Regulation Of Neuroplasticity Research Articles

Impact of miR-29c-3p in the Nucleus Accumbens on Methamphetamine-Induced Behavioral Sensitization and Neuroplasticity-Related Proteins.

Methamphetamine (METH) abuse inflicts both physical and psychological harm. While our previous research has established the regulatory role of miR-29c-3p in behavior sensitization, the underlying mechanisms and target genes remain incompletely understood. In this study, we employed the isobaric tags for relative and absolute quantitation (iTRAQ) technique in conjunction with Ingenuity pathway analysis (IPA) to probe the putative molecular mechanisms of METH sensitization through miR-29c-3p inhibition. Through a microinjection of AAV-anti-miR-29c-3p into the nucleus accumbens (NAc) of mice, we observed the attenuation of METH-induced locomotor effects. Subsequent iTRAQ analysis identified 70 differentially expressed proteins (DEPs), with 22 up-regulated potential target proteins identified through miR-29c-3p target gene prediction and IPA analysis. Our focus extended to the number of neuronal branches, the excitatory synapse count, and locomotion-related pathways. Notably, GPR37, NPC1, and IREB2 emerged as potential target molecules for miR-29c-3p regulation, suggesting their involvement in the modulation of METH sensitization. Quantitative PCR confirmed the METH-induced aberrant expression of Gpr37, Npc1, and Ireb2 in the NAc of mice. Specifically, the over-expression of miR-29c-3p led to a significant reduction in the mRNA level of Gpr37, while the inhibition of miR-29c-3p resulted in a significant increase in the mRNA level of Gpr37, consistent with the regulatory principle of miRNAs modulating target gene expression. This suggests that miR-29c-3p potentially influences METH sensitization through its regulation of neuroplasticity. Our research indicates that miR-29c-3p plays a crucial role in regulating METH-induced sensitization, and it identified the potential molecular of miR-29c-3p in regulating METH-induced sensitization.

General anesthetic agents induce neurotoxicity through oligodendrocytes in the developing brain.

General anesthetic agents can impact brain function through interactions with neurons and their effects on glial cells. Oligodendrocytes perform essential roles in the central nervous system, including myelin sheath formation, axonal metabolism, and neuroplasticity regulation. They are particularly vulnerable to the effects of general anesthetic agents resulting in impaired proliferation, differentiation, and apoptosis. Neurologists are increasingly interested in the effects of general anesthetic agents on oligodendrocytes. These agents not only act on the surface receptors of oligodendrocytes to elicit neuroinflammation through modulation of signaling pathways, but also disrupt metabolic processes and alter the expression of genes involved in oligodendrocyte development and function. In this review, we summarize the effects of general anesthetic agents on oligodendrocytes. We anticipate that future research will continue to explore these effects and develop strategies to decrease the incidence of adverse reactions associated with the use of general anesthetic agents.

Antioxidant and Anti-Inflammatory Effects of Garlic in Ischemic Stroke: Proposal of a New Mechanism of Protection through Regulation of Neuroplasticity.

Stroke represents one of the main causes of death and disability in the world; despite this, pharmacological therapies against stroke remain insufficient. Ischemic stroke is the leading etiology of stroke. Different molecular mechanisms, such as excitotoxicity, oxidative stress, and inflammation, participate in cell death and tissue damage. At a preclinical level, different garlic compounds have been evaluated against these mechanisms. Additionally, there is evidence supporting the participation of garlic compounds in other mechanisms that contribute to brain tissue recovery, such as neuroplasticity. After ischemia, neuroplasticity is activated to recover cognitive and motor function. Some garlic-derived compounds and preparations have shown the ability to promote neuroplasticity under physiological conditions and, more importantly, in cerebral damage models. This work describes damage/repair mechanisms and the importance of garlic as a source of antioxidant and anti-inflammatory agents against damage. Moreover, we examine the less-explored neurotrophic properties of garlic, culminating in proposals and observations based on our review of the available information. The aim of the present study is to propose that garlic compounds and preparations could contribute to the treatment of ischemic stroke through their neurotrophic effects.

Heterogeneity and synaptic plasticity analysis of hippocampus based on db-/- mice induced diabetic encephalopathy

