Bacterial peptidoglycan signalling in microglia: Activation by MDP via the NF-κB/MAPK pathway.

Bacterial peptidoglycan (PGN) fragments are commonly studied in the context of bacterial infections. However, PGN fragments recently gained recognition as signalling molecules from the commensal gut microbiota in the healthy host. Here we focus on the minimal bioactive PGN motif muramyl dipeptide (MDP), found in both Gram-positive and Gram-negative commensal bacteria, which signals through the Nod2 receptor. MDP from the gut microbiota translocates to the brain and is associated with changes in neurodevelopment and behaviour, yet there is limited knowledge about the underlying mechanisms. In this study we demonstrate that physiologically relevant doses of MDP induce rapid changes in microglial gene expression and lead to cytokine and chemokine secretion. In immortalised microglial (IMG) cells, C-C Motif Chemokine Ligand 5 (CCL5/RANTES) expression is acutely sensitive to the lowest physiologically prevalent dose (0.1 µg/ml) of MDP. As CCL5 plays an important role in memory formation and synaptic plasticity, microglial CCL5 might be the missing link in elucidating MDP-induced alterations in synaptic gene expression. We observed that a higher physiological dose of MDP elevates the expression of cytokines TNF-α and IL-1ß, indicating a transition toward a pro-inflammatory phenotype in IMG cells, which was validated in primary microglial cultures. Furthermore, MDP induces the translocation of NF-κB subunit p65 into the nucleus, which is blocked by MAPK p38 inhibitor SB202190, suggesting that an interplay of both the NF-κB and MAPK pathways is responsible for the MDP-specific microglial phenotype. These findings underscore the significance of different MDP levels in shaping microglial function in the CNS and indicate MDP as a potential mediator for early inflammatory processes in the brain. It also positions microglia as an important target in the gut microbiota-brain-axis pathway through PGN signalling.

Liposuction for Advanced Lymphedema in a Multidisciplinary Team Setting in Australia: 5-Year Follow-Up.

BACKGROUND: Liposuction for International Society of Lymphology late stage 2 or 3 limb lymphedema is an established surgical option to remove excessive adipose tissue deposition and has been performed in Australia since 2012 at the Australian Lymphoedema Education, Research, and Treatment (ALERT) Program of Macquarie University. METHODS: Between May of 2012 and May of 2017, 72 patients with unilateral primary or secondary lymphedema of the arm or leg underwent suction-assisted lipectomy using the Brorson protocol. This prospective study presents 59 of these patients who had consented to research with a 5-year follow-up. RESULTS: Of the 59 patients, 54 (92%) were women, 30 (51%) had leg lymphedema, and 29 (49%) had arm lymphedema. For patients with arm lymphedema, the median preoperative volume difference between the lymphedematous and the contralateral arm was 1061 mL, which was reduced to 79 mL 1 year after surgery and to 22 mL 5 years after surgery. For patients with leg lymphedema, the median preoperative volume difference was 3447 mL, which was reduced to 263 mL 1 year after surgery but increased to 669 mL 5 years after surgery. CONCLUSION: Suction-assisted lipectomy is a long-term option for the management of selected patients with International Society of Lymphology late stage 2 or 3 limb lymphedema when conservative management can offer no further improvement. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Complete Reduction of Leg Lymphedema after Liposuction: A 5-Year Prospective Study in 67 Patients without Recurrence.

