NO regulates the strength of synaptic inputs onto hippocampal CA1 neurons via NO-GC1/cGMP signalling

Abstract

GABAergic interneurons are the predominant source of inhibition in the brain that coordinate the level of excitation and synchronization in neuronal circuitries. However, the underlying cellular mechanisms are still not fully understood. Here we report nitric oxide (NO)/NO-GC1 signalling as an important regulatory mechanism of GABAergic and glutamatergic synaptic transmission in the hippocampal CA1 region. Deletion of the NO receptor NO-GC1 induced functional alterations, indicated by a strong reduction of spontaneous and evoked inhibitory postsynaptic currents (IPSCs), which could be compensated by application of the missing second messenger cGMP. Moreover, we found a general impairment in the strength of inhibitory and excitatory synaptic inputs onto CA1 pyramidal neurons deriving from NO-GC1KO mice. Finally, we disclosed one subpopulation of GABAergic interneurons, fast-spiking interneurons, that receive less excitatory synaptic input and consequently respond with less spike output after blockage of the NO/cGMP signalling pathway. On the basis of these and previous findings, we propose NO-GC1 as the major NO receptor which transduces the NO signal into cGMP at presynaptic terminals of different neuronal subtypes in the hippocampal CA1 region. Furthermore, we suggest NO-GC1-mediated cGMP signalling as a mechanism which regulates the strength of synaptic transmission, hence being important in gating information processing between hippocampal CA3 and CA1 region.

Downregulation of the CB1-Mediated Endocannabinoid Signaling Underlies D-Galactose-Induced Memory Impairment

“…Therefore, NO spillover from NOS over activation provides potential pathological sources of NO, which may lead to an impairment LTP and memory loss (Anaeigoudari et al, 2016;Wang and Han, 2018). One possible mechanism is that excessive NO can augment GABA release, regulating the strength of synaptic inputs onto hippocampal CA1 neuron (Neitz et al, 2015;Bradley and Steinert, 2016). In good agreement with it, we have observed that an increased tone of GABAergic activity might be involved in D-gal-induced LTP impairment (Figure 3).…”

Agmatine prevents acute chlorpromazine-induced neurotoxicity in rats

“…Aktivacija NMDA receptora glutamatom, uzrokuje influks jona Ca 2+ , koji se vezuje za kalmodulin i aktivira NOS, koja konvertuje O 2 i arginin u citrulin i NO, pri čemu NO zauzima značajno mesto u reakcijama koje posreduju kalmodulin i ciklični guanozin monofosfat (cGMP) (43). U ovoj studiji, već 24 h nakon davanja HPZ u odnosu na kontrolnu grupu, izmereno je povećanje koncentracije NO 2 +NO 3 u strijatumu, strukturi koja prima vlakna iz različitih izvora (Slika 1B).…”

Immunogold characteristics of VGLUT3‐positive GABAergic nerve terminals suggest corelease of glutamate

“…Activation of postsynaptic NMDA receptors in GABA synapses (including those containing VGLUT3) have been linked to triggering of Ca 2+ ‐dependent production of nitric oxide (NO) in postsynaptic compartments, which can act as a retrograde signal and increase the production of cyclic GMP in the presynaptic GABA terminal (Szabadits et al, ). This increase in NMDA receptor‐NO mediated cGMP could lead to increased release of GABA (Merino et al, ) and strengthening of inhibitory transmission, which in turn can regulate hippocampal network activity (Neitz et al, ). Likewise, activation of presynaptic NMDA receptors on GABA terminals can increase the release of GABA through a Ca 2+ ‐mediated mechanism, as shown in the cerebellum (Duguid and Smart, ).…”