Brain inflammation induces post-synaptic changes during early synapse formation in adult-born hippocampal neurons

Abstract

An inflammatory reaction in the brain is primarily characterized by activation of parenchymal microglial cells. Microglia regulate several aspects of adult neurogenesis, i.e. the continuous production of new neurons in the adult brain. Hippocampal neurogenesis is thought to be important for memory formation, but its role in brain diseases is not clear. We have previously shown that brain inflammation modulates the functional integration of newly formed hippocampal neurons. Here, we explored whether there is a defined time period during synaptic development when new neurons are susceptible to brain inflammation. Newly formed hippocampal neurons, born in an intact environment in the adult mouse brain, were exposed to lipopolysaccharide (LPS)-induced inflammation during either early or late phases of excitatory and inhibitory synaptogenesis. We used intra-hippocampal injections of GFP-retroviral vector (RV-GFP) to label the new neurons and ipsilateral LPS injection at either 1 or 4weeks post-RV-GFP injection. A single intra-hippocampal LPS injection induced an inflammatory response for at least 3weeks, including an acute transient pro-inflammatory cytokine release as well as a sub-acute and sustained change in microglial morphology. The general cytoarchitecture of the hippocampal dentate gyrus, including granule cell layer (GCL) volume, and astrocytic glial fibrillary acidic protein expression was not different compared to vehicle controls, and no Fluoro-Jade-positive cell death was observed. New neurons encountering this inflammatory environment exhibited no changes in their gross morphology. However, when inflammation occurred during early stages of synapse formation, we found a region-specific increase in the number of thin dendritic spines and post-synaptic density-95 (PSD-95) cluster formation on spines, suggesting an enhanced excitatory synaptic connectivity in the newborn neurons. No changes were observed in the expression of N-cadherin, an adhesion molecule primarily associated with excitatory synapses. At the inhibitory synapses, alterations due to inflammation were also evident during early but not later stages of synaptic development. Gephyrin, an inhibitory scaffolding protein, was down-regulated in the somatic region, while the adhesion molecules neuroligin-2 (NL-2) and neurofascin were increased in the somatic region and/or on the dendrites. The GABAA receptor-α2 subunit (GABAAR-α2) was increased, while pre/peri-synaptic GABA clustering remained unaltered. The disproportional changes in post-synaptic adhesion molecules and GABAA receptor compared to scaffolding protein expression at the inhibitory synapses during brain inflammation are likely to cause an imbalance in GABAergic transmission. These changes were specific for the newborn neurons and were not observed when estimating the overall expression of gephyrin, NL-2, and GABAAR-α2 in the hippocampal GCL. The expression of interleukin-1-type 1 receptor (IL-1R1) on preferentially the somatic region of new neurons, often in close apposition to NL-2 clu...

Endoplasmic Reticulum Stress and Disrupted Neurogenesis in the Brain Are Associated with Cognitive Impairment and Depressive-Like Behavior after Spinal Cord Injury

“…68 Adult new-born neurons are susceptible to brain inflammation. 38,39 Anti-inflammatory treatments prevent chronic brain inflammationmediated decreased neurogenesis. [68][69][70] Alterations of the number and/or morphology of microglial cells, as well as the up-regulation of inflammatory cytokines, such as IL-1a, IL-6, TNFa, have been implicated in cognitive and behavioral changes observed in depressed subjects.…”

“…Adult-born hippocampal neurons are sensitive to microglial activation, which can compromise survival and differentiation of newly-formed neurons. 38,39 Increased inflammation in the brain after SCI has been reported not only in pain regulatory areas, such as the brainstem and thalamus, but also in the hippocampus and cerebral cortex. 18,19,21,36,40,41 Moreover, SCI significantly increases M1-like microglial activation genes in the hippocampus, along with changes in M2a-like and M2c-like markers.…”

Dendritic Polyglycerol Sulfate Inhibits Microglial Activation and Reduces Hippocampal CA1 Dendritic Spine Morphology Deficits

“…48 Chronic inflammation is commonly viewed as deleterious to neurological functions. 49,50 In this study, we investigated microglia and dendritic structures in hippocampal CA1 region using organotypic in vitro cell cultures in the presence and absence of dPGS. This experimental paradigm allowed for the testing of dPGS by controlling the concentration and duration of exposure of the neural cell culture to the inflammogen and anti-inflammatory dPGS.…”

Absence of interleukin-1 receptor 1 increases excitatory and inhibitory scaffolding protein expression and microglial activation in the adult mouse hippocampus

“…2 We therefore set out to evaluate the expression of a panel of synaptic proteins known to regulate the E/I balance, by quantifying the fluorescence intensity using confocal microscopy, as previously described. 6,8 We found increased expression of PSD-95, a scaffolding protein found mainly on glutamatergic synapses, in both the GCL and inner and outer ML (iML and oML) in IL-1R1 KO mice compared to WT mice (Figure 1f-g). Surprisingly, the intensity of staining of the inhibitory scaffolding protein gephyrinbu immunohistochemistry was also increased in the iML and oML of IL-1R1 KO mice, whereas perisomatic expression in the GCL was unaltered (Figure 1h-i).…”

“…We utilized naïve adult (4-to 5-month-old) wild-type (WT) mice and IL-1R1 knockout (KO) mice, which were kindly provided by Dr Emmanuel Pinteaux, University of Manchester, UK. Microglial activation was assessed by quantifying the number and phenotype of Iba1 1 cells (i.e., ramified (surveying), intermediate and round/ameboid (phagocytic) morphologies), as visualized by immunohistochemistry, in perfused coronal brain sections, as previously described 6 ( Figure 1a-c). Interestingly, we detected more Iba1 1 cells in the granule cell layer (GCL) of the dentate gyrus (DG) in the hippocampus (Figure 1d) of the IL-1R1 KO animals than that of the WT animals.…”