GABAergic synapses onto SST and PV interneurons in the CA1 hippocampal region show cell-specific and integrin-dependent plasticity

Abstract

It is known that GABAergic transmission onto pyramidal neurons shows different forms of plasticity. However, GABAergic cells innervate also other inhibitory interneurons and plasticity phenomena at these projections remain largely unknown. Several mechanisms underlying plastic changes, both at inhibitory and excitatory synapses, show dependence on integrins, key proteins mediating interaction between intra- and extracellular environment. We thus used hippocampal slices to address the impact of integrins on long-term plasticity of GABAergic synapses on specific inhibitory interneurons (containing parvalbumin, PV + or somatostatin, SST +) known to innervate distinct parts of principal cells. Administration of RGD sequence-containing peptide induced inhibitory long-term potentiation (iLTP) at fast-spiking (FS) PV + as well as on SST + interneurons. Interestingly, treatment with a more specific peptide GA(C)RRETAWA(C)GA (RRETAWA), affecting α5β1 integrins, resulted in iLTP in SST + and iLTD in FS PV + interneurons. Brief exposure to NMDA is known to induce iLTP at GABAergic synapses on pyramidal cells. Intriguingly, application of this protocol for considered interneurons evoked iLTP in SST + and iLTD in PV + interneurons. Moreover, we showed that in SST + cells, NMDA-evoked iLTP depends on the incorporation of GABAA receptors containing α5 subunit to the synapses, and this iLTP is occluded by RRETAWA peptide, indicating a key role of α5β1 integrins. Altogether, our results revealed that plasticity of inhibitory synapses at GABAergic cells shows interneuron-specificity and show differences in the underlying integrin-dependent mechanisms. This is the first evidence that neuronal disinhibition may be a highly plastic process depending on interneuron type and integrins’ activity.

Bidirectional plasticity of GABAergic tonic inhibition in hippocampal somatostatin- and parvalbumin-containing interneurons

“…Thus, the overall synchronization of principal cells activity may be expected to increase (Pouille and Scanziani, 2001). Simultaneously, in the present report, we observed the upregulation of tonic inhibition in somatostatin-containing interneurons that target principal cells' dendrites in stratum lacunosum-moleculare, and this effect is accompanied by increased iLTP of mIPSCs (Brzdak et al, 2023). Considering that SST+ interneurons regulate local dendritic conductances and also excitatory synaptic plasticity, an increase in their tonic inhibition may result in less feedback inhibition onto principal cells (Chiu et al, 2013;Schulz et al, 2018).…”

“…This mechanism has been, however, implicated in the pyramidal neurons, and it remains to be elucidated whether or not it takes place also in interneurons investigated in the present study. In our recent study (Brzdak et al, 2023), we report that a brief treatment with NMDA evoked iLTP in SST+ and iLTD in PV+ interneurons. Thus, the effects on tonic conductance (present study) would thus sum up with analogous changes in phasic signaling in these neurons (Brzdak et al, 2023).…”

“…In our recent study (Brzdak et al, 2023), we report that a brief treatment with NMDA evoked iLTP in SST+ and iLTD in PV+ interneurons. Thus, the effects on tonic conductance (present study) would thus sum up with analogous changes in phasic signaling in these neurons (Brzdak et al, 2023). As principal cells' spiking and network oscillations were regulated through feedforward and feedback inhibition from PV+ interneurons targeting perisomatic areas, a decrease of tonic inhibition in these interneurons may lead to a more effective inhibition of principal cells (see Figure 4).…”

“…Considering that SST+ interneurons regulate local dendritic conductances and also excitatory synaptic plasticity, an increase in their tonic inhibition may result in less feedback inhibition onto principal cells (Chiu et al, 2013 ; Schulz et al, 2018 ). The opposite directions of synaptic (Brzdak et al, 2023 ) and primarily extrasynaptic tonic current plasticity of SST+ and PV+ were particularly interesting, considering the crucial impact of these interneurons on the local neuronal network and generation of theta rhythm (Sohal et al, 2009 ; Royer et al, 2012 ).…”

Extracellular matrix integrity regulates GABAergic plasticity in the hippocampus

“…Recently, our group has revealed that integrins modulate GABAergic synaptic transmission and plasticity. Specifically, interference with integrin-dependent adhesion blocks the induction of NMDA-iLTP in CA1 pyramidal cells or interneurons [20], [57]. However, we did not observe changes in levels of extended, presumably active, forms of integrin β1 or β3 (Fig.…”