Secretagogin is Expressed by Developing Neocortical GABAergic Neurons in Humans but not Mice and Increases Neurite Arbor Size and Complexity

Abstract

The neocortex of primates, including humans, contains more abundant and diverse inhibitory neurons compared with rodents, but the molecular foundations of these observations are unknown. Through integrative gene coexpression analysis, we determined a consensus transcriptional profile of GABAergic neurons in mid-gestation human neocortex. By comparing this profile to genes expressed in GABAergic neurons purified from neonatal mouse neocortex, we identified conserved and distinct aspects of gene expression in these cells between the species. We show here that the calcium-binding protein secretagogin (SCGN) is robustly expressed by neocortical GABAergic neurons derived from caudal ganglionic eminences (CGE) and lateral ganglionic eminences during human but not mouse brain development. Through electrophysiological and morphometric analyses, we examined the effects of SCGN expression on GABAergic neuron function and form. Forced expression of SCGN in CGE-derived mouse GABAergic neurons significantly increased total neurite length and arbor complexity following transplantation into mouse neocortex, revealing a molecular pathway that contributes to morphological differences in these cells between rodents and primates.

Ferret brain possesses young interneuron collections equivalent to human postnatal migratory streams

“…Young interneurons in the putative ferret postnatal streams express several markers associated with an origin in the ventral pallium (Ma et al, ; Raju et al, ). We found they express Sp8 and SCGN to varying degrees, two markers of interneurons shown to be expressed in cells originating in the caudal ganglionic eminence (CGE) and lateral ganglionic eminence (LGE).…”

“…Previously, secretagogin had been observed in neurons in multiple structures in the rodent brain, such as the RMS, olfactory bulb, hypothalamus, dentate gyrus and amygdala, but not cortex (Kosaka & Kosaka, ; Mulder et al, , ; Romanov et al, ). Recently, it was shown that human cortex contains SCGN+ interneurons, and forced expression in mice increases neurite outgrowth (Raju et al, ). The discovery that the ferret also contains SCGN+ interneurons, both in the white matter and cortex, that persist into adulthood, implies that SCGN+ interneurons may represent a change in cortical development found only in gyrencephalic brains whose function and circuit contributions can be further studied using ferret as a model.…”

“…Each stream did not co-express DCX and Sp8 to the same degree, with the MMS expressing the most and the DMS expressing the least (Figure 6d). Interestingly, DCX+ cells were also found to express SCGN, a calcium binding protein that is expressed in human cortical interneurons but not rodent cortical interneurons (Raju et al, 2018; Figure 6e). The degree of co-localization between DCX and SCGN was almost identical to that of DCX and Sp8 (Figure 6f).…”

“…Ferrets have been used as an animal model to study brain development for the past 30 years. Their brain size is significantly increased compared to rodents (Barnette et al, 2009;Raju et al, 2018). Like humans, and unlike rodents, they possess a gyrencephalic cortex (Barnette et al, 2009;Duque & McCormick, 2010;Johnson et al, 2018).…”

Differential expression of secretagogin immunostaining in the hippocampal formation and the entorhinal and perirhinal cortices of humans, rats, and mice

“…These differences have been interpreted by Mulder et al as uncovering phylogenetic differences in SCGN expression. More recently, it has also been reported that SCGN is expressed by developing neocortical GABAergic neurons in humans but not in mice (Raju, Spatazza, Stanco, Sorrells, & Kelley, ). In the human brain, SCGN immunostaining has been described in both cerebellar basket and stellate cells and in neurons of temporal, frontal, hippocampal, and hypothalamic regions (Gartner et al, ).…”