Glutamatergic Neurons of the Mouse Medial Septum and Diagonal Band of Broca Synaptically Drive Hippocampal Pyramidal Cells: Relevance for Hippocampal Theta Rhythm

Abstract

Neurons of the medial septum and diagonal band of Broca (MS-DBB) provide an important input to the hippocampus and are critically involved in learning and memory. Although cholinergic and GABAergic MS-DBB neurons are known to modulate hippocampal activity, the role of recently described glutamatergic MS-DBB neurons is unknown. Here, we examined the electrophysiological properties of glutamatergic MS-DBB neurons and tested whether they provide a functional synaptic input to the hippocampus. To visualize the glutamatergic neurons, we used MS-DBB slices from transgenic mice in which the green fluorescent protein is expressed specifically by vesicular glutamate transporter 2-positive neurons and characterized their properties using whole-cell patch-clamp technique. For assessing the function of the glutamatergic projection, we used an in vitro septohippocampal preparation, electrically stimulated the fornix or chemically activated the MS-DBB using NMDA microinfusions and recorded postsynaptic responses in CA3 pyramidal cells. We found that glutamatergic MS-DBB neurons as a population display a highly heterogeneous set of firing patterns including fast-, cluster-, burst-, and slow-firing. Remarkably, a significant proportion exhibited fast-firing properties, prominent I h , and rhythmic spontaneous firing at theta frequencies similar to those found in GABAergic MS-DBB neurons. Activation of the MS-DBB led to fast, AMPA receptormediated glutamatergic responses in CA3 pyramidal cells. These results describe for the first time the electrophysiological signatures of glutamatergic MS-DBB neurons, their rhythmic firing properties, and their capacity to drive hippocampal principal neurons. Our findings suggest that the glutamatergic septohippocampal pathway may play an important role in hippocampal theta oscillations and relevant cognitive functions.

Synergy of Direct and Indirect Cholinergic Septo-Hippocampal Pathways Coordinates Firing in Hippocampal Networks

“…Sorted units were classified as single units, multi units, or artifacts based on spike shape and variance, ratio between spike peak value and noise level, the interspike interval distribution of each cluster, and the presence of a refractory period (Ͻ3 ms) for the single units. In addition, cross-correlograms were used to verify the clustering procedure as described by Harris et al (2000). Putative interneurons and principal cells were classified according to their spike width (time between peak and succeeding minimum) and the first moment (mean) of the autocorrelation time derived from a spike autocorrelogram from 0 to 50 ms (Csicsvari et al, 1998).…”

“…Consistent with this notion, both hippocampal ACh release and hippocampal theta activity are increased during exploration or novelty experience, as well as during arousal or stress (Giovannini et al, 2001;Anzalone et al, 2009;Stanley et al, 2012; for reviews see Bland, 1986;Stewart and Fox, 1990;Buzsáki, 2002;Buzsáki and Moser, 2013). Conversely, lesions of cholinergic MSDB neurons or the septo-hippocampal pathway impair recognition of novel place (Cai et al, 2012) and spatial learning (Berger-Sweeney et al, 2001;Moreau et al, 2008).…”

“…In this structure, ACh is thought to promote functional network states that allow efficient encoding of novel information. In hippocampal networks, this is achieved by increasing theta activity and synchronization of neurons within and across regions, thus promoting synaptic plasticity (Pavlides et al, 1988;Hyman et al, 2003). At the same time, ACh inhibits recurrent CA3 networks relevant for information retrieval.…”

Vestibular stimulation enhances hippocampal long-term potentiation via activation of cholinergic septohippocampal cells

“…We showed here that cholinergic activation during a rotation-induced theta rhythm is required for the enhancement of LTP. GABAergic and glutamatergic neurons in the MS may participate in generating a theta rhythm [32,[80][81][82], but the participation of these non-cholinergic inputs in hippocampal LTP during rotation and walking has not been shown.…”

Optogenetic activation of septal cholinergic neurons suppresses sharp wave ripples and enhances theta oscillations in the hippocampus

“…These numerous sources of theta generators are believed to be coordinated by the reciprocal connections between the septum and hippocampus (23), but the nature of this spatial-temporal coordination is not well understood (24). Both cholinergic and GABAergic neurons, and a small fraction of VGlut2 immunoreactive neurons (25), are believed to play a critical role in such global coordination (26,27). Although GABAergic neurons of the MS were demonstrated to be entrained at theta frequency, identified cholinergic neurons did not show theta-related discharge pattern (28,29).…”