1/ #tweeprint time! If you are interested in #interneurons, #hippocampus and developmental mechanisms of neural circuit function, check out our new preprint “Hippocampal hub neurons maintain unique functional properties throughout their lifetime” biorxiv.org/content/10.110…
2/ Ten years ago, the Cossart lab discovered that rare GABAergic neurons are able to orchestrate single-handedly network dynamics in the CA3 region of the hippocampus . As these cells showed a remarkably high functional connectivity, they were termed ‘hub cells’.
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’).
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?
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?
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.
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. 
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.
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.
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.
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.
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.
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.
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.
