Dually innervated dendritic spines develop in the absence of excitatory activity and resist plasticity through tonic inhibitory crosstalk

Dendritic spines can be directly connected to both inhibitory and excitatory presynaptic terminals, resulting in nanometer-scale proximity of opposing synaptic functions. While dually innervated spines (DiSs) are observed throughout the central nervous system, their developmental timeline and functional properties remain uncharacterized. Here we used a combination of serial section electron microscopy, live imaging, and local synapse activity manipulations to investigate DiS development and function in rodent hippocam-pus. Dual innervation occurred early in development, even on spines where the excitatory input was locally silenced. Synaptic NMDA receptor currents were selectively reduced at DiSs through tonic GABAB receptor signaling. Accordingly, spine enlargement normally associated with long-term potentiation on singly inner-vated spines (SiSs) was blocked at DiSs. Silencing somatostatin interneurons or pharmacologically blocking GABABRs restored NMDA receptor function and structural plasticity to levels comparable to neighboring SiSs. Thus, hippocampal DiSs are stable structures where function and plasticity are potently regulated by nanometer-scale GABAergic signaling.

Automated summary

Dendritic spines in the hippocampus can be directly connected to inhibitory and excitatory presynaptic terminals, resulting in close proximity of opposing synaptic functions at the nanometer scale. By using a combination of electron microscopy, live imaging, and synaptic activity manipulations, researchers have found that dual innervation occurs early in development, even when the excitatory input is silenced. The NMDA receptor currents are selectively reduced at dually innervated spines through GABAB receptor signaling, blocking the spine enlargement associated with long-term potentiation. Silencing somatostatin interneurons or blocking GABAB receptors restores NMDA receptor function and structural plasticity at dually innervated spines. Therefore, GABAergic signaling at the nanometer scale strongly regulates the function and plasticity of hippocampal dual innervated spines.