Effects of Systemic Inflammation on Synaptogenesis in Developing Mouse Hippocampus
Synapses are specialized points of contact between neurons allowing for rapid transfer of signals in electrical or chemical form. Synaptic transmission and plasticity are integral to information processing and memory functions in any nervous system, regardless of its level of complexity. Chemical synapses can be broadly classified as excitatory or inhibitory, depending on how their activity affects the membrane potential of the postsynaptic neuron. The majority of excitatory synapses are made onto small protrusions in dendrite membrane termed dendritic spines, while inhibitory synaptic terminals contact smooth membrane of dendritic shafts and cell bodies. The initial process of synapse formation, or synaptogenesis, occurs early in animal development and in humans as well as in mice it takes place postnatally over an extended period of time. Many neurodevelopmental as well as neurodegenerative disorders involve synapse and spine abnormalities, suggesting that undisturbed synaptogenesis is important to development of a healthy brain. Astrocytes and microglia are non-neuronal cells which play supportive and protective roles and thus shape the environment within the nervous system. Although their function is critical to proper neuronal operation, under pathological conditions their activities can have deleterious effects on neurons and their synapses. The purpose of the presented research was to elucidate the potentially detrimental influence of glial activation on developing synapses. Using the lipopolysaccharide model of systemic inflammation we induced glial inflammatory response in mice at several points of postnatal development. Hippocampus, one of the best described brain structures was used as the region of interest. We observed varying levels of microglial activation depending on the age of the animal and similar levels of astrocyte reactivity at all ages. Morphometric analysis of dendritic spines identified a period of vulnerability, manifested as a decrease in spine density in response to inflammation. The density of presynaptic excitatory terminals was similarly affected. When the systemic inflammation was extended from 24h to 8 days, the negative effects on the excitatory terminals were more pronounced and suggested a reduced excitatory drive. The improvement of seizure outcomes confirmed this hypothesis. We also investigated synaptic development in the mouse model of Nasu-Hakola disease, a genetic neurodegenerative disorder characterized by dementia and microglial activation. We found that the mice failed to develop normal levels of excitatory presynaptic terminals, while exhibiting reduced susceptibility to seizures. Furthermore, inducing a systemic inflammation in these mice resulted in a decrease in inhibitory terminal density and higher seizure susceptibility. The results of this study demonstrate a period in postnatal development with elevated sensitivity to immune inflammatory responses. Using a mouse disease model we confirmed the impact of inflammation on synaptic development.
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