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A cavity was made in the brain (entorhinal cortex) of developing or adult rats, and a small piece of Gelfoam was emplaced to collect fluid secreted into the wound. The neuronotrophic activity of the fluid was assayed with sympathetic and parasympathetic neurons in culture. The results show that wounds in the brain of developing or adult rats stimulate the accumulation of neuronotrophic factors and that the activity of these factors increases over the first few days after infliction of the damage.

Bile acids are steroid acids found in the bile of mammals. The bile acid conjugate tauroursodeoxycholic acid (TUDCA) is neuroprotective in different animal models of stroke and neurological diseases. We have previously shown that TUDCA has anti-inflammatory effects on glial cell cultures and in a mouse model of acute neuroinflammation. We show now that microglial cells (central nervous system resident macrophages) express the G protein-coupled bile acid receptor 1/Takeda G protein-coupled receptor 5 (GPBAR1/TGR5) in vivo and in vitro. TUDCA binding to GPBAR1/TGR5 caused an increase in intracellular cAMP levels in microglia that induced anti-inflammatory markers, while reducing pro-inflammatory ones. This anti-inflammatory effect of TUDCA was inhibited by small interference RNA for GPBAR1/TGR5 receptor, as well as by treatment with a protein kinase A (PKA) inhibitor. In the mouse model of acute neuroinflammation, treating the animals with TUDCA was clearly anti-inflammatory. TUDCA biased the microglial phenotype in vivo and in vitro toward the anti-inflammatory. The bile acid receptor GPBAR1/TGR5 could be a new therapeutic target for pathologies coursing with neuroinflammation and microglia activation, such as traumatic brain injuries, stroke, or neurodegenerative diseases. TUDCA and other GPBAR1/TGR5 agonists need to be further investigated, to determine their potential in attenuating the neuropathologies associated with microglia activation. J. Cell. Physiol. 232: 2231-2245, 2017. © 2016 Wiley Periodicals, Inc.

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Secondary cultures of adult rat olfactory bulb (OB) contained three different types of cell: (i) process-bearing cells; (ii) macrophage-like cells and (iii) fusiform cells. The immunohistochemical properties of process-bearing cells closely corresponded to those described for ensheathing glia in vivo. The most distinctive feature of these cells was their immunoreactivity for low affinity nerve growth factor receptor (NGFR). Process-bearing cells also shared the ultrastructural properties of ensheathing glia in vivo, as well as the ability to ensheath olfactory axons. In contrast, macrophage-like cells had the immunostaining properties of microglia, and fusiform cells were likely capillary endothelial cells. Neurites outgrowing from olfactory epithelium explants, when co-cultured with adult OB cells, grew preferentially over NGFR positive cells. Olfactory neurites exhibited NGFR immunoreactivity and were enfolded by NGFR positive cells. After ensheathment, this immunoreactivity decreased from the neurite and disappeared from the glial membrane in contact with the neurite. However, NGFR immunoreactivity was maintained in the portion of the glial membrane not involved in ensheathing. In summary, ensheathing cells in vitro retained both the ultrastructure shown in vivo and the ability to ensheath olfactory neurites. The Schwann cell-like properties of ensheathing glia, could partially explain the permissibility of adult OB to axonal growth.

The molecular layer of the dentate gyrus of normal rats shows a large incidence ofperforated postsynaptic densities (PSDs). The perforations or discontinuities occur almost exclusively in PSDs located in spines showing a U-or W-shaped junctional profile (complex PSDs). Perforated PSDs account for 16-25% of the total complex PSD profiles in young adult rats and 12-29% of those in aged animals. The frequency of perforations in the inner molecular layer of the dentate gyrus undergoes significant changes during a cycle of nondegenerative synapse turnover induced by ipsilateral ablation ofthe entorhinal cortex. During the first 2 days postlesion nonperforated PSDs (simple PSDs) decrease sharply, whereas perforated PSDs change little. However, at later times (4-10 days) there is a significant increase in the number of perforated PSDs that balances the number of simple PSDs lost. Beyond 10 days postlesion the proportion of both types of PSD is restored slowly to normal-i.e., nonperforated PSDs increase in number and perforated PSDs decrease, returning to the values in unoperated animals by 120 days postlesion. This inverse relationship between small nonperforated PSDs and large perforated PSDs suggests a precursor-product relationship between them. We propose that perforated PSDs are intermediates in an ongoing cycle of synapse turnover that is a part of the normal maintenance and adaptation of the nervous system. Synapse replacement (synapse turnover) appears to be part of the normal program both for the maintenance ofthe peripheral and central nervous systems of adult vertebrates and for their adaptation to changing situations. Experimental evidence for the existence of this process is widespread (reviewed in refs. 1 and 2) but indirect, depending on inferences derived from the observation of characteristic degenerating and regenerating synaptic profiles. In normal animals the proportion of these profiles is generally small and furthermore, synapse turnover may occurwithout display ofsuch structures. Perhaps the greatest difficulty in studying synapse turnover in the adult is to devise a method to trigger it reliably in a statistically meaningful neuronal population. We have found that unilateral lesions of the entorhinal cortex initiate a cycle ofsynapse turnover in areas of the hippocampal formation that do not receive afferent input from the injured cortex (3, 4). The replacement ofsynapses thus induced is similar to the natural turnover process in unoperated animals in that degenerating profiles are never observed and synapse disconnection does not require the loss ofeither axonal or dendritic counterparts. However, an advantage with respect to the natural process is that synapse turnover can be elicited at will in a large synapse population and studies on the intermediate stages are possible. Here, we report the use of this method to study the structural changes that occur in the postsynaptic densities (PSDs) of asymmetric synapses in the hippocampal dentate gyrus during one cycle of synapse turnover.PS...