3/ A few years later, @PicardoMichel and others in the lab (in collaboration with @GordFishell lab) found that many hub cells were GABA cells born early in embryogenesis (thus termed ‘early-born GABA cells’ or ‘ebGABAs’).
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4/ We asked the following questions: 1. Are ebGABAs hub cells only in CA3 or throughout the hippocampus? 2. Are they hubs at the neonatal stage because they are more mature? Or this is due to a predermined program? 3. Do they remain distinct from other interneurons in adulthood?
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5/ We tested these questions in the CA1 region because CA1 circuits are well understood, and also because it is more accessible for in vivo calcium imaging. We used a Dlx1/2CreER;GFP line and administered tamoxifen at embryonic day E7.5 to tag the earliest born GABA cells.
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6/ First, we used large-scale calcium imaging in neonatal slices combined with stimulation ebGABAs using whole cell patch clamp. We found that stimulation of a single ebGABA (but not of random GABA cells) could modulate the network. Thus, ebGABAs exert a hub function even in CA1.pic.twitter.com/hKFPVXlBlL
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7/ We then examined ebGABAs in adulthood. Using immunohistochemical analysis and reconstruction of biotin-filled cells, we found that ebGABAs aren’t canonical interneurons. They express markers of long-range projecting cell types that target different brain areas.pic.twitter.com/o3NxuTVkV8
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8/ EbGABAs' firing patterns ex vivo appear more similar to pyramidal cells than interneurons, with strong adaptation upon strong depolarizing inputs, mainly due to depolarization block.pic.twitter.com/UuA0BOfMIw
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9/ Mapping ebGABAs' inputs with electrical or optogenetic stimulations, we found that these cells, unlike random GABA cells, receive little excitation by extra-hippocampal inputs. Instead, they are mostly recruited by intra-hippocampal ones.pic.twitter.com/tHQ5koDJW7
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10/ What about inhibition? Do ebGABAs show distinct inhibitory wiring? Indeed, we show that compared to random GABA cells they receive weak local inhibition (with very little inputs from PV+ neurons). Instead, they are mostly inhibited by long-range inputs from the medial septum.pic.twitter.com/gqG0JAqw8c
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11/ Finally, we imaged ebGABAs in vivo and found that these cells are among a minority of cells in the network that are activated by a variety of network states.pic.twitter.com/VSaYwbggKB
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12/ In summary, our study indicates that early-born hub cells could be a distributed feature of cortical circuits. In adulthood, these cells remain anatomically and functionally distinct from other GABA cells, speaking in favour of a predetermined program for their hub function.
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13/ Based on their unique wiring schemes, ebGABAs could exert a long-range hub function in adulthood, reading the activity of local cells and synchronizing them to other structures.
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