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Inhibition of nerve growth and plasticity in the CNS is to a large part mediated by Nogo-like signaling, now encompassing a plethora of ligands, receptors, co-receptors and modulators. Here we describe the distribution and levels of mRNA encoding 11 key genes involved in Nogo-like signaling (Nogo-A, Oligodendrocyte-Myelin glycoprotein (OMgp), Nogo receptor 1 (NgR1), NgR2, NgR3, Lingo-1, TNF receptor orphan Y (Troy), Olfactomedin, Lateral olfactory tract usher substance (Lotus) and membrane-type matrix metalloproteinase-3 (MT3-MPP)), as well as BDNF and GAPDH.
Expression was analyzed in nine different brain areas before, and at eight time points during the first 3 days after a strong neuroexcitatory stimulation, caused by one kainic acid injection. A temporo-spatial pattern of orderly transcriptional regulations emerges that strengthens the role of Nogo-signaling mechanisms for synaptic plasticity in synchrony with transcriptional increases of BDNF mRNA. For most Nogo-type signaling genes, the largest alterations of mRNA levels occur in the dentate gyrus, with marked alterations also in the CA1 region. Changes occurred somewhat later in several areas of the cerebral cortex. The detailed spatio-temporal pattern of mRNA presence and kainic acid-induced transcriptional response is gene-specific. We reveal that several different gene alterations combine to decrease (and later increase) Nogo-like signaling, as expected to allow structural plasticity responses. Other genes are altered in the opposite direction, suggesting that the system prepares in advance in order to rapidly restore balance.
However, the fact that Lingo-1 shows a seemingly opposite, plasticity inhibiting response to kainic acid (strong increase of mRNA in the dentate gyrus), may instead suggest a plasticity-enhancing intracellular function of this presumed NgR1 co-receptor. Animals Male mice (C57/Bl6) were purchased from Charles-River (Sulzfeld, Germany) at 12 weeks of age. This strain was chosen as it is the background strain used (or backcrossed to) for most of the genetic manipulations including our NgR1 overexpressing mice.
This strain is also the one mostly used in studies of plasticity, regeneration and behavior. Mice were group housed in litters of 5/cage with access to food and water ad libitum. All mice were kept in the same animal room on a 12/12 h light/dark cycle (lights on 06:00–18:00) and temperature was kept at 22–23°C with a relative humidity of 60%. Each cage had a small paper house and some paper towels for “enrichment”. Kainic Acid Administration The drug was administrated as a single injection in a dose that causes strong neuronal activation (30 mg/kg i.p.) without resulting in significant neuronal loss (Schauwecker and Steward, ).
Mice were injected in and kept in their home cage for the rest of the experiment. Following injection, the behavior of the animals was monitored by two experienced scientists and scored based on a standardized 6-grade seizure scale (Schauwecker and Steward, ). Only mice graded IV (rearing and falling over) or V (repeatedly rearing and falling over) were included in the subsequent analysis.
No difference in the seizure scores was seen between kainic acid groups. The groups receiving the kainic acid injection is referred to as the induced neuronal activity group. They were compared to mice without intervention, to investigate how an episode of strong neuronal activation alters baseline mRNA levels found in untreated controls. Tissue Preparation Mice were sacrificed (by decapitation) at the following time points; 1 h ( n = 7), 2 h ( n = 6), 4 h ( n = 5), 8 h ( n = 6), 12 h ( n = 5), 16 h ( n = 6), 24 h ( n = 6) and 72 h ( n = 6) after the kainic acid injection. As a control group, untreated mice ( n =13), denoted “0” h, were used. Following dissection, brains were immediately frozen on dry ice and kept at −80 °C until sectioning.
Brains were serially sectioned (section thickness 14 μm) at levels containing striatum and hippocampus, using a cryostat (Microm). Results Mice were injected with kainic acid in their home cage and kept for up to 72 h before being sacrificed and processed for in situ hybridization. There was no difference in the seizure scores between groups injected with kainic acid (data not shown).
We analyzed the expression of all genes in nine brain areas connected to emotional processing and memory. For each gene, the results were normalized to mice without any treatment, referred to as the “0 h” time point, and all data are represented as percentage change from 0 h.
Thus, we are comparing how strong neuronal activation by the kainic acid treatment changes activity of the chosen genes compared to mice without any intervention. In the following, we will describe alterations of individual genes. All results are also summarized in Figures,. BDNF mRNA The neurotrophin BDNF is expressed mainly in cortical and hippocampal brain areas (Ernfors et al., ) and of key importance for brain plasticity (Lu et al., ). BDNF mRNA levels are typically relatively low in the non-perturbed brain. Validating the current study protocol, we found fast and marked kainic acid induced increase of BDNF mRNA levels in almost all investigated areas (Figure ).
A closer look at the time course revealed that the rise of BDNF mRNA was faster in parts of the hippocampal formation than in cortical areas with clear increases 1 h after the KA challenge and peak levels after 2 h in the dentate gyrus and CA1 region. BDNF mRNA levels in medial and lateral CA3 regions peaked at 8 h. CA1 BDNF mRNA levels had returned to baseline by 8 h; by 24 h, BDNF mRNA levels in the dentate gyrus, and in the medial and lateral CA3 had also returned to baseline levels. Marked increases of BDNF mRNA were also found in several cortical areas.
