Distinct nanoscale architectures of GABAergic inhibitory synapses predict diverse synaptic output

Abstract

GABAergic synaptic inhibition is heterogenous across neuronal compartments, and plays a critical role in shaping local, cellular and circuit excitability. In pyramidal neurons, inhibition is mediated by GABAA receptors (GABAARs) clustered at the inhibitory postsynaptic domain (iPSD). Synaptic strength depends not only on the number of GABAARs within the iPSD, but also on their precise nanoscale organization into discrete sub-synaptic domains (SSDs). These SSDs often align with presynaptic GABA release sites to form nanocolumn structures that enhance synaptic efficacy. While nanocolumn organization is increasingly recognized as a key determinant of synaptic function, most studies of GABAergic synapses have focused on archetypal dendritic synapses, which control the plasticity and integration of excitatory inputs. Nonetheless, it remains unclear whether somatic synapses - which deliver and provide robust inhibition to suppress neuronal output - share a similar nanoscale organization. Here, we used complementary super-resolution imaging approaches to directly compare inhibitory synapses in somatic and dendritic compartments. We found that somatic synapses are larger and exhibit greater structural diversity and nanoscale complexity than dendritic synapses. Dendritic synapses display relatively compact architectures with GABAAR SSDs frequently arranged into nanocolumns. In contrast, somatic synapses show a broader range of organizations, including aligned nanocolumns as well as more disorganized configurations with additional misaligned release sites or receptor SSDs. Computational modeling revealed that these structural differences produce distinct functional outcomes, including increased IPSC amplitude and altered kinetics at somatic synapses. Together, our findings demonstrate that nanoscale organization differentially shapes inhibitory strength and signaling properties across neuronal compartments. SIGNIFICANCE STATEMENTDiverse GABAergic synaptic inhibition is crucial to control brain excitability and its efficacy is influenced by the nanoscale trans-synaptic alignment of GABAARs and GABA release sites. Although GABAAR nano-architecture is defined at dendritic synapses, the extent to which this organization is conserved across GABAergic synapses with distinct synaptic properties is unknown. Using super-resolution imaging methods, we report that inhibitory synapses in the soma are larger and more structurally diverse than dendritic synapses, exhibiting both aligned and more disorganized configurations. Combined with computational modeling indicating distinct nanoarchitectures can create heterogeneous inhibitory currents, these findings suggest a key role for nanoscale organization in the generation of diverse synaptic outputs across the neuron, which could serve distinct circuit functions.