Background: Lymphedema leads to adipose tissue deposition that cannot be removed using conservative methods. Previous studies have shown a complete reduction in excess volume in limbs with lymphedema when treated with liposuction and controlled compression therapy (CCT). We present the long-term outcomes of all patients treated with liposuction and CCT for lower extremity lymphedema (LEL) who were followed up for 5 years. Methods: Sixty-seven LEL patients underwent liposuction and CCT. Thirty-six patients had primary lymphedema and 31 patients had secondary lymphedema. The outcomes included excess leg volume over a follow-up period of 5 years. Any association between patient characteristics and treatment outcomes was analyzed. Results: The preoperative excess volume prior was 3515 mL [interquartile range (IQR): 2225-5455 mL], and the volume ratio to the unaffected leg was 1.35 (IQR: 1.25-1.53). One year after treatment, the excess volume decreased by 101% (IQR: 84-116). The decrease in excess volume continued during the 5-year follow-up, and at the end of the study, the excess volume had decreased by 115% (IQR: 98-124). No major complications were noted. Conclusions: Liposuction and CCT are safe and effective procedures for removing excess adipose tissue and normalizing the leg volume in patients with late-stage LEL. When no satisfactory results are obtained with conservative methods, such as complex decongestive therapy, and there is no or minimal pitting on limb examination, excess adipose tissue is present, and liposuction can be considered.

The RhoA-ROCK1/ROCK2 Pathway Exacerbates Inflammatory Signaling in Immortalized and Primary Microglia.

Neuroinflammation is a unifying factor among all acute central nervous system (CNS) injuries and chronic neurodegenerative disorders. Here, we used immortalized microglial (IMG) cells and primary microglia (PMg) to understand the roles of the GTPase Ras homolog gene family member A (RhoA) and its downstream targets Rho-associated coiled-coil-containing protein kinases 1 and 2 (ROCK1 and ROCK2) in neuroinflammation. We used a pan-kinase inhibitor (Y27632) and a ROCK1- and ROCK2-specific inhibitor (RKI1447) to mitigate a lipopolysaccharide (LPS) challenge. In both the IMG cells and PMg, each drug significantly inhibited pro-inflammatory protein production detected in media (TNF-α, IL-6, KC/GRO, and IL-12p70). In the IMG cells, this resulted from the inhibition of NF-κB nuclear translocation and the blocking of neuroinflammatory gene transcription (iNOS, TNF-α, and IL-6). Additionally, we demonstrated the ability of both compounds to block the dephosphorylation and activation of cofilin. In the IMG cells, RhoA activation with Nogo-P4 or narciclasine (Narc) exacerbated the inflammatory response to the LPS challenge. We utilized a siRNA approach to differentiate ROCK1 and ROCK2 activity during the LPS challenges and showed that the blockade of both proteins may mediate the anti-inflammatory effects of Y27632 and RKI1447. Using previously published data, we show that genes in the RhoA/ROCK signaling cascade are highly upregulated in the neurodegenerative microglia (MGnD) from APP/PS-1 transgenic Alzheimer's disease (AD) mice. In addition to illuminating the specific roles of RhoA/ROCK signaling in neuroinflammation, we demonstrate the utility of using IMG cells as a model for primary microglia in cellular studies.

Microglial Nogo delays recovery following traumatic brain injury in mice.

Nogo-A, B, and C are well described members of the reticulon family of proteins, most well known for their negative regulatory effects on central nervous system (CNS) neurite outgrowth and repair following injury. Recent research indicates a relationship between Nogo-proteins and inflammation. Microglia, the brain's immune cells and inflammation-competent compartment, express Nogo protein, although specific roles of the Nogo in these cells is understudied. To examine inflammation-related effects of Nogo, we generated a microglial-specific inducible Nogo KO (MinoKO) mouse and challenged the mouse with a controlled cortical impact (CCI) traumatic brain injury (TBI). Histological analysis shows no difference in brain lesion sizes between MinoKO-CCI and Control-CCI mice, although MinoKO-CCI mice do not exhibit the levels of ipsilateral lateral ventricle enlargement as injury matched controls. Microglial Nogo-KO results in decreased lateral ventricle enlargement, microglial and astrocyte immunoreactivity, and increased microglial morphological complexity compared to injury matched controls, suggesting decreased tissue inflammation. Behaviorally, healthy MinoKO mice do not differ from control mice, but automated tracking of movement around the home cage and stereotypic behavior, such as grooming and eating (termed cage "activation"), following CCI is significantly elevated. Asymmetrical motor function, a deficit typical of unilaterally brain lesioned rodents, was not detected in CCI injured MinoKO mice, while the phenomenon was present in CCI injured controls 1-week post-injury. Overall, our studies show microglial Nogo as a negative regulator of recovery following brain injury. To date, this is the first evaluation of the roles microglial specific Nogo in a rodent injury model.

