Long-Range GABAergic Projections of Cortical Origin in Brain Function

Abstract

The study of long-range GABAergic projections has traditionally been focused on those with subcortical origin. In the last few years, cortical GABAergic neurons have been shown to not only mediate local inhibition, but also extend long-range axons to remote cortical and subcortical areas. In this review, we delineate the different types of long-range GABAergic neurons (LRGNs) that have been reported to arise from the hippocampus and neocortex, paying attention to the anatomical and functional circuits they form to understand their role in behavior. Although cortical LRGNs are similar to their interneuron and subcortical counterparts, they comprise distinct populations that show specific patterns of cortico-cortical and cortico-fugal connectivity. Functionally, cortical LRGNs likely induce timed disinhibition in target regions to synchronize network activity. Thus, LRGNs are emerging as a new element of cortical output, acting in concert with long-range excitatory projections to shape brain function in health and disease.

Bilateral Intracortical Inhibition during Unilateral Motor Preparation and Sequence Learning

“…Nonetheless, another hint at a cross-hemispheric synchronisation comes from the result that bilateral M1s decreased SICI specifically when the right index finger initiated the sequences, suggesting that some parameters of a unilateral motor command are shared between the contralateral and ipsilateral M1s. Anatomically, such a joint bilateral decrease in SICI could be enabled by homotopic interhemispheric connections between bilateral M1s 43,44 , long-range projection GABAergic interneurons 45 , or could originate from motor areas upstream of M1 46,47 . Although the exact process by which SICI jointly decreases in bilateral M1s during unilateral motor preparation remains unclear, the second experiment replicated this finding in different groups of participants (Figure 5B-D).…”

The role of ketamine in major depressive disorders: Effects on parvalbumin-positive interneurons in hippocampus

“…These long-projection GABAergic neurons reach the EC and medial septum (MS) via the retrosplenial cortex, exerting potent regulation of behavioral control over local hippocampal circuits through numerous disinhibitory synaptic mechanisms. 19 As mentioned above, impaired hippocampal function has been related to MDD. The efferent pathways of the subiculum and HC connect to critical areas such as nucleus accumbens (NAc) and ventral tegmental area (VTA) involved in the dopaminergic neurotransmitter-mediated reward loop, leading to alterations in the reward circuitry and affecting cognition and enjoyment.…”

“…These long-projection GABAergic neurons reach the EC and medial septum (MS) via the retrosplenial cortex, exerting potent regulation of behavioral control over local hippocampal circuits through numerous disinhibitory synaptic mechanisms. 19…”

Long-range GABAergic projections contribute to cortical feedback control of sensory processing

“…Recent advances in genetic tools applied to cell-and circuit-tracing has allowed for the discovery of an increasing number of long-range GABAergic projection neurons in the cortex -where they may constitute 1-10% of the total GABAergic neurons in mice, rats, cats and monkeys (Higo, 2009;Higo et al, 2007;McDonald and Burkhalter, 1993;Tomioka and Rockland, 2007;Tomioka et al, 2005). Long-range projecting GABAergic neurons express a variety of classical markers for interneurons (Caputi et al, 2013;Melzer and Monyer, 2020;Urrutia-Piñones et al, 2022), sometimes forming intermingled populations within a single structure, where they exhibit distinct connectivity and exert various functions. For instance, bidirectional GABAergic projections between the hippocampus and entorhinal cortex synchronize the rhythmic network activity and gate spike-timing plasticity (Caputi et al, 2013;Melzer and Monyer, 2020), cortico-striatal and cortico-amygdala GABAergic projections regulate spike generation and excitability of their postsynaptic target and influence locomotion as well as reward coding (Lee et al, 2014;Melzer et al, 2017;Rock et al, 2016) In mammalian sensory systems, external stimuli trigger a feedforward flow of information from the sensory organ to the primary and higher-order sensory cortices via a set of subcortical structures, thereby defining a hierarchy between sensory brain regions.…”