Synaptic Targets of Medial Septal Projections in the Hippocampus and Extrahippocampal Cortices of the Mouse

J Neurosci. 2015 Dec 2;35(48):15812-26. doi: 10.1523/JNEUROSCI.2639-15.2015.


Temporal coordination of neuronal assemblies among cortical areas is essential for behavioral performance. GABAergic projections from the medial septum and diagonal band complex exclusively innervate GABAergic interneurons in the rat hippocampus, contributing to the coordination of neuronal activity, including the generation of theta oscillations. Much less is known about the synaptic target neurons outside the hippocampus. To reveal the contribution of synaptic circuits involving the medial septum of mice, we have identified postsynaptic cortical neurons in wild-type and parvalbumin-Cre knock-in mice. Anterograde axonal tracing from the septum revealed extensive innervation of the hippocampus as well as the subiculum, presubiculum, parasubiculum, the medial and lateral entorhinal cortices, and the retrosplenial cortex. In all examined cortical regions, many septal GABAergic boutons were in close apposition to somata or dendrites immunopositive for interneuron cell-type molecular markers, such as parvalbumin, calbindin, calretinin, N-terminal EF-hand calcium-binding protein 1, cholecystokinin, reelin, or a combination of these molecules. Electron microscopic observations revealed septal boutons forming axosomatic or axodendritic type II synapses. In the CA1 region of hippocampus, septal GABAergic projections exclusively targeted interneurons. In the retrosplenial cortex, 93% of identified postsynaptic targets belonged to interneurons and the rest to pyramidal cells. These results suggest that the GABAergic innervation from the medial septum and diagonal band complex contributes to temporal coordination of neuronal activity via several types of cortical GABAergic interneurons in both hippocampal and extrahippocampal cortices. Oscillatory septal neuronal firing at delta, theta, and gamma frequencies may phase interneuron activity.

Keywords: entorhinal; hippocampus; inhibition; interneuron; medial septum; retrosplenial.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Entorhinal Cortex / physiology*
  • Fluorescent Dyes / metabolism
  • Hippocampus / physiology*
  • Male
  • Matrix Attachment Region Binding Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Confocal
  • Microscopy, Electron
  • Nerve Tissue Proteins / metabolism
  • Neural Pathways / physiology*
  • Neurons / physiology*
  • Neurons / ultrastructure
  • Parvalbumins / genetics
  • Parvalbumins / metabolism
  • Phytohemagglutinins / metabolism
  • Septal Nuclei / cytology
  • Septal Nuclei / physiology*
  • Synapses / physiology*
  • Synapses / ultrastructure
  • Vesicular Inhibitory Amino Acid Transport Proteins


  • Fluorescent Dyes
  • Matrix Attachment Region Binding Proteins
  • Nerve Tissue Proteins
  • Parvalbumins
  • Phytohemagglutinins
  • Satb1 protein, mouse
  • Vesicular Inhibitory Amino Acid Transport Proteins
  • Viaat protein, mouse
  • leukoagglutinins, plants