Neurotransmitter-Specific Clustering Reveals Distinct Topological Roles in the Drosophila Brain Connectome

How does neurotransmitter identity shape the architecture of brain-wide neural cir cuits? We addressed this question by analyzing neurotransmitter-specific subnetworks within the FlyWire adult Drosophila connectome — 180,799 reciprocal synaptic pairs among 77,607 neurons. We report three major findings: (1) GABAergic neurons form highly clustered local modules, with GABA–GABA transitivity (0.396) exceeding cross transmitter GABA–ACh transitivity (0.0005) by ∼714-fold (95% CI: 607–883×, per mutation test p < 0.001, n = 1,000); (2) the network exhibits a heavy-tailed degree distribution (power-law exponent α = 2.37); and (3) most strikingly, 100% of the 20 highest-degree hub neurons are GABAergic, representing a 6.2-fold enrichment over the baseline GABAergic fraction (p < 10−9, binomial test). The network shows small world properties with 125× higher clustering than degree-matched random graphs. These findings suggest that inhibitory circuits form both dense local processing units and the global control backbone of the connectome. This dual topological role—local clustering plus hub dominance—parallels the organization of inhibitory interneuron networks in mammalian cortex, suggesting deep conservation of GABAergic circuit architecture across 600 million years of evolution.