INTRODUCTION: Plasticity in the brain comprises a range of mechanisms that alter synaptic strength and composition and plays a key role in memory encoding. Plastic changes may arise from both: coordinated activity of presynaptic stimulation and postsynaptic responces, and modifications not involving presynaptic activity. Also, plasticity at excitatory and inhibitory inputs onto principal cells has been extensively investigated, while long-term plastic changes at interneuron–interneuron (I-I) synapses remain less well characterized.

AIM(S): We investigated plastic changes at I-I synapses onto interneurons located in the stratum oriens of the hippocampus.

METHOD(S): Optogenetics was used to selectively activate VIP-positive presynaptic interneurons and applied protocols: with and without presynaptic stimulation (spike timing-dependent plasticity and depolarization-only protocols). Postsynaptic INs were characterized by electrophysiological properties and morphological features.

RESULTS: Our data showed uniform responses across all tested timing intervals (+60 ms, 0 ms, -60 ms) in STDP protocols. Postsynaptic fast-spiking interneurons exhibited no significant plastic changes, while OLM and other non-FS interneurons developed long-term depression of inhibitory inputs (iLTD). The lack of timing-specific changes suggests a nonassociative form of plasticity that does not require VIP-IN activation. Experiments omitting presynaptic stimulation further supported this conclusion. We then examined two molecular pathways potentially involved in this plasticity. Blocking endocannabinoid signaling with a CB1 receptor antagonist did not prevent iLTD induction. In contrast, blocking L-type voltage-gated Ca²⁺ channels alone did not abolish iLTD, but co-application of L- and T-type channel blockers significantly reduced the magnitude of I-I iLTD.

CONCLUSIONS: Hereon we demonstrate that inhibitory synapses onto interneurons in the stratum oriens undergo nonassociative forms of synaptic plasticity, likely mediated by postsynaptic Ca²⁺ influx.

FINANCIAL SUPPORT: OPUS 2021/43/B/NZ4/01675