title: Nicotine recruits a local glutamatergic circuit to excite septohippocampal GABAergic neurons.
abstract: Tonic impulse flow in the septohippocampal GABAergic pathway is essential for normal cognitive functioning and is sustained, in part, by acetylcholine (ACh) that is released locally via axon collaterals of septohippocampal cholinergic neurons. Septohippocampal cholinergic neurons degenerate in Alzheimer's disease and other neurodegenerative disorders. While the importance of the muscarinic effects of ACh on septohippocampal GABAergic neurons is well recognized, the nicotinic effects of ACh remain unstudied despite the reported benefits of nicotine on cognitive functioning. In the present study, using electrophysiological recordings in a rat brain slice preparation, rapid applications of nicotine excited 90% of retrogradely labelled septohippocampal GABA-type neurons with an EC50 of 17 microm and increased the frequency of spontaneously occurring, impulse-dependent fast GABAergic and glutamatergic synaptic currents via the alpha4beta2-nicotinic receptor. Interestingly, tetrodotoxin blocked all effects of nicotine on septohippocampal GABAergic type neurons, suggesting involvement of indirect mechanisms. We demonstrate that the effects of nicotine on septohippocampal GABA-type neurons involve recruitment of a novel, local glutamatergic circuitry as (i). Group I metabotropic glutamatergic receptor antagonists reduced the effects of nicotine; (ii). the number of nicotine responsive neurons was significantly reduced in recordings from slices that had been trimmed so as to reduce the number of glutamate-containing neurons within the slice preparation; (iii). in light and ultrastructural double immunocytochemical labelling studies vesicular glutamate 2 transporter immunoreactive terminals made synaptic contacts with parvalbumin-immunoreactive septohippocampal GABAergic neurons. The discovery of a local glutamatergic circuit within the septum may provide another avenue for restoring septohippocampal GABAergic functions in neurodegenerative disorders associated with a loss of septohippocampal cholinergic neurons.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine and the Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT 06508, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.forename: Tibor
authors.initials: T
authors.lastname: Hajszan
authors.forename: Csaba
authors.initials: C
authors.lastname: Leranth
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Alreja
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000157:Aconitine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000212:Acyclovir / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001285:Atropine / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D002038:Bungarotoxins / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D002452:Cell Count; D002794:Choline / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D003515:Cycloleucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004347:Drug Interactions; D004553:Electric Conductivity; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018756:GABA Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000648:ultrastructure; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D026901:Membrane Transport Proteins; D008854:Microscopy, Electron / Q000295:instrumentation / Q000379:methods; D009116:Muscarine / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010320:Parvalbumins / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D012118:Resorcinols / Q000494:pharmacology; D020665:Septum of Brain / Q000502:physiology* / Q000648:ultrastructure; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D013779:Tetrodotoxin / Q000494:pharmacology; D014403:Tubocurarine / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D050599:Vesicular Glutamate Transport Protein 2; D033921:Vesicular Transport Proteins; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C117789:7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester; D002038:Bungarotoxins; D002352:Carrier Proteins; D002867:Chromones; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D026901:Membrane Transport Proteins; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D018696:Neuroprotective Agents; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D010320:Parvalbumins; D012118:Resorcinols; C493475:Slc17a6 protein, rat; D050599:Vesicular Glutamate Transport Protein 2; D033921:Vesicular Transport Proteins; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; C054634:methyllycaconitine; D013779:Tetrodotoxin; C037591:buciclovir; D005680:gamma-Aminobutyric Acid; C079215:3,5-dihydroxyphenylglycine; D009538:Nicotine; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C056639:2-amino-5-phosphopentanoic acid; D001285:Atropine; D009116:Muscarine; D014633:Valine; D002794:Choline; D005998:Glycine; D014403:Tubocurarine; D000212:Acyclovir; D000157:Aconitine; D001640:Bicuculline