title: The synaptic protein encoded by the gene Slc10A4 suppresses epileptiform activity and regulates sensitivity to cholinergic chemoconvulsants.
abstract: The expanding number of disease-causing dysfunctions of synaptic proteins illustrates the importance of investigating newly discovered proteins involved in neuronal transmission. The gene Slc10A4 encodes a recently described carrier protein present in pre-synaptic terminals of cholinergic and monoaminergic neurons. The biological significance of this recently described transporter protein is currently unknown. We here investigated whether absence of the Slc10a4 protein has any impact on function of the cholinergic system. We first investigated the sensitivity of Slc10a4 null mice to cholinergic stimulus in vitro. In contrast to wild type mice, gamma oscillations occurred spontaneously in hippocampal slices from Slc10a4 null mice. Furthermore, moderate treatment of Slc10a4 null slices with the cholinergic agonist carbachol induced epileptiform activity. In vivo, 3-channel EEG measurements in freely behaving mice revealed that Slc10a4 null mice had frequent epileptiform spike-activity before treatment, and developed epileptic seizures, detected by EEG and accompanied by observable behavioral components, more rapidly after injection of the cholinergic agonist pilocarpine. Similar results were obtained on non-operated mice, as evaluated by behavioral seizures and post mortem c-Fos immunohistochemistry. Importantly, Slc10a4 null mice and wild type control mice were equally sensitive to the glutamatergic chemoconvulsant kainic acid, demonstrating that absence of Slc10a4 led to a selective cholinergic hypersensitivity. In summary, we report that absence of the recently discovered synaptic vesicle protein Slc10a4 results in increased sensitivity to cholinergic stimulation.
authors.affiliation: Department of Neuroscience, Uppsala University, Box 593, 751 24 Uppsala, Sweden. johan.zelano@neuro.uu.se
authors.forename: J
authors.initials: J
authors.lastname: Zelano
authors.forename: S
authors.initials: S
authors.lastname: Mikulovic
authors.forename: K
authors.initials: K
authors.lastname: Patra
authors.forename: M
authors.initials: M
authors.lastname: Kühnemund
authors.forename: M
authors.initials: M
authors.lastname: Larhammar
authors.forename: L
authors.initials: L
authors.lastname: Emilsson
authors.forename: R N
authors.initials: RN
authors.lastname: Leão
authors.forename: R
authors.initials: R
authors.lastname: Leao
authors.forename: K
authors.initials: K
authors.lastname: Kullander
mesh_terms: D000818:Animals; D000927:Anticonvulsants; D001522:Behavior, Animal / Q000187:drug effects; D018678:Cholinergic Agents / Q000494:pharmacology*; D003292:Convulsants / Q000494:pharmacology*; D004569:Electroencephalography; D055724:Electrophysiological Phenomena; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics*; D016762:Genes, fos / Q000187:drug effects; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000494:pharmacology*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics*; D010862:Pilocarpine / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D027981:Symporters / Q000235:genetics*; D013569:Synapses / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: D000927:Anticonvulsants; D018678:Cholinergic Agents; D003292:Convulsants; D009419:Nerve Tissue Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D016760:Proto-Oncogene Proteins c-fos; C000601541:SLC10A4 protein, mouse; D027981:Symporters; D033921:Vesicular Transport Proteins; D010862:Pilocarpine; C071908:sodium-bile acid cotransporter; D007608:Kainic Acid