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The early fetal development of human neocortical GABAergic interneurons.

Al-Jaberi N, Lindsay S, Sarma S, Bayatti N, Clowry GJ - Cereb. Cortex (2013)

Bottom Line: CALB2-positive cells increased steadily in the SVZ/VZ from 10 PCW but were not double-labeled with Ki-67.Expression of GABAergic genes was generally higher in the dorsal pallium than in the ganglionic eminences, with lower expression in the intervening ventral pallium.It is widely accepted that the cortical proliferative zones may generate CALB2-positive interneurons from mid-gestation; we now show that the anterior neocortical proliferative layers especially may be a rich source of interneurons in the early neocortex.

View Article: PubMed Central - PubMed

Affiliation: Institute of Neuroscience Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.

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Expression of GABAergic genes prior to cortical plate formation. Immunoreactivity for ASCL1 (A) GAD2 (B) and DLX2 (C) a little later was detectable both in cells of the proliferative ventricular zone (VZ) and postmitotic preplate (PP) confirming GABAergic neurons are born in the cortex at this early stage. Arrows point to radially orientated aggregates of cells expressing GAD2 and DLX2 suggesting these cells were being born in the ventricular zone and migrating radially. Low power images confirm that both OLIG2 (D, coronal section) and GAD2 (E, sagittal section) were as strongly expressed in the anterior/dorsal regions of the dorsal pallium as in the ganglionic eminences at this stage, although at higher magnification in coronal sections, it was possible to see a prominent tangential stream of cells (curved arrow) either expressing GAD2 (F) or CALB2 (G) apparently migrating from the ganglionic eminence toward the preplate. Scale bars = 50 μm in A, B, C; 500 μm in F, G; and 2 mm in D, E.
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BHT254F6: Expression of GABAergic genes prior to cortical plate formation. Immunoreactivity for ASCL1 (A) GAD2 (B) and DLX2 (C) a little later was detectable both in cells of the proliferative ventricular zone (VZ) and postmitotic preplate (PP) confirming GABAergic neurons are born in the cortex at this early stage. Arrows point to radially orientated aggregates of cells expressing GAD2 and DLX2 suggesting these cells were being born in the ventricular zone and migrating radially. Low power images confirm that both OLIG2 (D, coronal section) and GAD2 (E, sagittal section) were as strongly expressed in the anterior/dorsal regions of the dorsal pallium as in the ganglionic eminences at this stage, although at higher magnification in coronal sections, it was possible to see a prominent tangential stream of cells (curved arrow) either expressing GAD2 (F) or CALB2 (G) apparently migrating from the ganglionic eminence toward the preplate. Scale bars = 50 μm in A, B, C; 500 μm in F, G; and 2 mm in D, E.

Mentions: At 6.5–7.5 PCW, we confirmed the presence of GAD2 and CALB2 expressing neurons in the preplate as previously described (Meyer et al. 2000; Rakic and Zecevic 2003). In addition, DLX2 and ASCL1 immunoreactivity was observed. For all markers, positive cells were seen in VZ, sometimes in radially arranged clusters (Fig. 6). ASCL1 immunoreactivity was more prevalent in the VZ, whereas the others showed stronger expression in the preplate. This fits with the idea that ASCL1 is expressed earlier in the development of interneurons (see Introduction section) and strongly suggests that GABAergic cells are born in the cortical wall at this stage of development. ASCL1, DLX2, and GAD2 showed similar patterns of immunoreactivity between 8 and 12 PCW, with a mosaic of cells exhibiting either strong, moderate, and weak/no expression throughout the layers of the cortical wall (Fig. 7). They differ in that ASCL1 expression is generally more prominent in the VZ, whereas DLX2 was stronger in the SVZ. Despite being a marker for synaptic terminals in adult tissue (Erlander et al. 1991; Esclapez et al. 1994), GAD2 immunoreactivity was observed in proliferative layers (Fig. 6) as has been previously described (Petanjek et al. 2009). GAD1 TISH staining was also most prominent in the SVZ and CP at 9 PCW (Fig. 3C). In the CP, most GABAergic markers showed more expression in cells closer to the outer boundary with the marginal zone. The exception was CALB2, immunoreactivity which was most prominent in cells at the interface between the CP and the early SP. This confirms the previous suggestion (Meyer et al. 2000) that these CALB2 cells are pioneer cells sending axons toward the thalamus rather than GABAergic cells. CALB2-positive axons can be observed in the early SP, intermediate zone, and into the internal capsule and CALB2 positive GABAergic neurons may exist at other locations in the CP and early SP.Figure 6.


