Abstract
Cortical projection neurons are classified by hodology in corticocortical, commissural and corticofugal subtypes. Although cortical projection neurons had been regarded as only glutamatergic neurons, recently corticocortical GABAergic projection neurons has been also reported in several species. Here, we demonstrate corticofugal GABAergic projection neurons in the mouse frontal cortex. We employed viral-vector-mediated anterograde tracing, classical retrograde tracing, and immunohistochemistry to characterize neocortical GABAergic projection neurons. Injections of the Cre-dependent adeno-associated virus into glutamate decarboxylase 67 (GAD67)-Cre knock-in mice revealed neocortical GABAergic projections widely to the forebrain, including the cerebral cortices, caudate putamen (CPu), ventral pallidum (VP), lateral globus pallidus (LGP), nucleus accumbens, and olfactory tubercle (Tu). Minor GABAergic projections were also found in the mediodorsal thalamic nucleus, diagonal band of Broca, medial globus pallidus, substantial nigra, and dorsal raphe nucleus. Retrograde tracing studies also demonstrated corticofugal GABAergic projection neurons in the mouse frontal cortex. Further immunohistochemical screening with neurochemical markers revealed the majority of corticostriatal GABAergic projection neurons were positive for somatostatin (SS)-immunoreactivity. In contrast, corticothalamic GABAergic projection neurons were not identified by representative neurochemical markers for GABAergic neurons. These findings suggest that corticofugal GABAergic projection neurons are heterogeneous in terms of their neurochemical properties and target nuclei, and provide axonal innervations mainly to the nuclei in the basal ganglia.
Highlights
The overwhelming majority of long-range corticocortical connections in the cerebral cortex originate from glutamatergic pyramidal neurons
We concluded that the injection of associated viruses serotype 5 (AAVs)-Ef1a-DIO-hChR2-mCherry into the Cx of glutamate decarboxylase 67 (GAD67)-Cre knock-in mice can induce the expression of hChR2-mCherry in GABAergic neurons, but not glutamatergic neurons
We report that a subset of GABAergic neurons in the mouse frontal cortex project widely to cortical areas and subcortical nuclei throughout the forebrain and midbrain
Summary
The overwhelming majority of long-range corticocortical connections in the cerebral cortex originate from glutamatergic pyramidal neurons. Knowledge about corticocortical GABAergic projection neurons still remains sparse, growing evidence suggests that the vast majority of corticocortical GABAergic projection neurons are classified as the somatostatin (SS)-expressing neurons (Tomioka et al, 2005; Tomioka and Rockland, 2007; Higo et al, 2007, 2009; Jinno et al, 2007; McDonald et al, 2012; Melzer et al, 2012; McDonald and Zaric, 2015a,b) This knowledge about corticocortical GABAergic projection neurons has been most essential to estimate their functional significance until now (Tamamaki and Tomioka, 2010), since each GABAergic subpopulation classified by neurochemical properties would have the same morphological, and electrophysiological property (Markram et al, 2004; Ascoli et al, 2008). Lee et al (2014) have found that GABAergic axonal fibers from the medial frontal cortex widely distribute in various subcortical regions: the caudate putamen (CPu), nucleus accumbens, claustrum, and basolateral amygdala They have identified corticofugal GABAergic projection neurons as PV- or vasoactive intestinal peptide (VIP)-expressing subpopulations of GABAergic neurons. Those reports indicate corticofugal GABAergic projection neurons may be a distinct subpopulation from corticocortical GABAergic projection neurons because of their different neurochemical properties
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