Selective Depletion of Molecularly Defined Cortical Interneurons in Human Holoprosencephaly with Severe Striatal Hypoplasia

Abstract

Cortical excitatory glutamatergic projection neurons and inhibitory GABAergic interneurons follow substantially different developmental programs. In rodents, projection neurons originate from progenitors within the dorsal forebrain, whereas interneurons arise from progenitors in the ventral forebrain. In contrast, it has been proposed that in humans, the majority of cortical interneurons arise from progenitors within the dorsal forebrain, suggesting that their origin and migration is complex and evolutionarily divergent. However, whether molecularly defined human cortical interneuron subtypes originate from distinct progenitors, including those in the ventral forebrain, remains unknown. Furthermore, abnormalities in cortical interneurons have been linked to human disorders, yet no distinct cell population selective loss has been reported. Here we show that cortical interneurons expressing nitric oxide synthase 1, neuropeptide Y, and somatostatin, are either absent or substantially reduced in fetal and infant cases of human holoprosencephaly (HPE) with severe ventral forebrain hypoplasia. Notably, another interneuron subtype normally abundant from the early fetal period, marked by calretinin expression, and different subtypes of projection neuron were present in the cortex of control and HPE brains. These findings have important implications for the understanding of neuronal pathogenesis underlying the clinical manifestations associated with HPE and the developmental origins of human cortical interneuron diversity.

Coup-TF1&2 (Nr2f1 and Nr2f2) control subtype and laminar identity of MGE-derived neocortical interneurons

“…Alterations in CIN subtype numbers have been reported in postmortem brains from individuals with holoprosencephaly (Fertuzinhos et al, 2009) and neuropsychiatric disorders, and in mouse models of autism spectrum disorder and schizophrenia (Marin, 2012). We suggest that the SST + /PV + ratio should be measured in these individuals, as mutations in genes associated with neuropsychiatric disorders (NPAS3 and PTEN) alter the SST + /PV + ratio in mice with mutations of these genes (Vogt et al, 2015;Stanco et al, 2014).…”

Renewed focus on the developing human neocortex

“…prospective visual cortex, the majority of interneurons are actually generated within the cortical progenitor zones (Letinic et al 2002). This interpretation was supported by the use of double-label immunohistochemistry (Zecevic et al 2005;Mo & Zecevic, 2008) and in the analysis of malformations that involve deletion of the ganglionic eminence (Fertuzinhos et al 2009). Studies carried out in non-human primates have confirmed this to be the case at least in the macaque monkey (Petanjek et al 2009).…”

Transcriptional co-regulation of neuronal migration and laminar identity in the neocortex

“…Recently, it has been shown that chemokine signaling involving C-X-C motif ligand 12 (CXCL12) and its receptors CXCR4 and CXCR7 regulates the tangential migratory stream of interneurons (Sessa et al, 2010;Sánchez-Alcañiz et al, 2011;Wang et al, 2011). Although it has been suggested that some interneurons are derived from dorsal progenitors in the human fetal neocortex (Letinic et al, 2002;Yu and Zecevic, 2011), certain human interneuron subtypes are probably generated in the ventral telencephalon and enter the cortex via tangential migration (Fertuzinhos et al, 2009). Upon arrival in the neocortex, interneurons migrate radially to enter the CP (Nadarajah and Parnavelas, 2002;Ang et al, 2003;Yokota et al, 2007a) Prior to the onset of neurogenesis, neural progenitors (NPs) in the ventricular zone (VZ; blue) of the developing neocortex divide symmetrically to expand the progenitor pool, undergoing interkinetic nuclear migration (IKNM) as they progress through the cell cycle.…”