Optogenetic Activation of Septal Glutamatergic Neurons Drive Hippocampal Theta Rhythms

J Neurosci. 2016 Mar 9;36(10):3016-23. doi: 10.1523/JNEUROSCI.2141-15.2016.


The medial septum and diagonal band of Broca (MS-DBB) has an essential role for theta rhythm generation in the hippocampus and is critical for learning and memory. The MS-DBB contains cholinergic, GABAergic, and recently described glutamatergic neurons, but their specific contribution to theta generation is poorly understood. Here, we examined the role of MS-DBB glutamatergic neurons in theta rhythm using optogenetic activation and electrophysiological recordings performed in in vitro preparations and in freely behaving mice. The experiments in slices suggest that MS-DBB glutamatergic neurons provide prominent excitatory inputs to a majority of local GABAergic and a minority of septal cholinergic neurons. In contrast, activation of MS-DBB glutamatergic fiber terminals in hippocampal slices elicited weak postsynaptic responses in hippocampal neurons. In the in vitro septo-hippocampal preparation, activation of MS-DBB glutamatergic neurons did increase the rhythmicity of hippocampal theta oscillations, whereas stimulation of septo-hippocampal glutamatergic fibers in the fornix did not have an effect. In freely behaving mice, activation of these neurons in the MS-DBB strongly synchronized hippocampal theta rhythms over a wide range of frequencies, whereas activation of their projections to the hippocampus through fornix stimulations had no effect on theta rhythms, suggesting that MS-DBB glutamatergic neurons played a role in theta generation through local modulation of septal neurons. Together, these results provide the first evidence that MS-DBB glutamatergic neurons modulate local septal circuits, which in turn contribute to theta rhythms in the hippocampus.

Keywords: glutamatergic; hippocampus; septum; theta.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Channelrhodopsins
  • Choline O-Acetyltransferase / genetics
  • Choline O-Acetyltransferase / metabolism
  • Diagonal Band of Broca / physiology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Glutamates / metabolism*
  • Hippocampus / physiology*
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Membrane Potentials / genetics
  • Mice
  • Neural Pathways / physiology
  • Neurons / physiology*
  • Optogenetics*
  • Quinoxalines / pharmacology
  • Septal Nuclei / cytology*
  • Synapsins / genetics
  • Synapsins / metabolism
  • Theta Rhythm / physiology*
  • Vesicular Glutamate Transport Protein 2 / genetics
  • Vesicular Glutamate Transport Protein 2 / metabolism


  • Bacterial Proteins
  • Channelrhodopsins
  • Excitatory Amino Acid Antagonists
  • Glutamates
  • Luminescent Proteins
  • Quinoxalines
  • Synapsins
  • Vesicular Glutamate Transport Protein 2
  • yellow fluorescent protein, Bacteria
  • FG 9041
  • Choline O-Acetyltransferase