Elsevier

Neuroscience

Volume 126, Issue 3, 2004, Pages 599-610
Neuroscience

Modulation of septo-hippocampal θ activity by GABAA receptors: an experimental and computational approach1

https://doi.org/10.1016/j.neuroscience.2004.03.043Get rights and content

Abstract

θ Frequency oscillation of the septo-hippocampal system has been considered as a prominent activity associated with cognitive function and affective processes. It is well documented that anxiolytic drugs diminish septo-hippocampal oscillatory θ activity contributing to their either therapeutic or unwanted side effects. In the present experiments we applied a combination of computational and physiological techniques to explore the functional role of GABAA receptors in θ oscillation. In electrophysiological experiments extracellular single unit recordings were performed from medial septum/diagonal band of Broca with simultaneous hippocampal (CA1) electroencephalogram (EEG) recordings from anesthetized rats. Neurotransmission at GABAA receptors were modulated by means of pharmacological tools: the actions of the GABAA receptor positive allosteric modulator diazepam and inverse agonist/negative allosteric modulator FG-7142 were evaluated on septo-hippocampal activity. Systemic administration of diazepam inhibited, whereas FG-7142 enhanced θ oscillation of septal neurons and hippocampal EEG θ activity. In parallel to these experimental observations, a computational model has been constructed by implementing a septal GABA neuron model with a CA1 hippocampal model containing three types of neurons (including oriens and basket interneurons and pyramidal cells; latter modeled by multicompartmental techniques; for detailed model description with network parameters see online addendum: http://geza.kzoo.edu/theta). This connectivity made the network capable of simulating the responses of the septo-hippocampal circuitry to the modulation of GABAA transmission, and the presently described computational model proved suitable to reveal several aspects of pharmacological modulation of GABAA receptors. In addition, computational findings indicated different roles of distinctively located GABAA receptors in θ generation.

Section snippets

Animals

All studies were conducted with male Sprague–Dawley rats (270–300 g; Harlan, Indianapolis, IN, USA). Animals were housed in groups of four, kept under conditions of controlled temperature (21±1 °C) and lighting (lights on 06:00–18:00 h) and were given food pellets and water ad libitum. Studies were performed between 8:00 and 17:00 h. All procedures were carried out under an approved animal use protocol and were in compliance with the Animal Welfare Act Regulations (9 CFR Parts 1, 2 and 3) and

In vivo electrophysiology of the septo-hippocampal system

Activity of MS/DB neurons recorded from anesthetized rats showed a considerable variability in their activity and firing pattern. The mean firing rate of MS/DB neurons calculated during the control period was 19.4±3.7 spikes/s (n=17), ranging from 0.4 to 50.3 spikes/s. As it has been previously established (Bland et al., 1999, Ford et al., 1989, Vertes and Kocsis, 1997), firing pattern of MS/DB neurons was directly related to hippocampal EEG activity, showing oscillation during hippocampal θ

Discussion

The present findings demonstrate that systemic administration of the anxiolytic diazepam, a positive allosteric modulator of GABAA receptors inhibits, whereas the anxiogenic FG-7142, a negative allosteric modulator of GABAA receptors enhances θ activity of the septo-hippocampal system. Responses of the septo-hippocampal system observed in pharmacological experiments are mirrored by our computational septo-hippocampal model, at both neuronal and circuitry levels, when the actions of allosteric

Acknowledgements

This work was supported by grants from the OTKA (T038140) and the OMFB (IKTA-00064/2003 KPI), the Henry R. Luce Foundation and a research grant from Pharmacia/Pfizer.

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    Supplementary data associated with this article can be found at doi:10.1016/j.neuroscience.2004.03.043.

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