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, 15 (11), 1524-30

OLM Interneurons Differentially Modulate CA3 and Entorhinal Inputs to Hippocampal CA1 Neurons

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OLM Interneurons Differentially Modulate CA3 and Entorhinal Inputs to Hippocampal CA1 Neurons

Richardson N Leão et al. Nat Neurosci.

Abstract

The vast diversity of GABAergic interneurons is believed to endow hippocampal microcircuits with the required flexibility for memory encoding and retrieval. However, dissection of the functional roles of defined interneuron types has been hampered by the lack of cell-specific tools. We identified a precise molecular marker for a population of hippocampal GABAergic interneurons known as oriens lacunosum-moleculare (OLM) cells. By combining transgenic mice and optogenetic tools, we found that OLM cells are important for gating the information flow in CA1, facilitating the transmission of intrahippocampal information (from CA3) while reducing the influence of extrahippocampal inputs (from the entorhinal cortex). Furthermore, we found that OLM cells were interconnected by gap junctions, received direct cholinergic inputs from subcortical afferents and accounted for the effect of nicotine on synaptic plasticity of the Schaffer collateral pathway. Our results suggest that acetylcholine acting through OLM cells can control the mnemonic processes executed by the hippocampus.

Figures

Figure 1
Figure 1. Chrna2 is a marker for CA1 OLM interneurons
(a) Photomicrograph of a horizontal hippocampal slice of a Chrna2-Cre/R26tom mouse showing the distribution of Tomato+ cell bodies in SO. Note dense axonal arborizations of Tomato+ cells in SLM and the absence of Tomato+ cell bodies in CA3 or DG (scale bar=100µm). (b) Reconstruction of a biocytin filled Tomato+ neuron (scale bar=20µm, dendrites-red, axon-black); right inset, typical membrane response of a hippocampal Tomato+ neuron to hyper- and depolarizing current injection (scale bar=100ms/15mV). (c) Diagram of experimental setup (left) with TA stimulation (red) and green box delineating where VSD imaging was performed. The hippocampus diagram was adapted from ref. 47. VSD fluorescent responses to TA stimulation (10 pulses, 20Hz) were measured at rectangular regions in SR (black) and SLM (red). The excitation spread was defined as the ratio between the fluorescence variation in SR and SLM, measured 50ms after stimulus onset. Results comparing Chrna2-cre and Chrna2-cre/Viaatlx mice are shown in the right bar graph. Error bars denote ± s.e.m. (d) Expression of ChR2/YFP in Chrna2-cre cells in a hippocampal slice used for VSD imaging + optogenetic stimulation of OLMChR2 cells (top). Fluorescence changes at SR following SC stimulation in control with or without application of a 1.4mW laser light pulse (bottom left). Excitation of OLMChR2 cells with light produced an increase in the depolarization at SR following SC stimulation measured as the area under the curve of the fluorescence signal change in response to SC stimulation (bottom right). (e) Schematic and image of a PC dendritic voltage clamp recording at SR (left). Recordings of typical traces show excitation from AMPA EPSCs (isolated by blocking NMDA with dAP5) elicited by SC stimulation in control (black) and during blue light stimulation (horizontal bar) targeted at CA1 SO (red). The boxplot shows increased summation of AMPA mediated EPSCs during blue light stimulation of the CA1 SO region (red) compared to no light stimulation (black). *p<0.05.
Figure 2
Figure 2. OLMα2 cells inhibit interneurons that synapse on PC proximal dendrites
(a) Schematic of experimental setup (upper left). IPSCs in an SR interneuron (RN) were elicited by 20ms light pulse stimulation of OLMα2 cells transduced with Cre-inducible hChR2 (OLMChR2). Glutamatergic EPSCs were blocked by dAP5 and CNQX. Application of picrotoxin (PTX) abolished the postsynaptic response to blue light. Inset, APs triggered in an OLMChR2 cell by a 20ms light pulse. (b) Current clamp recordings showing EPSPs in the same SR interneuron as in a (black) elicited by SC stimulation (arrows). RN spiking elicited by concomitant current injection during SC stimulation lowered post-synaptic PC responses, as evidenced by voltage imaging of PCs electroporated with VSD. Changes in potential were measured at the region of interest delimited by the green rectangle shown on the top right micrograph; scale bar=20µm. (c) Bottom, reconstruction of the SR interneuron (filled with biocytin) shown in a and b. Top, confocal imaging showing synaptic contacts (arrows) between OLM cell axons (red) and RN dendrites (green). Scale bar=20µm. (d) IPSCs in a bistratified interneuron (BS) elicited by 20ms light pulse stimulation of OLMChR2 cells. The reconstruction of the BS interneuron is shown on the top left panel. Scale bar=50µm.
Figure 3
Figure 3. OLMα2 cells suppress LTP in the TA pathway
Potentiation of TA synapses after wTBS in hippocampal slices of animals transduced with hChR2 (Chrna2-cre/ChR2 and Chrna2-cre/Viaatlx/ChR2 mice) in control conditions (no light) and when a light pulse was applied 5 min prior to and during TA wTBS (see Methods). Top traces show fEPSPs before (black line), 10 min (dashed black line) and 30 min (red line) after wTBS (normalized to the peak amplitude). Bar graphs show the mean normalized slope 30 min after wTBS (*p<0.05). Error bars denote ± s.e.m. Schematic shows overview of stimulation setup.
Figure 4
Figure 4. OLMα2 cells enhance LTP in the SC pathway
(a) Potentiation of SC synapses in Chrna2-cre/ChR2 and Chrna2-cre/Viaatlx/ChR2 mice in control conditions (no light) and with a light pulse applied 5 min prior to and during SC wTBS. Top traces show normalized fEPSPs before (black line), 10 min (dashed black line) and 30 min (red line) after wTBS. Bar graphs show the mean normalized slope 30 min after wTBS. Error bars denote ± s.e.m. (b) Same as in a, but with 1µM bath-applied nicotine instead of light stimulation. Schematics show overview of stimulation setups.
Figure 5
Figure 5. OLMα2 cells receive remote cholinergic input
(a) Cholinergic EPSCs elicited by FF stimulation (gray; isolated by the application of glutamate and GABA receptor blockers; the black trace shows the average EPSC). The average EPSCs after the addition of the α7-blocker MLA (green trace) and the nicotine blocker MEC (red trace) are also shown. Peak EPSC amplitudes are shown on the right bar graph. Error bars denote ± s.e.m. Schematic shows overview of stimulation setup. (b) Average paired pulse ratio of FF-induced cholinergic EPSC in OLMα2 cells as a function of the inter-pulse interval. Error bars denote ± s.e.m. The top traces show examples of 25ms (left) and 100ms (right) inter-pulse intervals.

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