Metaplastic regulation of CA1 Schaffer collateral pathway plasticity by Hebbian mGluR1a-mediated plasticity at excitatory synapses onto somatostatin-expressing interneurons

Abstract

Cortical GABAergic interneurons represent a highly diverse neuronal type that regulates neural network activity. In particular, interneurons in the hippocampal CA1 oriens/alveus (O/A-INs) area provide feedback dendritic inhibition to local pyramidal cells and express somatostatin (SOM). Under relevant afferent stimulation patterns, they undergo long-term potentiation (LTP) of their excitatory synaptic inputs through multiple induction and expression mechanisms. However, the cell type specificity of these different forms of LTP and their specific contribution to the dynamic regulation of the CA1 network remain unclear. Here we recorded from SOM-expressing interneurons (SOM-INs) in the O/A region from SOM-Cre-Ai3 transgenic mice in whole cell patch-clamp. Results indicate that, like in anatomically identified O/A-INs, theta burst stimulation (TBS) induced a Hebbian form of LTP dependent on metabotropic glutamate receptor type 1a (mGluR1a) in SOM-INs, but not in parvalbumin-expressing interneurons (PV-INs), another mainly non-overlapping interneuron subtype in CA1. In addition, we demonstrated using field recordings from transgenic mice expressing archaerhodopsin Arch3 selectively in SOM-INs, that a prior conditioning TBS in O/A, to induce mGluR1a-dependent LTP in SOM-INs, up-regulated LTP in the Schaffer collateral pathway of pyramidal cells. This effect was prevented by light-induced hyperpolarization of SOM-INs during TBS, or by application of the mGluR1a antagonist LY36785, indicating a necessity for mGluR1a and SOM-INs activation. These results uncover that SOM-INs perform an activity-dependent metaplastic control on hippocampal CA1 microcircuits in a cell-specific fashion. Our findings provide new insights on the contribution of interneuron synaptic plasticity in the regulation of the hippocampal network activity and mnemonic processes.

Significance Statement: Long term potentiation (LTP) is an important cellular mechanism of learning and memory. Although it has been extensively characterized in principal cells of the hippocampus, it also occurs in inhibitory GABAergic interneurons, known to orchestrate hippocampal network activity. Interneurons are highly diverse and many subtypes are distinguished, endowed with distinct functions. However, their cell-type specific contribution and how LTP in these interneurons regulate hippocampal CA1 microcircuits remain open questions. Here we found that LTP occurring in the Schaffer collateral pathway of CA1 pyramidal cells was up-regulated by prior induction of mGluR1a-dependent LTP in somatostatin-expressing interneurons. These results reveal a metaplastic control of the hippocampal CA1 network which can help to understand interneuron subtype-specific contribution in hippocampus-dependent learning and memory.