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bioRxiv · 10.1101/2025.08.31.673310

Somatostatin released by single O-LM interneurons slowly inhibits intrinsic neuronal excitability in a paracrine and autocrine manner

Musella, M. L.·Sammari, M.·Ajal, C.·Le Cor, A.·Russier, M.·Debanne, D.·Incontro, S.
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Abstract

Somatostatin (SST) is a neuropeptide known to inhibit both neuronal excitability and excitatory synaptic transmission in principal neurons. While SST is expressed in some GABAergic interneurons such as Oriens-Lacunosum Moleculare (O-LM) cells, the precise conditions governing SST release remain poorly defined. We show here that, in the presence of GABAA receptor antagonist, single O-LM interneurons of CA1 are able to inhibit pyramidal neuron excitability when O-LM cells fire at frequencies above 20 Hz. This inhibition is suppressed by the SST receptor antagonist cyclo-SST and is absent when the O-LM interneuron is located more than 150 {micro}m from the pyramidal cell. Likewise, a single O-LM cell was also able to inhibit the intrinsic excitability of another O-LM cell, provided the two cells are in proximity. Exogeneous application of SST transiently inhibits excitatory synaptic transmission and intrinsic excitability in O-LM interneurons through SST1 and SST2, respectively. Notably, this transient inhibition became sustained when clathrin-dependent endocytosis of SST receptors was blocked. Blocking of SST receptors reduced NMDA receptor-mediated responses, prevented induction of both synaptic and intrinsic potentiation in pyramidal neurons and reduced the coherence of theta oscillations. These findings reveal that SST released by O-LM interneurons constitutes an additional inhibitory mechanism, modulating both synaptic excitation and intrinsic excitability beyond the transient inhibition mediated by GABA release.

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Musella, M. L., Sammari, M., Ajal, C., Le Cor, A., Russier, M., Debanne, D., Incontro, S.. 2025-09-03. Somatostatin released by single O-LM interneurons slowly inhibits intrinsic neuronal excitability in a paracrine and autocrine manner. https://doi.org/10.1101/2025.08.31.673310

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