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The memory deficits associated with Alzheimer's disease result to a great extent from hippocampal network dysfunction. The coordination of this network relies on theta (symbol) oscillations generated in the medial septum. Here, we investigated in rats the impact of hippocampal amyloid beta (Abeta) injections on the physiological and cognitive functions that depend on the septohippocampal system. Hippocampal Abeta injections progressively impaired behavioral performances, the associated hippocampal theta power, and theta frequency response in a visuospatial recognition test. These alterations were associated with a specific reduction in the firing of the identified rhythmic bursting GABAergic neurons responsible for the propagation of the theta rhythm to the hippocampus, but without loss of medial septal neurons. Such results indicate that hippocampal Abeta treatment leads to a specific functional depression of inhibitory projection neurons of the medial septum, resulting in the functional impairment of the temporal network.

Cholinergic and GABAergic neurons in the medial septum-diagonal band of Broca (MS-DB) project to the hippocampus where they are involved in generating theta rhythmicity. So far, the functional properties of neurochemically identified MS-DB neurons are not fully characterized. In this study, MS-DB neurons recorded in urethane anesthetized rats and in unanesthetized restrained rats were labeled with neurobiotin and processed for immunohistochemistry against glutamic acid decarboxylase (GAD), parvalbumin (PV), and choline acetyltransferase (ChAT). The majority of the 90 labeled neurons (75.5%) were GAD+. Among them, 34.0% were also PV+, but none were ChAT+. Only 8.8% of the labeled neurons were found ChAT+. Remaining neurons (15.5%) were not identified. In anesthetized rats, all of the PV/GAD+ and 65% of GAD+ neurons exhibited burst-firing activity at the theta frequency. PV/GAD+ neurons displayed higher discharge rate and longer burst duration compared with GAD+ neurons. At variance, all of the ChAT+ neurons were slow-firing. Cluster-firing and tonic-firing were observed in GAD+ and unidentified neurons. In unanesthetized rats, during wakefulness or rapid eye movement sleep with hippocampal theta, the bursting neurons were PV/GAD+ or GAD+, whereas all of the ChAT+ neurons were slow-firing. Across the sleep–wake cycle, the GABAergic component of the septohippocampal pathway was always more active than the cholinergic one. The fact that cholinergic MS-DB neurons do not display theta-related bursting or tonic activity but have a very low firing rate questions how acetylcholine exerts its activating role in the septohippocampal system.

The hippocampal slice preparation was used to classify cholinergic effects in terms of muscarinic receptor subtypes (M1 or M2) and biochemical effector systems linked to these effects in CA1 pyramidal cells. Based on the action of the M1 antagonist pirenzepine and the M2 antagonist gallamine, the muscarinic-induced membrane depolarization and blockade of the afterhyperpolarization appear to result from activation of an M1 receptor, while the cholinergic depression of the EPSP and the blockade of a potassium current termed the M-current appears to involve the activation of an M2 receptor. All of the muscarinic actions could be observed in pertussis toxin-treated hippocampi, suggesting that a pertussis toxin-sensitive G-protein is not involved in these actions. Cholinergic agents that are weak agonists of phosphoinositide (PI) turnover are fully effective in all of the muscarinic actions except the blockade of the M-current on which they had little agonist activity and actually blocked the action of full agonists. These results strongly suggest that the blockade of the M-current may involve stimulation of PI turnover. In addition, we show that the blockade of the M-current is mimicked by intracellular application of inositol trisphosphate. Our results do not show any obvious relationship between the muscarinic receptor subtypes and the biochemical effector systems.