Streamlining Tangible 3D Printed and Intangible XR Content Creation and Evaluation: The ENTICE Experience.

ENTICE aimed to use co-creative methodologies in order to build a solid creation pipeline for medical experiential content. The project has developed and evaluated immersive learning resources and tools aiming to support well-defined learning objectives using tangible and intangible resources (AR/VR/MR, 3D printing) that are highly sought in the fields of anatomy and surgery. In this paper the preliminary results from the evaluation of the learning resources and tools in 3 countries as well as the lessons learnt are presented towards to the improvement of the medical education process.

Power-assisted Liposuction for Lymphedema: A Cost-utility Analysis.

Lymphedema is a chronic, debilitating disease that has been described as the largest breast cancer survivorship burden. Debulking surgery has been shown to improve extremity volume, improve patient quality of life, and decrease the incidence of cellulitis in the literature. This procedure is routinely covered in numerous other developed countries, yet it is still inconsistently covered in the United States. Methods: Extremity volumes from all patients who underwent debulking surgery of the upper extremity at two institutions between December 2017 and January 2020 with at least 12 months follow-up were included. Procedural costs were calculated using Medicare reimbursement data. Average utility scores were obtained for each health state using a visual analog scale, then converted to quality-adjusted life years. A decision tree was generated, and incremental cost-utility ratios were calculated. Sensitivity analyses were performed to evaluate our findings. Results: Debulking surgery is associated with a higher clinical effectiveness (quality-adjusted life year) of 27.05 compared to conservative management (23.34), with a relative cost reduction of $74,487. Rollback analysis favored debulking surgery as the cost-effective option compared to conservative management. The resulting negative incremental cost-utility ratio of -20,115.07 favored debulking surgery and indicated a dominant strategy. Conclusion: Our study supports the use of debulking surgery for the treatment of chronic lymphedema of the upper extremity.

Liposuction and Controlled Compression Therapy Reduce the Erysipelas Incidence in Primary and Secondary Lymphedema.

Background: Skin infections are a recurring problem for people with lymphedema, and lymphedema has been proven to be the single most important risk factor for developing erysipelas in the leg. This study aimed to determine whether liposuction for late-stage lymphedema reduces the rate of erysipelas in lower extremity lymphedema. Methods: One-hundred twenty-four patients with a median age of 49 years who had liposuction and controlled compression therapy for lower extremity lymphedema were included. Excess volumes were calculated before and after surgery. Median preoperative and postoperative patient years at risk were 11 and 5 years, respectively. Results: With a total of 1680 preoperative person years at risk and 335 bouts of erysipelas experienced in 64 patients, the preoperative incidence rate was 0.20 bouts per person per year, and the period prevalence was 52%. Postoperatively, the patients were followed over a total of 763 person years at risk, and 28 patients experienced a total of 53 bouts of erysipelas, resulting in a postoperative incidence rate of 0.07 bouts per person per year, and a period prevalence of 23%. This represents a 65% decrease in the erysipelas incidence rate (P < 0.001). The preoperative median excess volume of 3158 ml was reduced with a median of 100% (P < 0.0001). Conclusions: Liposuction and controlled compression therapy significantly reduce the risk for erysipelas in lower extremity lymphedema and completely reduces the excess volume. This finding is similar to our previous research including patients with upper extremity lymphedema.

Five Hours Total Sleep Deprivation Does Not Affect CA1 Dendritic Length or Spine Density.

