The presence of pacemaker HCN channels identifies theta rhythmic GABAergic neurons in the medial septum

Abstract

The medial septum (MS) is an indispensable component of the subcortical network which synchronizes the hippocampus at theta frequency during specific stages of information processing. GABAergic neurons exhibiting highly regular firing coupled to the hippocampal theta rhythm are thought to form the core of the MS rhythm-generating network. In recent studies the hyperpolarization-activated, cyclic nucleotide-gated non-selective cation (HCN) channel was shown to participate in theta synchronization of the medial septum. Here, we tested the hypothesis that HCN channel expression correlates with theta modulated firing behaviour of MS neurons by a combined anatomical and electrophysiological approach. HCN-expressing neurons represented a subpopulation of GABAergic cells in the MS partly overlapping with parvalbumin (PV)-containing neurons. Rhythmic firing in the theta frequency range was characteristic of all HCN-expressing neurons. In contrast, only a minority of HCN-negative cells displayed theta related activity. All HCN cells had tight phase coupling to hippocampal theta waves. As a group, PV-expressing HCN neurons had a marked bimodal phase distribution, whereas PV-immunonegative HCN neurons did not show group-level phase preference despite significant individual phase coupling. Microiontophoretic blockade of HCN channels resulted in the reduction of discharge frequency, but theta rhythmic firing was perturbed only in a few cases. Our data imply that HCN-expressing GABAergic neurons provide rhythmic drive in all phases of the hippocampal theta activity. In most MS theta cells rhythm genesis is apparently determined by interactions at the level of the network rather than by the pacemaking property of HCN channels alone.

GABAergic Neurons of the Medial Septum Lead the Hippocampal Network during Theta Activity

“…In this study, partly the same datasets were analyzed as those published in the studies by Borhegyi et al (2004) and Varga et al (2008) (supplemental Table 1, available at www.jneurosci.org as supplemental material). Thus, only a brief description of electrophysiological and anatomical methods will be provided here (for full details, see the cited references and supplemental Methods, available at www.jneurosci.org as supplemental material).…”

“…Coronal sections of 60 m thick were cut on a vibratome from the tissue blocks. The immunofluorescent identification of neurons with the list of used primary and secondary antibodies is described by Borhegyi et al (2004) and Varga et al (2008) and also in the supplemental material (available at www.jneurosci.org). HCN1-immunoreactive neurons are referred to as HCN immunoreactive throughout this paper.…”

“…Thus, in this study, we investigated the following possible scenarios: (1) putative pacemaker MS neurons lead hippocampal field theta and hippocampal interneurons, proving a pacemaker role for the MS; (2) the activity changes of hippocampal interneurons precede those of MS cells, supporting the theory of hippocampal pacing of theta; (3) no significant temporal difference can be observed, which raises the possibility of a septal and a hippocampal pacemaker alternating or operating coincidentally, or a potential hidden pacemaker synchronizing the two areas. By implementing the circular statistical Z-shift method (Siapas et al, 2005), we demonstrated that alterations in the activity of the previously identified candidate pacemaker neurons (Borhegyi et al, 2004;Varga et al, 2008) in the MS precede those of putative hippocampal interneurons as well as corresponding changes in hippocampal field theta. Then, by using an information theoretical approach based on mutual information (MI) (Panzeri et al, 2007), we could show that the candidate pacemaker population of PV/HCN neurons share a higher amount of information with hippocampal theta than PV/HCN-immunonegative cells.…”

Distribution of type 1 cannabinoid receptor‐expressing neurons in the septal‐hypothalamic region of the mouse: Colocalization with GABAergic and glutamatergic markers

“…Various cognitive processes of the hippocampus depend on the theta rhythm which is generated and propagated to the hippocampus by GABAergic neurons located in the MS-DBB complex (Borhegyi et al, 2004;Varga et al, 2008) which selectively innervate GABAergic interneurons in the hippocampus (Freund and Antal, 1988).…”

Functional changes in the septal GABAergic system of animals with a model of temporal lobe epilepsy

“…The synchronization of the activity of a greater portion of the neuronal population in MSDB and the formation of theta-oscillations in response to the entry of significant afferent stimuli are provided by the GABAergic system (Vinogradova et al 1998;Wu et al 2000;Borhegyi et al 2004;Varga et al 2008).…”