Cadherins orchestrate specific patterns of perisomatic inhibition onto distinct pyramidal cell populations

Julie Jézéquel, Giuseppe Condomitti, Tim Kroon, Fursham Hamid, Stella Sanalidou, Teresa Garcés, Patricia Maeso, Maddalena Balia, Zhaohui Hu, Setsuko Sahara and Beatriz Rico ()
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Julie Jézéquel: King’s College London
Giuseppe Condomitti: King’s College London
Tim Kroon: King’s College London
Fursham Hamid: King’s College London
Stella Sanalidou: King’s College London
Teresa Garcés: King’s College London
Patricia Maeso: King’s College London
Maddalena Balia: King’s College London
Zhaohui Hu: King’s College London
Setsuko Sahara: King’s College London
Beatriz Rico: King’s College London

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract GABAergic interneurons were thought to regulate excitatory networks by establishing unselective connections onto diverse pyramidal cell populations, but recent studies demonstrate the existence of a cell type-specific inhibitory connectome. How and when interneurons establish precise connectivity patterns among intermingled populations of excitatory neurons remains enigmatic. We explore the molecular mechanisms orchestrating the emergence of cell type-specific inhibition in the mouse cerebral cortex. We demonstrate that layer 5 intra- (L5 IT) and extra-telencephalic (L5 ET) neurons express unique transcriptional programs, allowing them to shape parvalbumin- (PV+) and cholecystokinin-positive (CCK+) interneuron wiring. We identified Cdh12 and Cdh13, two cadherin superfamily members, as underpinnings of cell type- and input-specific inhibitory patterns of L5 pyramidal cell populations. Multiplex monosynaptic tracing revealed a minimal overlap between IT and ET presynaptic inhibitory networks and suggests that different PV+ basket cell populations innervate distinct L5 pyramidal cell types. Here, we unravel the contribution of cadherins in shaping cell-type-specific cortical interneuron wiring.

Date: 2025
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DOI: 10.1038/s41467-025-59635-z

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