Interestingly, these changes all peaked at 4 h, hence 2 h later than in the dentate gyrus and CA1. The largest increase was seen in cingulate (6-fold) and S1 sensory (4-fold) cortex, lesser increases were noted in enthorhinal and retrosplenial cortex. The duration of effects in cortical areas and CA1 was 8 h, as opposed to 12–16 h in CA3 and the dentate gyrus. BDNF mRNA levels were also increased in amygdala during the first 16 h with a peak at 4 h.
GAPDH mRNA We used GAPDH mRNA hybridization to serve as an expression control in all areas of interest. In the non-stimulated brain, GAPDH mRNA was robustly found in cortical and hippocampal formation neurons. The levels of GAPDH mRNA did not change significantly at any time in any area except for a late, significant 50% increase ( p. OMgp mRNA Oligodendrocyte-Myelin glycoprotein (OMgp) is expressed by both neurons and oligodendroglia and serves as a ligand for NgR1 and PirB (Wang et al.,; Atwal et al., ). Relatively low OMgp mRNA hybridization signals were noted in most cortical areas, although a stronger signal was noted in piriform cortex.
OMgp mRNA levels were not significantly altered in either the dentate gyrus or CA3. However, levels were upregulated in CA1 (76%, p. Nogo-A mRNA This ligand, originally identified in myelin (Caroni and Schwab, ), is also expressed by neurons (Josephson et al., ).
Unlike OMgp mRNA, Nogo-A mRNA was widely expressed in the untreated brain and present at higher levels than OMgp mRNA. Nogo-A mRNA levels were rather stable over time and across brain areas. However, levels were significantly, albeit modestly affected in the dentate gyrus and amygdala (Figure ). In the dentate gyrus Nogo-A mRNA was significantly upregulated between 8 h and 16 h after kainic acid (peak 16 h 88% increase, p. NgR1 mRNA NgR1 was the first identified Nogo receptor (Fournier et al., ), and binds the Nogo66 segment of Nogo, as well as OMgp (Wang et al., ) and MAG (Liu et al., ). Its expression is exclusively neuronal (Fournier et al.,; Josephson et al., ).
As expected, we find robust, gray matter-specific expression of NgR1mRNA in cerebral cortex, amygdala, habenula and the hippocampal formation of untreated animals. Lesser amounts of NgR1 mRNA were found in thalamus, while striatum did not express detectable amounts of NgR1 mRNA.
NgR1 mRNA levels were found to be significantly altered in two regions, the hippocampal CA1 area, and the dentate gyrus (Figure ). In CA1, levels had declined already at the first studied time point, 1 h, and continued to drop until 4 h when levels were down by 52% ( p = 0.002). Expression of NgR1 mRNA in CA1 had returned to baseline levels at the 8 h timepoint, and no further significant changes were seen in CA1. In the dentate gyrus, NgR1 mRNA levels also decreased during the early phase and thus mirrored changes in CA1, but with a slightly faster time course and larger amplitude. Expression was significantly downregulated at 1 h ( p = 0.014) and a maximal down-regulation was seen after 2 h when there was a 55% reduction of mRNA levels ( p. Three day time course of alterations of NgR1, Troy and Lingo-1 mRNA in response to kainic acid. For legend, see Figure.
By and large, all four analyzed cortical areas, cingulate, enthorinal, retrosplenial and sensory cortex, undergo a modest but not significant decrease of NgR1 mRNA. This is similar to that noted for CA1, CA3 and amygdala, although NgR1 mRNA levels in cortical areas appear not to have returned to pre-kainic acid levels at 72 h (31 of 32 measured time points in cortical areas are. Lingo-1 Being GPI-linked to the cell membrane, the NgRs depend on co-receptors for signaling. Lingo-1 has been identified as a NgR1 co-receptor, interacting with another co-receptor, p75 and NgR1 (Mi et al., ). However, more recent work questions the site of action of Lingo-1, suggesting an intracellular role instead (Meabon et al., ).
Untreated mice had robust presence of mRNA encoding the presumed NgR1 co-receptor Lingo-1 in cerebral cortex (Figure ) and in CA1 and CA3, while the granule cell layers in the dentate gyrus had a lower expression of Lingo-1 mRNA. The strongest hippocampal expression was seen in CA3 (Figure ). Strikingly, Lingo-1 mRNA expression levels were significantly increased in six out of nine regions by the kainic acid challenge. The most profound relative change was seen in the dentate gyrus were mRNA was strongly upregulated at all time points after KA stimulation, peaking at 8 h (771% upregulation, p. Troy We next assessed TNF receptor orphan Y (Troy), a second co-receptor for NgR1 (Park et al., ) that can replace p75. In untreated mice, Troy mRNA was present in the hippocampal formation, cerebral cortex and in many subcortical brain areas.
