Involvement of cholinergic and gabaergic systems in the fragile X knockout mice.
Fragile X syndrome is an inherited cause of mental retardation. We used extra- and intracellular recordings in brain slices obtained from wild type and fragile X knockout mice to establish whether bath application of the cholinergic agent carbachol (5 microM) induces different responses in neurons of the subiculum, a limbic structure involved in learning and memory. We found that carbachol diminished excitatory post-synaptic responses induced by CA1 stratum radiatum stimulation in wild type mice, but caused an unexpected increase in knockout animals. Moreover, these responses augmented in knockout mice after carbachol washout, a phenomenon that resembled the muscarinic long-term potentiation seen in wild type mice during application of carbachol and GABA(A) receptor antagonists. We also used paired-pulse stimulation to determine whether the changes in synaptic excitability induced by carbachol were caused by pre- or post-synaptic mechanism. Under control conditions, this protocol induced facilitation in both wild type and knockout mice; in contrast, during carbachol application, this facilitatory effect was seen in wild type mice only. In conclusion, our data highlight for the first time differences in cholinergic and GABA-ergic mechanisms that may contribute to the phenotype of fragile X patients.
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IRCCS Neuromed, Località Camerelle, 86077 Pozzilli (IS), Italy.
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D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology*; D018679:Cholinergic Agonists / Q000494:pharmacology*; D004195:Disease Models, Animal; D004347:Drug Interactions; D004558:Electric Stimulation; D051860:Fragile X Messenger Ribonucleoprotein 1; D005600:Fragile X Syndrome / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D018756:GABA Antagonists / Q000494:pharmacology*; D006624:Hippocampus / Q000033:anatomy & histology / Q000187:drug effects* / Q000503:physiopathology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010852:Picrotoxin / Q000494:pharmacology*; D016601:RNA-Binding Proteins; D011950:Receptors, Cholinergic / Q000502:physiology; D011963:Receptors, GABA-A / Q000502:physiology; D013997:Time Factors
D001285:Atropine; D002217:Carbachol; D018679:Cholinergic Agonists; D051860:Fragile X Messenger Ribonucleoprotein 1; D018756:GABA Antagonists; D018727:Muscarinic Antagonists; D009419:Nerve Tissue Proteins; D010852:Picrotoxin; D016601:RNA-Binding Proteins; D011950:Receptors, Cholinergic; D011963:Receptors, GABA-A; C497684:Fmr1 protein, mouse