Intrahippocampal injection of IL‐1β upregulates Siah1‐mediated degradation of synaptophysin by activation of the ERK signaling in male rat

Abstract

Interleukin-1β (IL-1β) has been described to exert important effect on synapses in the brain. Here, we explored if the synapses in the hippocampus would be adversely affected following intracerebral IL-1β injection and, if so, to clarify the underlying molecular mechanisms. Adult male Sprague-Dawley rats were divided into control, IL-1β, IL-1β + PD98059, and IL-1β + MG132 groups and then sacrificed for detection of synaptophysin (syn) protein level, synaptosome glutamate release, and synapse ultrastructure by western blotting, glutamate kit and electron microscopy, respectively. These rats were tested by Morris water maze for learning and memory ability. It was determined by western blotting whether IL-1β exerted the effect of on syn and siah1 expression in primary neurons via extracellular regulated protein kinases (ERK) signaling pathway. Intrahippocampal injection of IL-1β in male rats and sacrificed at 8d resulted in a significant decrease in syn protein, damage of synapse structure, and abnormal release of neurotransmitters glutamate. ERK inhibitor and proteosome inhibitor treatment reversed the above changes induced by IL-1β both in vivo and in vitro. In primary cultured neurons incubated with IL-1β, the expression level of synaptophysin was significantly downregulated coupled with abnormal glutamate release. Furthermore, use of PD98059 had confirmed that ERK signaling pathway was implicated in synaptic disorders caused by IL-1β treatment. The present results suggest that exogenous IL-1β can suppress syn protein level and glutamate release. A possible

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“…SYN is well known for its involvement in synaptic plasticity mechanisms, and it is one of the most crucial proteins within synaptic vesicles. The synaptic vesicle is a site within the presynaptic neuron where neurotransmitters are stored 11 . An increase in SYN levels can enhance neurotransmitter secretion into the synaptic space, thereby facilitating synaptic transmission between neurons 49 .…”

“…Notably, microtubule-associated protein 2 (MAP2) is a protein enriched in dendrites and serves as a marker for synaptic plasticity 10 . On the other hand, synaptic proteins, including synaptophysin (SYN), are involved in synaptic plasticity and transmission 11 . Any changes in the levels of these proteins may be associated with abnormal dendritic and synaptic function.…”

Estrogen-immuno-neuromodulation disorders in menopausal depression

“…In conclusion, a significant decrease in estrogen levels disrupts immune homeostasis, particularly the levels of the immune factors TNF-α, IL-1β, IL-4, IL-6, IL-10 and IL-18 through the ERα/ERβ/GPER-associated NLRP3/NF-κB signaling pathway, which involves many signaling molecules, such as TLR2, TLR4, P2X7R, SIRT1, CREB, MS-KIF18A, PI3K, AKT, Gs, cAMP, PKA, PJA1, Serpina3n, Src, and MMP-9 [ 19 – 24 , 41 , 43 , 44 , 47 – 49 , 52 , 54 – 56 , 58 ]. Subsequently, the increase of inflammatory cytokine levels causes BBB destruction [ 25 , 62 – 74 , 165 ], the dysfunction of neurotransmitters such as 5-HT [ 80 – 85 ], DA [ 86 – 97 ], NE [ 98 – 105 ], GABA [ 29 , 30 , 106 – 113 ] and Glu [ 79 , 114 – 121 ], BDNF deficiency and dysfunction [ 26 , 128 – 135 ], and attenuation of neuroplasticity [ 136 – 146 ], which are key factors in the onset and progression of depression (Fig. 10 ).…”

“…9 ). In contrast, Zhou et al reported that IL-1β can upregulate the degradation of the synaptophysin protein by the E3 ligase siah1 via the ERK signaling pathway and subsequently inhibit the release of Glu, which impaired the learning and memory ability of rats [ 121 ].…”