Sleep is essential for long term memory function. However, the neuroanatomical consequences of sleep loss are disputed. Sleep deprivation has been reported to cause both decreases and increases of dendritic spine density. Here we use Thy1-GFP expressing transgenic mice to investigate the effects of acute sleep deprivation on the dendritic architecture of hippocampal CA1 pyramidal neurons. We found that 5 h of sleep deprivation had no effect on either dendritic length or dendritic spine density. Our work suggests that no major neuroanatomical changes result from a single episode of sleep deprivation.

Liposuction of Breast Cancer-Related Arm Lymphedema Reduces Fat and Muscle Hypertrophy.

Background: Adipose tissue deposition is a known consequence of lymphedema. A previous study showed that the affected arm in patients with nonpitting breast cancer-related lymphedema (BCRL) had a mean excess volume of 73% fat and 47% muscle. This condition impairs combined physiotherapy as well as more advanced microsurgical methods. Liposuction is, therefore, a way of improving the effects of treatment. This study aims to evaluate the tissue changes in lymphedematous arms after liposuction and controlled compression therapy (CCT) in patients with nonpitting BCRL. Methods and Results: Eighteen women with an age of 61 years and a duration of arm lymphedema (BCRL) of 9 years were treated with liposuction and CCT. Tissue composition of fat, lean (muscle), and bone mineral was analyzed through dual energy X-ray absorptiometry (DXA) before, and at 3 and 12 months after surgery. Excess volumes were also measured with plethysmography. The median DXA preoperative excess volume was 1425 mL (704 mL fat volume, 651 mL lean volume). The DXA excess volume at 3 months after surgery was 193 mL (-196 mL fat volume, 362 mL lean volume). At 12 months after surgery, the median excess DXA volume was 2 mL (-269 mL fat volume, 338 mL lean volume). From before surgery to 3 months after surgery, the median DXA excess volume reduced by 85% (p < 0.001) (fat volume reduction 128% (p < 0.001), lean volume reduction 37% (p = 0.016)). From before surgery to 12 months after surgery, it reduced by 100% (p < 0.001) (fat volume reduction 139% [p < 0.001], lean volume reduction 54% [p = 0.0013]). Conclusions: Liposuction and CCT effectively remove the excess fat in patients with nonpitting BCRL, and a total reduction of excess arm volume is achievable. A postoperative decrease in excess muscle volume is also seen, probably due to the reduced weight of the arm postoperatively.

The metabolite GLP-1 (9-36) is neuroprotective and anti-inflammatory in cellular models of neurodegeneration.

Glucagon-like peptide-1 (GLP-1) is best known for its insulinotropic action following food intake. Its metabolite, GLP-1 (9-36), was assumed biologically inactive because of low GLP-1 receptor (GLP-1R) affinity and non-insulinotropic properties; however, recent studies contradict this assumption. Increased use of FDA approved GLP-1 analogues for treating metabolic disorders and neurodegenerative diseases raises interest in GLP-1 (9-36)'s biological role. We use human SH-SY5Y neuroblastoma cells and a GLP-1R over-expressing variety (#9), in both undifferentiated and differentiated states, to evaluate the neurotrophic/neuroprotective effects of GLP-1 (9-36) against toxic glutamate exposure and other oxidative stress models (via the MTS, LDH or ROS assays). In addition, we examine GLP-1 (9-36)'s signaling pathways, including cyclic-adenosine monophosphate (cAMP), protein kinase-A (PKA), and 5' adenosine monophosphate-activated protein kinase (AMPK) via the use of ELISA, pharmacological inhibitors, or GLP-1R antagonist. Human HMC3 and mouse IMG microglial cell lines were used to study the anti-inflammatory effects of GLP-1 (9-36) against lipopolysaccharide (LPS) (via ELISA). Finally, we applied GLP-1 (9-36) to primary dissociation cultures challenged with α-synuclein or amyloid-ß and assessed survival and morphology via immunochemistry. We demonstrate evidence of GLP-1R, cAMP, PKA, and AMPK-mediated neurotrophic and neuroprotective effects of GLP-1 (9-36). The metabolite significantly reduced IL-6 and TNF-α levels in HMC3 and IMG microglial cells, respectively. Lastly, we show mild but significant effects of GLP-1 (9-36) in primary neuron cultures challenged with α-synuclein or amyloid-ß. These studies enhance understanding of GLP-1 (9-36)'s effects on the nervous system and its potential as a primary or complementary treatment in pathological contexts.

