  
M. Stefan ◽  
H. Ji ◽  
R. A. Simmons ◽  
D. E. Cummings ◽  
R. S. Ahima ◽  
...  
Keyword(s):  
Mouse Model ◽  
Growth Retardation ◽  
Failure To Thrive ◽  
Severe Hypoglycemia ◽  
Liver Glycogen ◽  
Postnatal Life ◽  
Prader Willi Syndrome ◽  
Loss Of Function ◽  
Compensatory Mechanisms ◽  
Energy Deficiency

Prader-Willi syndrome (PWS) has a biphasic clinical phenotype with failure to thrive in the neonatal period followed by hyperphagia and severe obesity commencing in childhood among other endocrinological and neurobehavioral abnormalities. The syndrome results from loss of function of several clustered, paternally expressed genes in chromosome 15q11-q13. PWS is assumed to result from a hypothalamic defect, but the pathophysiological basis of the disorder is unknown. We hypothesize that a fetal developmental abnormality in PWS leads to the neonatal phenotype, whereas the adult phenotype results from a failure in compensatory mechanisms. To address this hypothesis and better characterize the neonatal failure to thrive phenotype during postnatal life, we studied a transgenic deletion PWS (TgPWS) mouse model that shares similarities with the first stage of the human syndrome. TgPWS mice have fetal and neonatal growth retardation associated with profoundly reduced insulin and glucagon levels. Consistent with growth retardation, TgPWS mice have deregulated liver expression of IGF system components, as revealed by quantitative gene expression studies. Lethality in TgPWS mice appears to result from severe hypoglycemia after postnatal d 2 after depletion of liver glycogen stores. Consistent with hypoglycemia, TgPWS mice appear to have increased fat oxidation. Ghrelin levels increase in TgPWS reciprocally with the falling glucose levels, suggesting that the rise in ghrelin reported in PWS patients may be secondary to a perceived energy deficiency. Together, the data reveal defects in endocrine pancreatic function as well as glucose and hepatic energy metabolism that may underlie the neonatal phenotype of PWS.

scholarly journals HSAN-VI

2020 ◽  
Vol 6 (1) ◽  
pp. e389 ◽  
Author(s):  
Anisha Lynch-Godrei ◽  
Rashmi Kothary
Keyword(s):  
Mouse Model ◽  
Disease Severity ◽  
Bullous Pemphigoid ◽  
Autonomic Neuropathy ◽  
Genetic Disorder ◽  
Specific Effect ◽  
Sensory Neuropathy ◽  
Compensatory Mechanisms ◽  
Initial Characterization

Hereditary sensory and autonomic neuropathy (HSAN-VI) is a recessive genetic disorder that arises because of mutations in the human dystonin gene (DST, previously known as bullous pemphigoid antigen 1). Although initial characterization of HSAN-VI reported it as a sensory neuropathy that was lethal in infancy, we now know of a number of heterozygous mutations in DST that result in milder forms of the disease. Akin to what we observe in the mouse model dystonia musculorum (Dstdt), we believe that the heterogeneity of HSAN-VI can be attributed to a number of dystonin isoforms that the mutation affects. Lack of neuronal isoform dystonin-a2 is likely the universal determinant of HSAN-VI because all reported human cases are null for this isoform, as are all Dstdt mouse alleles. Compensatory mechanisms by intact dystonin-a isoforms also likely play a role in regulating disease severity, although we have yet to determine what specific effect dystonin-a1 and dystonin-a3 have on the pathogenesis of HSAN-VI.

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