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The Journal of Neuroscience, May 15, 2000, 20(10):3900-3908
Cholinergic Excitation of Septohippocampal GABA But Not
Cholinergic Neurons: Implications for Learning and Memory
Min
Wu1,
Marya
Shanabrough2,
Csaba
Leranth2, 3, and
Meenakshi
Alreja1, 3
Departments of 1 Psychiatry, 2 Obstetrics
and Gynecology, and 3 Neurobiology, Yale University School
of Medicine and the Ribicoff Research Facilities, Connecticut Mental
Health Center, New Haven, Connecticut 06508
The medial septum/diagonal band (MSDB), which gives rise to the
septohippocampal pathway, is a critical locus for the mnemonic effects
of muscarinic drugs. Infusion of muscarinic cholinergic agonists into
the MSDB enhance learning and memory processes both in young and aged
rats and produce a continuous theta rhythm in the hippocampus.
Intraseptal muscarinic agonists also alleviate the amnesic syndrome
produced by systemic administration of muscarinic receptor antagonists.
It has been presumed, but not proven, that the cellular mechanisms
underlying the effects of muscarinic agonists in the MSDB involve an
excitation of septohippocampal cholinergic neurons and a subsequent
increase in acetylcholine (ACh) release in the hippocampus. Using a
novel fluorescent labeling technique to selectively visualize live
septohippocampal cholinergic neurons in rat brain slices, we have found
that muscarinic agonists do not excite septohippocampal cholinergic
neurons, instead they inhibit a subpopulation of cholinergic neurons.
In contrast, unlabeled neurons, confirmed to be noncholinergic,
septohippocampal GABA-type neurons using retrograde marking and
double-labeling techniques, are profoundly excited by muscarine. Thus,
the cognition-enhancing effects of muscarinic drugs in the MSDB cannot
be attributed to an increase in hippocampal ACh release. Instead,
disinhibitory mechanisms, caused by increased impulse flow in the
septohippocampal GABAergic pathway, may underlie the
cognition-enhancing effects of muscarinic agonists.
Key words:
theta rhythm; 192IgG; p75 receptor; neurotrophin; acetylcholine; memory; cognition; disinhibition
Copyright © 2000 Society for Neuroscience 0270-6474/00/20103900-09$05.00/0
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