Forebrain NgR1 Overexpression Impairs DA Release Suggesting Synergy of Local and Global Synaptic Plasticity Mechanisms.

Structural synaptic reorganizations needed to permanently embed novel memories in the brain involve complex plasticity-enhancing and plasticity-inhibiting systems. Increased neural activity is linked to rapid downregulation of Nogo receptor 1 (NgR1), needed to allow local structural synaptic plasticity. This local regulation of plasticity is thought to be moderated by global systems, such as the ascending cholinergic and monoaminergic systems, adding significance to locally increased neural activity. Here we address the reverse possibility that the global systems may also be influenced by the status of local plasticity. Using NgR1-overexpressing mice, with impaired plasticity and long-term memory, we measured the ability to release dopamine (DA), implicated in regulating plasticity and memory. In vivo chronoamperometric recording with high temporal and spatial resolution revealed severe impairment of potassium chloride (KCl)-induced increase of extracellular DA in the dorsal striatum of mice overexpressing NgR1 in forebrain neurons. A similar, but lesser, impairment of DA release was seen following amphetamine delivery. In contrast, potassium chloride-evoked DA release in NgR1 knockout (KO) mice led to increased levels of extracellular DA. That NgR1 can impair DA signaling, thereby further dampening synaptic plasticity, suggests a new role for NgR1 signaling, acting in synergy with DA signaling to control synaptic plasticity. Significance Statement:The inverse correlation between local NgR1 levels and magnitude of KCl-inducible amounts of DA release in the striatum reinforces the rule of NgR1 as a regulator of structural synaptic plasticity and suggests synergy between local and global plasticity regulating systems.

Glucagon-like peptide-1 (GLP-1)-based receptor agonists as a treatment for Parkinson's disease.

INTRODUCTION: Accumulating evidence supports the evaluation of glucagon-like peptide-1 (GLP-1) receptor (R) agonists for the treatment of the underlying pathology causing Parkinson's Disease (PD). Not only are these effects evident in models of PD and other neurodegenerative disorders but recently in a randomized, double-blind, placebo-controlled clinical trial, a GLP-1R agonist has provided improved cognition motor functions in humans with moderate PD. AREAS COVERED: In this mini-review, we describe the development of GLP-1R agonists and their potential therapeutic value in treating PD. Many GLP-1R agonists are FDA approved for the treatment of metabolic disorders, and hence can be rapidly repositioned for PD. Furthermore, we present preclinical data offering insights into the use of monomeric dual- and tri-agonist incretin-based mimetics for neurodegenerative disorders. These drugs combine active regions of GLP-1 with those of glucose-dependent insulinotropic peptide (GIP) and/or glucagon (Gcg). EXPERT OPINION: GLP-1Ragonists offer a complementary and enhanced therapeutic value to other drugs used to treat PD. Moreover, the use of the dual- or tri-agonist GLP-1-based mimetics may provide combinatory effects that are even more powerful than GLP-1R agonism alone. We advocate for further investigations into the repurposing of GLP-1R agonists and the development of classes of multi-agonists for PD treatment.

Genetic Screening of Plasticity Regulating Nogo-Type Signaling Genes in Migraine.

