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Published on: August 15, 2017
Adenylyl cyclases: expression in the developing rat thalamus and their role in absence epilepsy
Petra Ehling1, Tatyana Kanyshkova, Arnd Baumann
1Neurology Clinic-Inflammatory Disorders of the Nervous System and Neurooncology, and Institute of Physiology I - Neuropathophysiology, Westfälische Wilhelms-University, ICB, Mendelstr. 7, 48149, Muenster, Germany. Petra.Ehling@uni-muenster.de
Abstract:
Adenylyl cyclases (ACs) synthesize the second messenger cyclic AMP (cAMP) which influences the function of multiple ion channels. Former studies point to a malfunction of cAMP-dependent ion channel regulation in thalamocortical relay neurons that contribute to the development of the absence epileptic phenotype of a rat genetic model (WAG/Rij). Here, we provide detailed information about the thalamic gene and protein expression of Ca(2+)/calmodulin-activated AC isoforms in rat thalamus. Data from WAG/Rij were compared to those from non-epileptic controls (August-Copenhagen Irish rats) to elucidate whether differential expression of ACs contributes to the dysregulation of thalamocortical activity. At one postnatal stage (P21), we found the gene expression of two specific Ca(2+)-activated AC isoforms (AC-1 and AC-3) to be significantly down-regulated in epileptic tissue, and we identified the isoform AC-1 to be the most prominent one in both strains. However, Western blot data and analysis of enzymatic AC activity revealed no differences between the two strains. While basal AC activity was low, cAMP production was boosted by application of a forskolin derivative up to sevenfold. Despite previous hints pointing to a major contribution of ACs, the presented data show that there is no apparent causality between AC activity and the occurrence of the epileptic phenotype.
Insights
This study investigated adenylyl cyclase (AC) expression in a rat model of absence epilepsy. Despite altered gene expression of AC-1 and AC-3 in epileptic rats, overall AC activity did not differ, suggesting ACs are not causal to epilepsy.
Area of Science:
- Neuroscience
- Molecular Biology
- Epilepsy Research
Background:
- Adenylyl cyclases (ACs) produce cyclic AMP (cAMP), a crucial second messenger regulating ion channel function.
- Thalamocortical relay neurons exhibit cAMP-dependent ion channel dysregulation linked to absence epilepsy in WAG/Rij rats.
- The role of specific Ca(2+)/calmodulin-activated AC isoforms in epilepsy pathogenesis remains unclear.
Purpose of the Study:
- To characterize the gene and protein expression of Ca(2+)/calmodulin-activated AC isoforms in the rat thalamus.
- To compare AC expression and activity between epileptic WAG/Rij rats and non-epileptic controls.
- To determine if differential AC expression contributes to thalamocortical activity dysregulation in absence epilepsy.
Main Methods:
- Quantitative gene expression analysis (e.g., RT-PCR) of AC isoforms in rat thalamus.
- Western blot analysis to assess protein levels of specific AC isoforms.
- Measurement of enzymatic AC activity and cAMP production in brain tissue.
Main Results:
- Gene expression of Ca(2+)-activated AC isoforms AC-1 and AC-3 was significantly downregulated at postnatal day 21 in epileptic WAG/Rij rats compared to controls.
- AC-1 was identified as the most prominent isoform in both rat strains.
- Western blot and enzymatic activity assays revealed no significant differences in AC protein levels or activity between epileptic and control rats.
- Basal AC activity was low but could be significantly increased by forskolin stimulation in both groups.
Conclusions:
- While gene expression of specific AC isoforms (AC-1, AC-3) is altered in the epileptic rat model, this does not translate to differences in overall AC activity or protein levels.
- The study indicates that adenylyl cyclase activity is unlikely to be the primary cause of the observed thalamocortical dysregulation and absence epilepsy phenotype in WAG/Rij rats.
- Further research is needed to explore other molecular mechanisms underlying epilepsy in this model.
