Patterns of seizures, hippocampal injury and neurogenesis in three models of status epilepticus in galanin receptor type 1 (GalR1) knockout mice.
The neuropeptide galanin exhibits anticonvulsant effects in experimental epilepsy. Two galanin receptor subtypes, GalR1 and GalR2, are present in the brain. We examined the role of GalR1 in seizures by studying the susceptibility of GalR1 knockout (KO) mice to status epilepticus (SE) and accompanying neuronal injury. SE was induced in GalR1 KO and wild type (WT) mice by Li-pilocarpine, 60 min electrical perforant path stimulation (PPS), or systemic kainic acid (KA). Seizures were analyzed using Harmonie software. Cell injury was examined by FluoroJade B- and terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end labeling; neurogenesis was studied using bromodeoxyuridine labeling. Compared with WT littermates, GalR1 KO showed more severe seizures, more profound injury to the CA1 pyramidal cell layer, as well as injury to hilar interneurons and dentate granule cells upon Li-pilocarpine administration. PPS led to more severe seizures in KO, as compared with WT mice. No difference in the extent of neuronal degeneration was observed between the mice of two genotypes in CA1 pyramidal cell layer; however, in contrast to WT, GalR1 KO developed mild injury to hilar interneurons on the side of PPS. KA-induced seizures did not differ between GalR1 KO and WT animals, and led to no injury to the hippocampus in either of experimental group. No differences were found between KO and WT mice in both basal and seizure-induced neuronal progenitor proliferation in all seizure types. Li-pilocarpine led to more extensive glia proliferation in GalR1 KO than in WT, and in both mouse types in two other SE models. In conclusion, GalR1 mediate galanin protection from seizures and seizure-induced hippocampal injury in Li-pilocarpine and PPS models of limbic SE, but not under conditions of KA-induced seizures. The results justify the development and use of GalR1 agonists in the treatment of certain forms of epilepsy.
Mazarati
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West Los Angeles Veteran Administration Medical Center, Research 151, 11301 Wilshire Boulevard, CA 90073, USA. mazarati@ucla.edu
Lu
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Shinmei
S
S
Badie-Mahdavi
H
H
Bartfai
T
T
D000818:Animals; D018891:Dentate Gyrus / Q000503:physiopathology; D004338:Drug Combinations; D004558:Electric Stimulation; D006624:Hippocampus / Q000473:pathology* / Q000503:physiopathology*; D007608:Kainic Acid; D018021:Lithium Chloride; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology; D019580:Perforant Pathway; D010862:Pilocarpine; D044091:Receptor, Galanin, Type 1 / Q000172:deficiency*; D013226:Status Epilepticus / Q000139:chemically induced / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D013234:Stem Cells / Q000473:pathology
D004338:Drug Combinations; D044091:Receptor, Galanin, Type 1; D010862:Pilocarpine; D018021:Lithium Chloride; D007608:Kainic Acid