کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
3069342 | 1580646 | 2015 | 9 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Cortical alterations in a model for absence epilepsy and febrile seizures: In vivo findings in mice carrying a human GABA(A)R gamma2 subunit mutation Cortical alterations in a model for absence epilepsy and febrile seizures: In vivo findings in mice carrying a human GABA(A)R gamma2 subunit mutation](/preview/png/3069342.png)
• Cortical without thalamic alterations in absence epilepsy mice (G2R43Q) suggest a cortical disease focus.
• Layer 2/3 + 5/6 cells exhibit increased response variance and MP-shift after PTZ i.p.
• Cortical WC- and VSDI-responses to whisker stimuli are unchanged in G2R43Q.
• VSDI-measured cortical responses exhibit unchanged tangential signal spread in G2R43Q.
• Intact synaptic GABA-inhibition in G2R43Q, but apparent changes of tonic inhibition.
Childhood absence epilepsy (CAE) is one of the most common forms of epilepsy among children. The study of a large Australian family demonstrated that a point mutation in the gene encoding the gamma2 subunit of the GABA(A) receptor (G2R43Q) leads to an autosomal dominantly inherited form of CAE and febrile seizures (FS). In a transgenic mouse model carrying the gamma2 (R43Q) mutation heterozygous animals recapitulate the human phenotype. In-vitro experiments indicated that this point mutation impairs cortical inhibition and thus increases the likelihood of seizures.Here, using whole-cell (WC) and extracellular (EC) recordings as well as voltage-sensitive dye imaging (VSDI), we systematically searched for an in vivo correlate of cortical alterations caused by the G2R43Q mutation, as suggested by the mentioned in vitro results. We measured spontaneous and whisker-evoked activity in the primary somatosensory cortex and ventral posteriomedial nucleus of the thalamus (VPM) before and after intraperitoneal injection of the ictogenic substance pentylenetetrazol (PTZ) in urethane-anesthetized G2R43Q mice and controls in a blinded setting.Compared to wildtype controls in G2R43Q mice after PTZ injection we found 1.) Increased cortical spontaneous activity in layer 2/3 and layer 5/6 pyramidal neurons (increased standard deviation of the mean membrane potential in WC recordings), 2.) Increased variance of stimulus evoked cortical responses in VSDI experiments. 3.) The cortical effects are not due to increased strength or precision of thalamic output. In summary our findings support the hypothesis of a cortical pathology in this mouse model of human genetic absence epilepsy. Further study is needed to characterize underlying molecular mechanisms.
Journal: Neurobiology of Disease - Volume 77, May 2015, Pages 62–70