NDNF is selectively expressed by neocortical, but not habenular neurogliaform cells

Abstract

The lateral habenula (LHb) is a brain structure which is known to be pathologically hyperactive in depression, whereby it shuts down the brains' reward systems. Interestingly, inhibition of the LHb has been shown to have an antidepressant effect, hence making the LHb a fascinating subject of study for developing novel antidepressant therapies. Despite this however, the exact mechanisms by which inhibitory signalling is processed within the LHb remain incompletely understood. Some studies have proposed the existence of locally targeting inhibitory interneuron populations within the LHb. One such population is believed to be akin to neocortical neurogliaform cells, yet specific molecular markers for studying these neurons are sparse and hence their function remains elusive. Recently, neuron‐derived neurotrophic factor (NDNF) has been proposed as one such marker for neocortical neurogliaform cells. Using a combination of histological, physiological and optogenetic tools, we hence sought to first validate if NDNF was selectively expressed by such inhibitory neurons within the neocortex, and then if it was confined to a similar population within the LHb. While we report this to be true for the neocortex, we find no such evidence within the LHb; rather that NDNF is expressed without restriction to a particular neuronal subpopulation. These results hence indicate that molecular markers can represent broadly diverse populations of neurons on a region‐to‐region basis and that therefore each population as defined by molecular marker expression should be validated in each brain structure.

Inhibition Within the Lateral Habenula—Implications for Affective Disorders

“…Note however that the expression patterns of GABAergic markers within the LHb appears to differ between mice and rats (Quina et al, 2020), with VGAT expression in rats observed in the medial LHb and GAD-2 expression largely absent (Zhang et al, 2018;Quina et al, 2020). Furthermore, early electrophysiological and morphological studies have proposed that a population of neurons akin to the very distinctive cortical neurogliaform interneuron exists within the LHb in rats (Weiss and Veh, 2011;Wagner et al, 2016), although these neurons appear to be different to their cortical counterparts at least in that they do not express similar molecular markers (Webster et al, 2021).…”

A combinatory genetic strategy for targeting neurogliaform neurons in the mouse basolateral amygdala

“…Nevertheless, the potential heterogeneity of NDNF+ GABAergic interneuron populations has also been described in the mouse somatosensory cortex as NDNF expression can be detected in GABAergic canopy cells, which are functionally distinct from NGFCs (Schumann et al, 2019). Furthermore, in non-cortical-like brain structures, such as lateral habenula, NDNF expression fails to selectively label NGFCs (Webster et al, 2021), while NGFCs derived from MGE and CGE show distinct molecular properties (Tricoire et al, 2011; Overstreet-Wadiche and McBain, 2015; Niquille et al, 2018). Further investigation is thus required to determine whether the combinatory strategy presented in this study covers the entire BLA NGFC population.…”

A combinatory genetic strategy for targeting neurogliaform neurons in the mouse basolateral amygdala

“…Nevertheless, the potential heterogeneity of NDNF+ GABAergic interneuron populations has also been described in the mouse somatosensory cortex as NDNF expression can be detected in GABAergic canopy cells, which are functionally distinct from NGFCs ( Schuman et al, 2019 ). Furthermore, in non-cortical-like brain structures, such as lateral habenula, NDNF expression fails to selectively label NGFCs ( Webster et al, 2021 ), while NGFCs derived from MGE and CGE show distinct molecular properties ( Tricoire et al, 2010 , 2011 ; Overstreet-Wadiche and McBain, 2015 ; Niquille et al, 2018 ). Further investigation is thus required to determine whether the combinatory strategy presented in this study covers the entire BLA NGFC population.…”