GABAergic Projections from the Medial Septum Selectively Inhibit Interneurons in the Medial Entorhinal Cortex

Abstract

The medial septum (MS) is required for theta rhythmic oscillations and grid cell firing in the medial entorhinal cortex (MEC). While GABAergic, glutamatergic, and cholinergic neurons project from the MS to the MEC, their synaptic targets are unknown. To investigate whether MS neurons innervate specific layers and cell types in the MEC, we expressed channelrhodopsin-2 in mouse MS neurons and used patch-clamp recording in brain slices to determine the response to light activation of identified cells in the MEC. Following activation of MS axons, we observed fast monosynaptic GABAergic IPSPs in the majority (Ͼ60%) of fast-spiking (FS) and low-threshold-spiking (LTS) interneurons in all layers of the MEC, but in only 1.5% of nonstellate principal cells (NSPCs) and in no stellate cells. We also observed fast glutamatergic responses to MS activation in a minority (Ͻ5%) of NSPCs, FS, and LTS interneurons. During stimulation of MS inputs at theta frequency (10 Hz), the amplitude of GABAergic IPSPs was maintained, and spike output from LTS and FS interneurons was entrained at low (25-60 Hz) and high (60 -180 Hz) gamma frequencies, respectively. By demonstrating cell type-specific targeting of the GABAergic projection from the MS to the MEC, our results support the idea that the MS controls theta frequency activity in the MEC through coordination of inhibitory circuits.

Rebound spiking in layer II medial entorhinal cortex stellate cells: Possible mechanism of grid cell function

“…Anterograde and retrograde tracing studies (Alonso & Köhler, 1984) have shown the EC receives anatomically specific inputs from the MSDB; inputs to medial EC tend to come from the most medial portions of the MSDB, where the most dense MSDB PV cell population is located (Alonso, Coveñas, Lara, & Aijón, 1990; Kiss, Patel, Baimbridge, & Freund, 1990). Recently it has been shown that optogenetic stimulation of axons of GABAergic medial septal cells causes monosynaptic IPSPs in over 60% of medial EC interneurons (Gonzalez-Sulser et al, 2014). The study distinguished mEC interneuron subtypes in terms of fast spiking and low-threshold spiking behaviors.…”

Inter- and intra-animal variation of integrative properties of stellate cells in the medial entorhinal cortex

“…An experimentally measured liquid junction potential of 12.9 mV was not corrected for. Stellate cells were identified by their large sag response and the characteristic waveform of their action potential afterhyperpolarization (see (Alonso and Klink, 1993;Gonzalez-Sulser et al, 2014;Nolan et al, 2007;Pastoll et al, 2012a) ).…”

“…The unidentified population had firing properties typical of layer 2 interneurons (cf. (Gonzalez-Sulser et al, 2014) ). A principal component analysis (PCA)( Figure 3D-F) clearly separated the L2PC population from the SC population, but did not identify subpopulations of SCs.…”

Theta oscillations gate the transmission of reliable sequences in the medial entorhinal cortex

“…In a biophysically realistic computational model of an MEC microcircuit we show that a stable grid pattern can be generated by coupling the network to theta oscillations from the medial septum 6,13 . Theta oscillations create periodic windows where the network is alternately receptive or resistant to perturbations.…”