The long and short of GABAergic neurons

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GABA (γ-aminobutyric acid) is the primary inhibitory neurotransmitter in the adult brain. Studies on GABAergic cells have focused almost exclusively on local interneurons neglecting those inhibitory neurons projecting to different brain areas, the ‘long-range GABAergic cells’. This review focuses on some common features and peculiarities of ‘corticofugal’ and ‘corticopetal’ GABAergic cells. Similarly to their local counterpart, long-range GABAergic cells show immunohistochemical diversity and contact locally both excitatory and inhibitory cells. Distally, long-range GABAergic cells often target other inhibitory neurons. This feature endows them with the ability to control remote target areas via disinhibition. On the basis of few functional studies that investigated their participation in synchronous network activity, we propose that long-range GABAergic neurons play a critical role in the temporal coordination of neuronal activity in distant brain areas.

Highlights

► We review selected corticopetal and corticofugal long-range GABAergic projections. ► Different technical approaches are discussed. ► GABAergic long-range projecting cells constitute a heterogeneous population. ► Long-range GABAergic neurons preferentially target inhibitory interneurons in distant brain regions. ► We propose that long-range GABAergic neurons synchronize distant neuronal networks.

Section snippets

Technical approaches to discover and study long-range GABAergic projections

Classical tracing studies constitute the major approach that has been used so far (reviewed in [11]). The most common anterograde tracers were tritiated amino acids, biotinylated dextran amine (BDA) and plant lectines (wheat germ agglutinin (WGA) and phaseolus vulgaris leucoagglutinin). Frequently used retrograde tracers include horseradish peroxidase, fast blue, diamino yellow, fluorogold, choleratoxin subunit b and fluorescently tagged beads. Retrograde tracings led to the identification of

Bidirectional GABAergic connectivity between hippocampus and medial septum

The septum has been long known to act as a pacemaker for rhythmic theta activity in the hippocampus, a major brain region involved in learning and memory. The long-range GABAergic connectivity between hippocampus and septum has been extensively studied with a wide range of technical approaches. A remarkable feature of this connectivity resides in the fact that long-range GABAergic cells connect the two brain structures in a bidirectional fashion. Tracing studies combined with

Bidirectional GABAergic connectivity between hippocampus and entorhinal cortex

The hippocampal–entorhinal formation comprises many cells that are spatially tuned and is thus thought to be the substrate for spatial maps and spatial learning [23]. The information transfer between these adjacently located brain areas has been attributed to bidirectional glutamatergic projections that have been extensively studied [24]. The presence of long-range entorhino-hippocampal [25] and hippocampo-entorhinal GABAergic projections [26] was revealed by retrograde tracing studies.

Neocortical long-range GABArgic connections

Within the neocortex, long-range projections were found to connect different areas both ipsilaterally and contralaterally and were identified in different species, including mouse [12], rat [32], guinea pig [33], cat [34] and monkey [35]. Immunohistochemical analysis showed that these neurons certainly do not constitute a homogeneous class. It was reported that a large proportion expresses SOM, NPY and neuronal nitric oxide synthase (nNOS) (reviewed in [36••]), with a high probability that

Corticofugal and corticopetal long-range projections

Long-range GABAergic cells have also been found to connect neocortical with subcortical areas. In contrast to the well-established and characterized cholinergic basal forebrain–cortex projection known to modulate the activity of target cells in a state-dependent manner [39], much less is known about long-range GABAergic projections. However, their presence could be easily inferred based on the simple observation that some subcortical nuclei that project to the cortex (e.g. ventral pallidum)

Diversity of long-range GABAergic cells

On the basis of the expression of marker proteins, it can be inferred that in many brain regions long-range GABAergic cells constitute a heterogeneous cell population (Table 1). This is fairly scarce information if one considers the numerous variables that are taken into consideration when attempts were made to classify short-range, that is, local GABAergic interneurons. There is, however, a certain leitmotiv regarding the immunoidentity of long-range GABAergic cells, namely that those

Targets of long-range GABAergic cells

It seems logical to take target areas into account when attempting to classify long-range GABAergic cells, however, some long-range GABAergic cells project to multiple target areas. For instance, based on reconstruction data of in vivo filled cells, Jinno and colleagues [20] demonstrated that source cells located in the hippocampus project to the medial septum and subiculum. In addition, the in vitro filled hippocampal cells studied by Losonczy and colleagues [65] reveal projections in the

Functions of long-range GABAergic projections and other open questions

Despite the increasing number of studies that convincingly demonstrate the presence of long-range GABAergic cells in the forebrain, more knowledge pertaining to the identity of target cells is warranted if we are to understand how they control macrocircuits. Since most studies employed anterograde tracing combined with EM and occasionally with immunohistochemistry, they fall short of revealing information regarding the morphology, location and electrophysiological properties of the targeted

Concluding remarks

Even if one were to take into account only the studies mentioned above, one can conclude that long-range GABAergic cells are not a rare cell population. In fact it is striking that several brain regions are connected bidirectionally via long-range GABAergic cells that project preferentially to inhibitory cells in the target area. It is thus tempting to speculate that long-range GABAergic cells subserve synchronous activity between distant brain regions (Figure 2).

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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