Non-Hebbian Long-Term Depression at VIP Interneuron Inputs Selectively Tunes Inhibition in Disinhibitory Circuits of...

Control of synaptic inhibition at the network level is essential for neuronal computation; however, the mechanism by which inhibitory I → I synapses between interneurons adjust their strength remains unclear. Here, we describe a non-Hebbian form of inhibitory long-term depression (iLTD) that operates at vasoactive intestinal peptide (VIP) interneuron inputs onto stratum oriens interneurons in the hippocampal CA1 region.

Whole-cell recordings of oriens interneurons combined with optogenetic VIP-positive input activation in mouse hippocampal slices.

Repeated postsynaptic burst firing alone was sufficient to induce a persistent weakening of VIP-mediated I → I inhibitory transmission onto oriens interneurons. This plasticity was insensitive to presynaptic stimulation paired with postsynaptic burst spiking, confirming its non-Hebbian character. The observed iLTD required postsynaptic calcium influx through L- and T-type voltage-gated calcium channels but was independent of endocannabinoid signaling, indicating a postsynaptic mechanism. To better define the cell-specificity of plastic changes at I → I synapses on oriens interneurons, we compared these findings with plasticity induced by analogous protocols at inhibitory synapses formed by two major interneuron types (parvalbumin- and somatostatin-positive) onto pyramidal neurons. These synapses, however, followed classical and subtype-specific Hebbian spike-timing-dependent rules and were unaffected by postsynaptic burst activity. Notably, physiologically relevant theta-burst stimulation of excitatory inputs to oriens interneurons induced heterosynaptic I → I iLTD and increased the excitatory/inhibitory balance in these cells, thereby enhancing their recruitment.

Our findings identify a cell-type-specific, activity-history-dependent rule of inhibitory I → I plasticity that weakens disinhibition in a non-Hebbian manner, revealing a novel physiological mechanism that modulates gain within hippocampal microcircuits.