Structural organization of long-range GABAergic projection system of the hippocampus

Abstract

GABA is a key mediator of neural activity in the mammalian central nervous system, and a diverse set of GABAergic neurons utilize GABA as a transmitter. It has been widely accepted that GABAergic neurons typically serve as interneurons while glutamatergic principal cells send excitatory signals to remote areas. In general, glutamatergic projection neurons monosynaptically innervate both principal cells and local GABAergic interneurons in each target area, and these GABAergic cells play a vital role in modulation of the activity of principal cells. The formation and recall of sensory, motor and cognitive representations require coordinated fast communication among multiple areas of the cerebral cortex, which are thought to be mostly mediated by glutamatergic neurons. However, there is an increasing body of evidence showing that specific subpopulations of cortical GABAergic neurons send long-range axonal projections to subcortical and other cortical areas. In particular, a variety of GABAergic neurons in the hippocampus project to neighboring and remote areas. Using anatomical, molecular and electrophysiological approaches, several types of GABAergic projection neurons have been shown to exist in the hippocampus. The target areas of these cells are the subiculum and other retrohippocampal areas, the medial septum and the contralateral dentate gyrus. The long-range GABAergic projection system of the hippocampus may serve to coordinate precisely the multiple activity patterns of widespread cortical cell assemblies in different brain states and among multiple functionally related areas.

Keywords: GABAergic neuron; hippocampus; long-range projection; medial septum; multiregional coordination; retrosplenial cortex; subiculum.

Figure 1

Summary diagram of the GABAergic efferents of the hippocampus. The long-range GABAergic projection system (blue) and major glutamatergic circuit (red) of the hippocampus and related limbic structures are schematically described. Four extrahippocampal targets are colored in green: medial septum (MS), subiculum (Sub Area), retrosplenial cortex (Rsp Ctx) and contralateral dentate gyrus (cDG). This figure highlights the efferent GABAergic pathway of the hippocampus, and thus its local collaterals and related glutamatergic circuits are only partially described. In the dentate gyrus, some of the hilar GABAergic neurons project to the medial septum (1) and others project to the cDG via the commissural pathway (2). The existence of GABAergic cells projecting to both the medial septum and the cDG has not been proven. The granule cells (g) in the dentate gyrus (DG) send mossy fiber axons to the ipsilateral CA3 area, while hilar mossy cells (m) send commissural axon to the contralateral side of the dentate gyrus. In the CA3 region, GABAergic cells projecting to the medial septum are scattered throughout all the layers (3). Some of the CA3 pyramidal cells (p) project back to the dentate gyrus, but they were omitted from this diagram for simplicity. In the CA1 region, there are three types of GABAergic projection neurons, i.e., those projecting exclusively to the medial septum (4), projecting to both the medial septum and subicular/retrosplenial area (5), and projecting exclusively to the subicular/retrosplenial area (6). In the CA1 region, the pyramidal cells (p) project not only to the subicular area but also to the lateral septum (not shown). In addition to the above hippocampal GABAergic projection neurons, earlier studies have also shown the existence of other interareal GABAergic connections in parallel to the glutamatergic circuits. For instance, the projection from the presubiculum comprises a small inhibitory component from GABAergic neurons (7) and targets entorhinal interneurons (van Haeften et al., 1997). The perforant path that originates from the entorhinal cortex may also have a small GABAergic component (8) in addition to the main glutamatergic projection (Germroth et al., 1989).

Figure 2

Distributions of retrogradely labeled GABAergic projection neurons following Fluoro-gold injection into the medial septum (A) or the subiculum (B). Each panel represents a 70-μm thick triple immunofluorescence labeled section for somatostatin (SOM), metabotropic glutamate receptor 1α (mGluR1α) and muscarinic acetylcholine receptor type 2 (M2R). (A) The H-MS cells are distributed in all regions of the hippocampus. In the CA1 area, most of them are in the stratum oriens (so). In the CA3 area, they are in the all layers, whereas they are restricted to the hilus (h) in the dentate gyrus (DG). Virtually all H-MS cells are SOM-positive, and the majority of them are SOM-positive/mGluR1α-positive/M2R-negative. In addition, there are also some triple-positive cells and SOM-positive/mGluR1α-negative/M2R-positive cells. (B) The H-Sub cells are mainly present in the CA1 region, and rarely found in the CA3 region and in the dentate gyrus. In the CA1 area, SOM-positive/mGluR1α-positive/M2R-negative projection cells are mostly detected in the stratum oriens, whereas SOM-negative/mGluR1α-negative/M2R-positive cells are present throughout all layers. In addition, SOM-negative/mGluR1α-positive/M2R-negative cells are distributed in strata radiatum (sr) and lacunosum-moleculare (slm). There are a few H-Sub cells immunonegative for all three molecules. Scale bar in (A) = 500 μm [applies to (A) and (B)]. gl, granule cell layer; ml, molecular layer; sl, stratum lucidum; sp, stratum pyramidale. Panels (A) and (B) are modified and reproduced from Jinno et al. (2007), with permission of the publisher.