Integrins Bidirectionally Regulate the Efficacy of Inhibitory Synaptic Transmission and Control GABAergic Plasticity

Abstract

For many decades, synaptic plasticity was believed to be restricted to excitatory transmission. However, in recent years, this view started to change, and now it is recognized that GABAergic synapses show distinct forms of activity-dependent long-term plasticity, but the underlying mechanisms remain obscure. Herein, we asked whether signaling mediated by b1 or b3 subunit-containing integrins might be involved in regulating the efficacy of GABAergic synapses, including the NMDA receptor-dependent inhibitory long-term potentiation (iLTP) in the hippocampus. We found that activation of b3 integrin with fibrinogen induced a stable depression, whereas inhibition of b1 integrin potentiated GABAergic synapses at CA1 pyramidal neurons in male mice. Additionally, compounds that interfere with the interaction of b1 or b3 integrins with extracellular matrix blocked the induction of NMDA-iLTP. In conclusion, we provide the first evidence that integrins are key players in regulating the endogenous modulatory mechanisms of GABAergic inhibition and plasticity in the hippocampus.

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

“…It is interesting to note that in our recent study Wiera et al, (2022) we found that whereas application of RGD depressed GABAergic transmission recorded from pyramidal neurons, RRETAWA potentiated it. Therefore, whereas observed here effect of RRETAWA in SST + INs was similar to that described in principal cells by Wiera et al, (2022), impact of RGD in PV + and SST + INs tended to be the opposite with respect to that in pyramidal cells 30 . Again, we may attribute these diverging effects to different sets of integrins involved and thereby to different intracellular molecular modulatory pathways.…”

“…In an electrophysiological study, Chan et al (2006) have shown that in a model in which β1 integrin was knocked out in forebrain excitatory neurons, an impaired synaptic transmission through AMPA receptors and weakened NMDAR-dependent long-term potentiation were observed 15 . In the context of integrin-dependent modulation of glutamatergic (especially NMDAR-dependent) drive it is worth mentioning that in the present study application of RRETAWA peptide interfering with α5β1 integrins prevented NMDAR-dependent induction of iLTP in SST + INs similar to iLTP in pyramidal cells described in our recent report 30 . It may be hypothesized that this effect of integrins on iLTP might be, at least in part, due to their action on NMDARs.…”

“…We found that administration of the GRGDSP peptide led to potentiation of inhibitory transmission in FS PV + and SST + INs, while no effect was observed in nFS cells, thus, for RGD-binding integrins, the potentiating effect was predominant. This finding appears particularly interesting in the light of our recent results that administration of GRGDSP peptide resulted in depression of GABAergic transmission recorded from pyramidal cells in CA1 region 30 . Thus, as a result of plasticity mediated by RGD-binding integrins, the pyramidal cells could be partially disinhibited as the PV + and SST + interneurons innervating the principal cell both perisomatically and at distal dendrites would be functionally weakened by enhanced inhibitory drive.…”

“…It may be hypothesized that this effect of integrins on iLTP might be, at least in part, due to their action on NMDARs. On the other hand, in our recent study we have reported that fibrinogen-induced iLTD onto pyramidal cells required the activity of calcineurin but not of Src, CaMKII or PKC kinase 30 . We may thus speculate that NMDA-induced iLTD at inhibitory synapse onto PV + INs described here might involve analogous molecular player.…”

“…The effect of integrins on GABAergic synaptic transmission was studied by applying the integrin-interfering peptides after baseline recordings at concentrations previously used by our group 30 . In the figures their effect is presented for the entire recording time after peptide administration (0–30 min) but in results section a numerical value obtained for the time window 16–18 min.…”