Scientific Understanding of Consciousness
Interneurons Project Long-Range in Hippocampus and Entorhinal Cortex
Science 23 March 2012: Vol. 335 no. 6075 pp. 1506-1510
Sarah Melzer1, Magdalena Michael1, Antonio Caputi1, Marina Eliava1, Elke C. Fuchs1, Miles A. Whittington2, Hannah Monyer1
1Department of Clinical Neurobiology of the Medical Faculty of Heidelberg University and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
2Institute of Neurosciences, The Medical School, Newcastle University, Framlington Place, Newcastle, NE2 4HH, UK.
The hippocampus and entorhinal cortex play a pivotal role in spatial learning and memory. The two forebrain regions are highly interconnected via excitatory pathways. Using optogenetic tools, we identified and characterized long-range γ-aminobutyric acid–releasing (GABAergic) neurons that provide a bidirectional hippocampal-entorhinal inhibitory connectivity and preferentially target GABAergic interneurons. Activation of long-range GABAergic axons enhances sub- and suprathreshold rhythmic theta activity of postsynaptic neurons in the target areas.
The excitatory projections connecting the hippocampus and entorhinal cortex account for the functional interdependence of these two brain regions. Excitatory neurons in the hippocampus and entorhinal cortex are under control of local γ-aminobutyric acid–releasing (GABAergic) interneurons. Some GABAergic neurons also project long distance. For example, long-range–projecting GABAergic cells connect hippocampus with medial septum and other extra-hippocampal brain areas, suggesting that interregional GABAergic connectivity might be less rare than was previously assumed.
To test for the presence of hippocampal GABAergic neurons projecting to the medial enthorinal cortex (MEC), we injected the retrograde tracer fluorogold (FG) into the MEC of wild-type mice. In addition to the expected labeling of numerous excitatory cells, we found FG+ neurons in stratum oriens and stratum radiatum of CA1 and in the hilus of the dentate gyrus (DG), indicating retrogradely labeled GABAergic cells. We detected FG-labeled cells coexpressing somatostatin in stratum oriens of CA1 (23 cells, nine mice) and also in the hilus of the DG (14 cells, nine mice)
Using immmunohistochemistry, electron microscopy (EM), and whole-cell patch-clamp recordings, we subsequently investigated whether long-range–projecting hippocampal SOM+ neurons form inhibitory synapses in the MEC.
Hippocampal SOM+ long-range–projecting neurons preferentially targeted GABAergic interneurons in the MEC.
FG injection into the MEC suggested that in addition to SOM+ cells, other hippocampal GABAergic neurons project to the MEC.
Retrograde labeling experiments have indicated the presence of long-range–projecting GABAergic cells in the opposite direction, from the entorhinal cortex to the hippocampus.
We also analyzed the entorhinal-hippocampal connections anatomically and functionally.
To establish the immunochemical identity of MEC GABAergic projection neurons, we combined FG retrograde labeling and immunohistochemistry, using different interneuron markers.
To directly investigate whether long-range GABAergic cells modulate the activity of targeted cells, we recorded sub- and suprathreshold activity in targeted interneurons in slices of the MEC and the hippocampus during stimulation of long-range–projecting axons.
Last, because theta oscillations can be induced pharmacologically in acute hippocampal slices we analyzed whether recruitment of long-range GABAergic cells affected network activity.
Using optogenetic viral tracing, we identified long-range GABAergic neurons connecting the hippocampus and the MEC. Furthermore, we provided functional evidence that long-range GABAergic neurons target local interneurons whose activity they modulate. It has been postulated that long-range–projecting GABAergic neurons might be an ideal substrate to precisely coordinate activity between distant brain regions. Long-range GABAergic neurons in the hippocampal-entorhinal formation might well account for the highly synchronized theta activity in the hippocampus and entorhinal cortex and thus contribute to the proposed mechanisms underlying spatial and temporal coding and ultimately spatial memory.
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