title: The GABAA receptor agonist muscimol induces an age- and region-dependent form of long-term depression in the mouse striatum.
abstract: Several forms of long-term depression (LTD) of glutamatergic synaptic transmission have been identified in the dorsal striatum and in the nucleus accumbens (NAc). Such experience-dependent synaptic plasticity might play important roles in reward-related learning. The GABAA receptor agonist muscimol was recently found to trigger a long-lasting depression of glutamatergic synaptic transmission in the NAc of adolescent mice, but the mechanisms that underlie this novel form of LTD were not studied. Here we examined the effect of muscimol applied in the perfusion solution on the amplitude of field excitatory postsynaptic potentials/population spikes (fEPSP/PSs) in mouse brain slices. We found that muscimol depressed the fEPSP/PS in the NAc of adolescent mice but not adult mice, through both postsynaptic and presynaptic mechanisms. Indeed, muscimol altered the fEPSP/PS paired-pulse ratio, depolarized the membrane of projection neurons, and decreased the frequency, but not amplitude, of spontaneous excitatory postsynaptic currents in the NAc of adolescent mice. The LTD induced by muscimol likely involved endocannabinoids, metabotropic glutamate receptors (mGluRs), but not TRPV1 receptors. Muscimol-LTD was occluded by prior induction of LTD through low-frequency stimulation (LFS) of the slice, demonstrating a common pathway in the induction of LFS-LTD and muscimol-LTD. We also found that muscimol induced a form of LTD in the dorsolateral striatum of adult but not adolescent mice. This LTD was mediated by endocannabinoids but did not involve mGluRs or TRPV1 receptors. These results identify a novel form of synaptic plasticity, and its mechanisms of induction, which is age and region dependent. These findings may contribute to a better understanding of the increased susceptibility of the adolescent brain to long-term synaptic changes in regions associated with reward mechanisms.
authors.affiliation: The Karolinska Institute, Department of Physiology and Pharmacology, Section of Molecular Neurophysiology, 171 77 Stockholm, Sweden.
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: The Karolinska Institute, Department of Physiology and Pharmacology, Section of Molecular Neurophysiology, 171 77 Stockholm, Sweden.
authors.forename: Ning
authors.initials: N
authors.lastname: Yao
authors.affiliation: The Karolinska Institute, Department of Physiology and Pharmacology, Section of Molecular Neurophysiology, 171 77 Stockholm, Sweden karima.chergui@ki.se.
authors.forename: Karima
authors.identifier: 0000-0001-5702-0422
authors.initials: K
authors.lastname: Chergui
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000502:physiology*; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D058785:GABA-A Receptor Agonists / Q000008:administration & dosage*; D036881:Long-Term Synaptic Depression / Q000187:drug effects*; D008297:Male; D008810:Mice, Inbred C57BL; D009118:Muscimol / Q000008:administration & dosage*; D010880:Piperidines / Q000008:administration & dosage; D011720:Pyrazoles / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000502:physiology; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors / Q000502:physiology; D011963:Receptors, GABA-A / Q000502:physiology*; D050916:TRPV Cation Channels
chemical_list: D018691:Excitatory Amino Acid Antagonists; D058785:GABA-A Receptor Agonists; C578936:Grm5 protein, mouse; D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D064529:Receptor, Metabotropic Glutamate 5; D011963:Receptors, GABA-A; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D009118:Muscimol; C103505:AM 251; C121465:6-methyl-2-(phenylethynyl)pyridine