Histamine innervation and activation of septohippocampal GABAergic neurones: involvement of local ACh release.
Recent studies indicate that the histaminergic system, which is critical for wakefulness, also influences learning and memory by interacting with cholinergic systems in the brain. Histamine-containing neurones of the tuberomammillary nucleus densely innervate the cholinergic and GABAergic nucleus of the medial septum/diagonal band of Broca (MSDB) which projects to the hippocampus and sustains hippocampal theta rhythm and associated learning and memory functions. Here we demonstrate that histamine, acting via H(1) and/or H(2) receptor subtypes, utilizes direct and indirect mechanisms to excite septohippocampal GABA-type neurones in a reversible, reproducible and concentration-dependent manner. The indirect mechanism involves local ACh release, is potentiated by acetylcholinesterase inhibitors and blocked by atropine methylbromide and 4-DAMP mustard, an M(3) muscarinic receptor selective antagonist. This indirect effect, presumably, results from a direct histamine-induced activation of septohippocampal cholinergic neurones and a subsequent indirect activation of the septohippocampal GABAergic neurones. In double-immunolabelling studies, histamine fibres were found in the vicinity of both septohippocampal cholinergic and GABAergic cell types. These findings have significance for Alzheimer's disease and other neurodegenerative disorders involving a loss of septohippocampal cholinergic neurones as such a loss would also obtund histamine effects on septohippocampal cholinergic and GABAergic functions and further compromise hippocampal arousal and associated cognitive functions.
Department of Psychiatry, CMHC 335A, Yale University School of Medicine, 34 Park Street, New Haven, CT 06508, USA.
Changqing
C
Xu
Kimmo A
KA
Michelsen
Min
M
Wu
Elena
E
Morozova
Pertti
P
Panula
Meenakshi
M
Alreja
D000109:Acetylcholine / Q000502:physiology*; D000818:Animals; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D006632:Histamine / Q000494:pharmacology / Q000502:physiology*; D006633:Histamine Antagonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011969:Receptors, Histamine H1 / Q000187:drug effects / Q000502:physiology; D011970:Receptors, Histamine H2 / Q000187:drug effects / Q000502:physiology; D012686:Septal Nuclei / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D006633:Histamine Antagonists; D018727:Muscarinic Antagonists; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D005680:gamma-Aminobutyric Acid; D006632:Histamine; D000109:Acetylcholine