Migraine is the sixth most prevalent disease in the world and a substantial number of experiments have been conducted to analyze potential differences between the migraine brain and the healthy brain. Results from these investigations point to the possibility that development and aggravation of migraine may include grey matter plasticity. Nogo-type signaling is a potent plasticity regulating system in the CNS and consists of ligands, receptors, co-receptors and modulators with a dynamic age- and activity-related expression in cortical and subcortical regions. Here we investigated a potential link between migraine and five key Nogo-type signaling genes: RTN4, OMGP, MAG, RTN4R and LINGO1, by screening 15 single nucleotide polymorphisms (SNPs) within these genes. In a large Swedish migraine cohort (749 migraine patients and 4032 controls), using a logistic regression with sex as covariate, we found that there was no such association. In addition, a haplotype analysis was performed which revealed three haplotype blocks. These blocks had no significant association with migraine. However, to robustly conclude that Nogo-type genotypes signaling do not influence the prevalence of migraine, further studies are encouraged.

Incretin Mimetics as Rational Candidates for the Treatment of Traumatic Brain Injury.

Traumatic brain injury (TBI) is becoming an increasing public health issue. With an annually estimated 1.7 million TBIs in the United States (U.S) and nearly 70 million worldwide, the injury, isolated or compounded with others, is a major cause of short- and long-term disability and mortality. This, along with no specific treatment, has made exploration of TBI therapies a priority of the health system. Age and sex differences create a spectrum of vulnerability to TBI, with highest prevalence among younger and older populations. Increased public interest in the long-term effects and prevention of TBI have recently reached peaks, with media attention bringing heightened awareness to sport and war related head injuries. Along with short-term issues, TBI can increase the likelihood for development of long-term neurodegenerative disorders. A growing body of literature supports the use of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon (Gcg) receptor (R) agonists, along with unimolecular combinations of these therapies, for their potent neurotrophic/neuroprotective activities across a variety of cellular and animal models of chronic neurodegenerative diseases (Alzheimer's and Parkinson's diseases) and acute cerebrovascular disorders (stroke). Mild or moderate TBI shares many of the hallmarks of these conditions; recent work provides evidence that use of these compounds is an effective strategy for its treatment. Safety and efficacy of many incretin-based therapies (GLP-1 and GIP) have been demonstrated in humans for the treatment of type 2 diabetes mellitus (T2DM), making these compounds ideal for rapid evaluation in clinical trials of mild and moderate TBI.

Role of Nogo Receptor-1 for Recovery of Balance, Cognition, and Emotion after Mild Traumatic Brain Injury in Mice.

Mild traumatic brain injury (mTBI) constitutes 75 ∼ 90% of all TBI cases and causes various physical, cognitive, emotional, and other psychological symptoms. Nogo receptor 1 (NgR1) is a regulator of structural brain plasticity during development and in adulthood. Here, we used mice that, in the absence of doxycycline, overexpress NgR1 in forebrain neurons (MemoFlex) to determine the role of NgR1 in recovery from mTBI with respect to balance, cognition, memory, and emotion. We compared wild-type (WT), MemoFlex, and MemoFlex + doxycycline mice to the same three groups subjected to mTBI. mTBI was induced by a controlled 30-g weight drop. We found that inability to downregulate NgR1 significantly impairs recovery from mTBI-induced impairments. When the NgR1 transgene was turned off, recovery was similar to that of WT mice. The results suggest that the ability to regulate NgR1 signaling is needed for optimal recovery of motor coordination and balance, spatial memory, cognition, and emotional functions after mTBI.

A Nogo-Like Signaling Perspective from Birth to Adulthood and in Old Age: Brain Expression Patterns of Ligands, Receptors and Modulators.

