Abstract
In human prefrontal cortex (PFC), ~85% of γ-aminobutyric acid (GABA)-expressing neurons can be subdivided into non-overlapping groups by the presence of calbindin (CB), calretinin (CR) or parvalbumin (PV). Substantial research has focused on the differences in the laminar locations of the cells bodies of these neurons, with limited attention to the distribution of their axon terminals, their sites of action. We previously reported that in non-human primates subtypes of these cells are distinguishable by differences in terminal protein levels of the GABA synthesizing enzymes glutamic acid decarboxylase 65 (GAD65) and GAD67. Here we used multi-label fluorescence microscopy in human PFC to assess: (1) the laminar distributions of axon terminals containing CB, CR, or PV; and (2) the relative protein levels of GAD65, GAD67 and vesicular GABA transporter (vGAT) in CB, CR and PV terminals. The densities of the different CB, CR and PV terminal subpopulations differed across layers of the PFC. PV terminals comprised two subsets based on the presence of only GAD67 (GAD67+) or both GADs (GAD65/GAD67+), whereas CB and CR terminals comprised three subsets (GAD65+, GAD67+, or GAD65/GAD67+). The densities of the different CB, CR and PV GAD terminal subpopulations also differed across layers. Finally, within each of the three calcium-binding protein subpopulations intra-terminal protein levels of GAD and vGAT differed by GAD subpopulation. These findings are discussed in the context of the laminar distributions of CB, CR and PV cell bodies and the synaptic targets of their axons.
Highlights
The questions ‘‘Why does the cortex have layers? What is the function of layering? How do cortical neurons integrate information across different layers?’’ are challenging to answer for the human neocortex because it is not possible to perform the types of tract tracing and electrophysiological studies that have provided key insights in other species
Our findings suggest that each cortical layer receives a unique type and amount of inhibition from GABAergic CB, CR and PV neurons that may reflect the intra- and inter-laminar processing demands required for proper prefrontal cortex (PFC) functioning
Similar to our previous findings in the macaque monkey PFC (Fish et al, 2011, 2013; Rocco et al, 2016b), we found in the human PFC three subpopulations of vesicular GABA transporter (vGAT) terminals based on glutamic acid decarboxylase (GAD) content: glutamic acid decarboxylase 65 (GAD65)+, GAD67+ and GAD65/GAD67+
Summary
The questions ‘‘Why does the cortex have layers? What is the function of layering? How do cortical neurons integrate information across different layers?’’ are challenging to answer for the human neocortex because it is not possible to perform the types of tract tracing and electrophysiological studies that have provided key insights in other species. GAD67 is primarily active (∼72%) and is activity-regulated mainly by transcription In concert, these findings suggest that the two GAD isoforms: (1) provide complementary means for regulating GABA synthesis; and (2) are involved differentially in the spatial and temporal processing of information by GABA-containing neurons (Wilson and Groves, 1981; Contreras et al, 1992; Mercugliano et al, 1992; Feldblum et al, 1993, 1995; Esclapez et al, 1994; Pedneault and Soghomonian, 1994; Soghomonian et al, 1994; Wilson and Kawaguchi, 1996; Bowers et al, 1998; Soghomonian and Martin, 1998)
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