The early fetal development of human neocortical GABAergic interneurons.

Al-Jaberi N, Lindsay S, Sarma S, Bayatti N, Clowry GJ - Cereb. Cortex (2013)

Expression of GABAergic genes prior to cortical plate formation. Immunoreactivity for ASCL1 (A) GAD2 (B) and DLX2 (C) a little later was detectable both in cells of the proliferative ventricular zone (VZ) and postmitotic preplate (PP) confirming GABAergic neurons are born in the cortex at this early stage. Arrows point to radially orientated aggregates of cells expressing GAD2 and DLX2 suggesting these cells were being born in the ventricular zone and migrating radially. Low power images confirm that both OLIG2 (D, coronal section) and GAD2 (E, sagittal section) were as strongly expressed in the anterior/dorsal regions of the dorsal pallium as in the ganglionic eminences at this stage, although at higher magnification in coronal sections, it was possible to see a prominent tangential stream of cells (curved arrow) either expressing GAD2 (F) or CALB2 (G) apparently migrating from the ganglionic eminence toward the preplate. Scale bars = 50 μm in A, B, C; 500 μm in F, G; and 2 mm in D, E.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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BHT254F6: Expression of GABAergic genes prior to cortical plate formation. Immunoreactivity for ASCL1 (A) GAD2 (B) and DLX2 (C) a little later was detectable both in cells of the proliferative ventricular zone (VZ) and postmitotic preplate (PP) confirming GABAergic neurons are born in the cortex at this early stage. Arrows point to radially orientated aggregates of cells expressing GAD2 and DLX2 suggesting these cells were being born in the ventricular zone and migrating radially. Low power images confirm that both OLIG2 (D, coronal section) and GAD2 (E, sagittal section) were as strongly expressed in the anterior/dorsal regions of the dorsal pallium as in the ganglionic eminences at this stage, although at higher magnification in coronal sections, it was possible to see a prominent tangential stream of cells (curved arrow) either expressing GAD2 (F) or CALB2 (G) apparently migrating from the ganglionic eminence toward the preplate. Scale bars = 50 μm in A, B, C; 500 μm in F, G; and 2 mm in D, E.
Mentions: At 6.5–7.5 PCW, we confirmed the presence of GAD2 and CALB2 expressing neurons in the preplate as previously described (Meyer et al. 2000; Rakic and Zecevic 2003). In addition, DLX2 and ASCL1 immunoreactivity was observed. For all markers, positive cells were seen in VZ, sometimes in radially arranged clusters (Fig. 6). ASCL1 immunoreactivity was more prevalent in the VZ, whereas the others showed stronger expression in the preplate. This fits with the idea that ASCL1 is expressed earlier in the development of interneurons (see Introduction section) and strongly suggests that GABAergic cells are born in the cortical wall at this stage of development. ASCL1, DLX2, and GAD2 showed similar patterns of immunoreactivity between 8 and 12 PCW, with a mosaic of cells exhibiting either strong, moderate, and weak/no expression throughout the layers of the cortical wall (Fig. 7). They differ in that ASCL1 expression is generally more prominent in the VZ, whereas DLX2 was stronger in the SVZ. Despite being a marker for synaptic terminals in adult tissue (Erlander et al. 1991; Esclapez et al. 1994), GAD2 immunoreactivity was observed in proliferative layers (Fig. 6) as has been previously described (Petanjek et al. 2009). GAD1 TISH staining was also most prominent in the SVZ and CP at 9 PCW (Fig. 3C). In the CP, most GABAergic markers showed more expression in cells closer to the outer boundary with the marginal zone. The exception was CALB2, immunoreactivity which was most prominent in cells at the interface between the CP and the early SP. This confirms the previous suggestion (Meyer et al. 2000) that these CALB2 cells are pioneer cells sending axons toward the thalamus rather than GABAergic cells. CALB2-positive axons can be observed in the early SP, intermediate zone, and into the internal capsule and CALB2 positive GABAergic neurons may exist at other locations in the CP and early SP.Figure 6.

Bottom Line: CALB2-positive cells increased steadily in the SVZ/VZ from 10 PCW but were not double-labeled with Ki-67.Expression of GABAergic genes was generally higher in the dorsal pallium than in the ganglionic eminences, with lower expression in the intervening ventral pallium.It is widely accepted that the cortical proliferative zones may generate CALB2-positive interneurons from mid-gestation; we now show that the anterior neocortical proliferative layers especially may be a rich source of interneurons in the early neocortex.

View Article: PubMed Central - PubMed

Affiliation: Institute of Neuroscience Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.

Show MeSH
Related in: MedlinePlus