We found Troy mRNA levels to be significantly altered in three regions (Figure ). Like NgR1, Troy mRNA was rather rapidly downregulated in the dentate gyrus by kainic acid, significantly so at 2 h (41% downregulation, p = 0.02).
Surprisingly, Troy mRNA levels in the dentate gyrus demonstrated a bi-phasic down/up regulation pattern, returning to baseline or above by 4 h, before being down-regulated again at 8 h (45%, p. NgR2 Less is known about ligands and co-receptors for the NgR1 related receptors NgR2 and NgR3. NgR2, however, binds MAG, and with higher affinity than NgR1 (Robak et al., ). In untreated mice, mRNA encoding NgR2 is present in lower amounts and fewer areas than NgR1 mRNA. There is a scattered presence of NgR2 mRNA in the inner half of the cerebral cortex, and a stronger presence in claustrum and habenula.
In the hippocampal formation, CA1 and CA3, but not CA2, express NgR2 mRNA, as does the dentate gyrus. The effects of a kainic acid challenge on NgR2 mRNA levels differed dramatically from those on NgR1 by being upregulated in seven out of the nine examined brain areas. In the dentate gyrus, the mRNA level peaked after 8 h (212% upregulation, p. NgR3 NgR3 has been reported to function as a CSPG receptor (Dickendesher et al., ). In the untreated mouse, we found low levels of NgR3 mRNA. Similarly to NgR2, NgR3 mRNA levels were strongly upregulated in several brain areas following the strong kainic acid induced increase of neuronal activity. Similar to NgR2, NgR3 mRNA levels were most strongly upregulated in the dentate gyrus, also peaked at 8 h (327%, p.
LgI1 When Adam22 is associated with NgR1, this complex attracts the secreted Adam22 ligand LGI1, leading to blockade of NgR1 signaling (Thomas et al.,; Figure ). In the untreated mouse brain, levels of mRNA encoding LGI1 were prominent in CA3 compartments and the dentate gyrus, with robust levels also found in the cerebral cortex and amygdala. However, unlike the situation for all other investigated genes, LGI1 mRNA levels seemed not to be significantly regulated by kainic acid in either high- or low-expressing areas (data not shown). Lotus By binding to NgR1, Lotus inhibits Nogo-mediated signaling (Sato et al., ).
In the untreated mouse brain, Lotus mRNA is expressed in many areas, including cortex, hippocampus, the lateral olfactory tract and piriform cortex, but also in striatum, islands of Calleja, and in many subcortical and brain stem nuclei. Levels of mRNA encoding Lotus were dramatically increased in the dentate gyrus with a peak at 8 h (785%, p. Bosch wfd 2072 manual high school indianapolis. Olfactomedin Originally isolated from frog olfactory neuroepithelium (Snyder et al., ), olfactomedin mRNA was later found to be present in rat and mouse brains, including hippocampus and the cerebral cortex and given the alternative name pancortin. This highly conserved, secreted glycoprotein inhibits signaling by the NgR1 complex (Nakaya et al., ). We found olfactomedin mRNA to be robustly present in many brain areas, including the cortices, the hippocampal formation and amygdala. Olfactomedin mRNA is also present in striatum and thalamus.
Interestingly, this gene seems to have much lower expression in the CA2 area than in other parts of the hippocampus. Following kainic acid treatment, the Olfactomedin mRNA level in the dentate gyrus stands out by undergoing a marked, significant decrease, reaching its lowest level at 4 h, followed by a significant increase to above baseline levels, peaking at 16 h. This pattern is very similar to the changes of NgR1 mRNA levels. Strikingly, Olfactomedin 1 mRNA levels in all nine investigated brain areas are decreased below baseline at 24 h. MT3-MMP This metalloproteinase associates with NgR1 and cleaves it. The N-terminal fragment is soluble and can bind to Nogo-A, thus blocking it from binding to membrane-bound NgR1 (Ferraro et al., ).
Messenger RNA encoding MT3-MMP was found in cortical areas, amygdala, hippocampus, striatum and the reticular thalamic nucleus of untreated mice. A striking feature of the MT3-MMP mRNA distribution was that the highest levels were found in the granule cell layer of the dentate gyrus. Kainic acid caused MM3-MMP mRNA to be decrease in medial CA3 at 4 h and then increase to a peak level at 8 h.
The same pattern, although smaller in magnitude, was found in the dentate gyrus. MT3-MMP mRNA levels in the lateral CA3 showed a similar, even lesser pronounced, and thus non-significant pattern of alterations. In fact, MT3-MMP mRNA levels were the lowest at 4 h in eight of the nine investigated areas. In cortical areas MT3-MMP mRNA levels were largely stable as were levels in amygdala. Additional Genes of Interest Above we have provided detailed information about location of transcripts and the effects of a strong excitatory stimulus on the transcriptional activity of 11 selected key genes involved in Nogo-like nerve growth inhibitory signaling, as well as BDNF and GAPDH mRNA. We did not observe measurable levels of mRNA encoding S1PR2, PirB, BlyS or p75 in the chosen areas of interest. This remained true even after kainic acid treatment.
MAG was not examined due to its very limited expression in the gray matter. Further, we did not investigate the CSPG group of proteins.