In one of the most remarkable events in neural development, newly born interneurons disperse throughout the brain to populate strikingly distinct structures including the cortex, hippocampus, striatum and amygdala. Our recent studies suggest that relegation to a particular neural structure is stochastic rather than determined (Bandler et al., 2022; Fishell and Kepec, 2020), suggesting that the further refinement of interneuron identity relies upon local cues received upon their integration into particular structures. This presents us with the challenge of understanding how specific subtypes acquire region-specific identity, most notably their specific afferent and efferent connectivity. Using a combination of optogenetics-assisted patch-clamp recording, viral tracing and spatio-transcriptomics. (Ibrahim et al., Neuron 2021; Pouchelon et al, Cell Reports 2021, Favuzzi et al, Cell 2021), we continued to examine the impact of local environments on interneuron, specification, maturation and survival. These approaches are helping to unravel the daunting question of how local circuit assembly is achieved. In parallel, the genetic ability to target ever more specific interneuron subtypes is allowing us to query their role in cortical function. Currently, our laboratory is revealing the roles of interneuron subtypes using two-photon calcium imaging, with a focus on SST and LAMP5 (NDNF) interneurons, whose roles in computation through their targeting of layer I-III dendrites has long been a mystery.

Figure 1 - Developmental changes in the connectivity of L1 interneurons

Figure 2 - Presynaptic inputs to PV and SST cINs are primarily determined by their areal location

Figure 3 - The organization and development of cortical interneuron presynaptic circuits are area specific

Selected References

Favuzzi E, Huang S, Saldi GA, Binan L, Ibrahim LA, Fernández-Otero M, Cao Y, Zeine A, Sefah A, Zheng K, Xu Q, Khlestova E, Farhi SL, Bonneau R, Datta SR, Stevens B, Fishell G. GABA-receptive microglia selectively sculpt developing inhibitory circuits. Cell. 2021 Jul 22;184(15):4048-4063.e32. PMID: 34233165 

Ibrahim LA, Huang S, Fernandez-Otero M, Sherer M, Qiu Y, Vemuri S, Xu Q, Machold R, Pouchelon G, Rudy B, Fishell G. Bottom-up inputs are required for establishment of top-down connectivity onto cortical layer 1 neurogliaform cells. Neuron. 2021 Nov 3;109(21):3473-3485.e5. PMID: 34478630 

Pouchelon G, Dwivedi D, Bollmann Y, Agba CK, Xu Q, Mirow AMC, Kim S, Qiu Y, Sevier E, Ritola KD, Cossart R, Fishell G. The organization and development of cortical interneuron presynaptic circuits are area specific. Cell Rep. 2021 Nov 9;37(6):109993. PMID: 34758329 

Ibrahim LA, Schuman B, Bandler R, Rudy B, Fishell G Mining the jewels of the cortex's crowning mystery. Curr Opin Neurobiol. 2020 Aug;63:154-161. doi: 10.1016/j.conb.2020.04.005. Epub 2020 May 29.PMID: 32480351