An appropriate strength of Nogo-like signaling is important to maintain synaptic homeostasis in the CNS. Disturbances have been associated with schizophrenia, MS and other diseases. Blocking Nogo-like signaling may improve recovery after spinal cord injury, stroke and traumatic brain injury. To understand the interacting roles of an increasing number of ligands, receptors and modulators engaged in Nogo-like signaling, the transcriptional activity of these genes in the same brain areas from birth to old age in the normal brain is needed. Thus, we have quantitatively mapped the innate expression of 11 important genes engaged in Nogo-like signaling. Using in situ hybridization, we located and measured the amount of mRNA encoding Nogo-A, OMgp, NgR1, NgR2, NgR3, Lingo-1, Troy, Olfactomedin, LgI1, ADAM22, and MAG, in 18 different brain areas at six different ages (P0, 1, 2, 4, 14, and 104 weeks). We show gene- and area-specific activities and how the genes undergo dynamic regulation during postnatal development and become stable during adulthood. Hippocampal areas underwent the largest changes over time. We only found differences between individual cortical areas in Troy and MAG. Subcortical areas presented the largest inter-regional differences; lateral and basolateral amygdala had markedly higher expression than other subcortical areas. The widespread differences and unique expression patterns of the different genes involved in Nogo-like signaling suggest that the functional complexes could look vastly different in different areas.

Spatiotemporal and Long Lasting Modulation of 11 Key Nogo Signaling Genes in Response to Strong Neuroexcitation.

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.

NgR1: A Tunable Sensor Regulating Memory Formation, Synaptic, and Dendritic Plasticity.

Nogo receptor 1 (NgR1) is expressed in forebrain neurons and mediates nerve growth inhibition in response to Nogo and other ligands. Neuronal activity downregulates NgR1 and the inability to downregulate NgR1 impairs long-term memory. We investigated behavior in a serial behavioral paradigm in mice that overexpress or lack NgR1, finding impaired locomotor behavior and recognition memory in mice lacking NgR1 and impaired sequential spatial learning in NgR1 overexpressing mice. We also investigated a role for NgR1 in drug-mediated sensitization and found that repeated cocaine exposure caused stronger locomotor responses but limited development of stereotypies in NgR1 overexpressing mice. This suggests that NgR1-regulated synaptic plasticity is needed to develop stereotypies. Ex vivo magnetic resonance imaging and diffusion tensor imaging analyses of NgR1 overexpressing brains did not reveal any major alterations. NgR1 overexpression resulted in significantly reduced density of mature spines and dendritic complexity. NgR1 overexpression also altered cocaine-induced effects on spine plasticity. Our results show that NgR1 is a negative regulator of both structural synaptic plasticity and dendritic complexity in a brain region-specific manner, and highlight anterior cingulate cortex as a key area for memory-related plasticity.

Orchestrated regulation of Nogo receptors, LOTUS, AMPA receptors and BDNF in an ECT model suggests opening and closure of a window of synaptic plasticity.

Electroconvulsive therapy (ECT) is an efficient and relatively fast acting treatment for depression. However, one severe side effect of the treatment is retrograde amnesia, which in certain cases can be long-term. The mechanisms behind the antidepressant effect and the amnesia are not well understood. We hypothesized that ECT causes transient downregulation of key molecules needed to stabilize synaptic structure and to prevent Ca2+ influx, and a simultaneous increase in neurotrophic factors, thus providing a short time window of increased structural synaptic plasticity. Here we followed regulation of NgR1, NgR3, LOTUS, BDNF, and AMPA subunits GluR1 and GluR2 flip and flop mRNA levels in hippocampus at 2, 4, 12, 24, and 72 hours after a single episode of induced electroconvulsive seizures (ECS) in rats. NgR1 and LOTUS mRNA levels were transiently downregulated in the dentate gyrus 2, 4, 12 and 4, 12, 24 h after ECS treatment, respectively. GluR2 flip, flop and GluR1 flop were downregulated at 4 h. GluR2 flip remained downregulated at 12 h. In contrast, BDNF, NgR3 and GluR1 flip mRNA levels were upregulated. Thus, ECS treatment induces a transient regulation of factors important for neuronal plasticity. Our data provide correlations between ECS treatment and molecular events compatible with the hypothesis that both effects and side effects of ECT may be caused by structural synaptic rearrangements.