Chronic hyperglycemia can cause changes in synaptic plasticity of hippocampal cells, which has accelerated the pathological process of cognitive dysfunction. However, the heterogeneity of the hippocampal cell populations under long term high glucose statement remains largely unknown. To mimic chronic hyperglycemia induced cognitive function deficit in vivo, db-/- diabetic mice was selected and Novel Object Recognition(NOR) behavior tests were performed. Based on diabetic induced cognitive impairment(CI) animal model, single-cell RNA sequencing was performed in the hippocampus of CI group (21,379 cells) or control group (20,045 cells), and single cell RNA sequencing was applied, and then the single cell atlas of gene expression was profiled. The comprehensive analysis explicated 18 nerve cell clusters, including 9 distinct sub-clusters, More in-depth analysis of oligodendrocyte precursor cells(OPCs) showed five distinct OPCs sub-clusters including expressing marker gene Lingo2-OPCs, Kcnc1-OPCs, Sst-OPCs, Slc6a1-OPCs and Lhfpl3-OPCs, which seems to be able to proliferate, migrate, and finally differentiate into mature oligodendrocytes and produce myelin. To be noted, differentially expressed genes(DEGs) of the Sst-OPCs sub-cluster indicated that the genes participating in neuroactive ligand-receptor interaction, nervous system development and inflammatory process were up-regulated in diabetic induced cognitive impairment(DCI) groups compared to normal control groups. Integrating the data of neuroplasticity regulation, the 20th top-enriched biological process was associated with neuroplasticity regulation in CI groups compared to control groups. Among these neuroplasticity-related genes, the intersectional gene Sstr2 may play an important role in neuroplasticity regulation. Focused on neuroplasticity regulation and its related specific genes may provide potential new clues for the treatment of diabetes mellitus complicated with cognitive impairment. In summary, we showed the comprehensively transcriptional landscape of hippocampal cells in the db-/- diabetic mice with cognitive dysfunction, distinctive cell sub-clusters and the gene expression characteristics were identified, and also their special functions were proposed, which may give new clues and potential targets for diagnosis and treatment of diabetic encephalopathy.

Changes in neurotrophic signaling pathways in brain areas of the chronic mild stress rat model of depression as a signature of ketamine fast antidepressant response/non-response

Major Depressive Disorder (MDD) is a highly debilitating disorder characterized by a persistent feeling of sadness and anhedonia. Traditional antidepressants have a delayed onset of action and lack of efficacy in up to one third of patients, leading to treatment resistant depression (TRD). Recent years have witnessed a revolutionary treatment of TRD with the introduction of the fast-acting antidepressant ketamine. However, ketamine's mechanisms of action are still poorly understood. Here, we used the chronic mild stress animal model of depression on male rats to investigate the involvement of neurotrophic signaling pathways in stress vulnerability/resilience and fast antidepressant response/non-response to acute subanesthetic ketamine. We performed our analysis on both the hippocampus and the prefrontal cortex, two brain areas implicated in stress-related disorders, considering different subcellular fractions. We measured the activation by phosphorylation of protein kinase B (AKT), extracellular signal-regulated kinases (ERKs), glycogen synthase kinase-3 beta (GSK3 β), mammalian target of rapamycin (mTOR), and eukaryotic elongation factor 2 (eEF2), key effectors in the regulation of neuroplasticity and glutamatergic transmission which were previously associated to ketamine's fast antidepressant effect. We showed here for the first time that both stress and ketamine induced brain area and subcellular fraction specific changes in these pathways. Our study represents the first attempt to identify molecular mechanisms underlying the response/non-response to ketamine in an animal model of depression. This approach could give a crucial contribution to the study of etiopathogenetic mechanisms as well as to the identification of novel targets for the development of innovative therapeutic strategies.

Epigenetic embedding of childhood adversity: mitochondrial metabolism and neurobiology of stress-related CNS diseases.

This invited article ad memoriam of Bruce McEwen discusses emerging epigenetic mechanisms underlying the long and winding road from adverse childhood experiences to adult physiology and brain functions. The conceptual framework that we pursue suggest multidimensional biological pathways for the rapid regulation of neuroplasticity that utilize rapid non-genomic mechanisms of epigenetic programming of gene expression and modulation of metabolic function via mitochondrial metabolism. The current article also highlights how applying computational tools can foster the translation of basic neuroscience discoveries for the development of novel treatment models for mental illnesses, such as depression to slow the clinical manifestation of Alzheimer's disease. Citing an expression that many of us heard from Bruce, while "It is not possible to roll back the clock," deeper understanding of the biological pathways and mechanisms through which stress produces a lifelong vulnerability to altered mitochondrial metabolism can provide a path for compensatory neuroplasticity. The newest findings emerging from this mechanistic framework are among the latest topics we had the good fortune to discuss with Bruce the day before his sudden illness when walking to a restaurant in a surprisingly warm evening that preluded the snowstorm on December 18th, 2019. With this article, we wish to celebrate Bruce's untouched love for Neuroscience.

Irisin at the Croasroad of Autophagy and BNDF Signaling for Neuroplasticity Regulation

Irisin at the Croasroad of Autophagy and BNDF Signaling for Neuroplasticity Regulation

Possible Effects of Acupuncture in Poststroke Aphasia.

Neural plasticity promotes the reorganization of language networks and is an essential recovery mechanism for poststroke aphasia (PSA). Neuroplasticity may be a pivotal bridge to elucidate the potential recovery mechanisms of acupuncture for aphasia. Therefore, understanding the neuroplasticity mechanism of acupuncture in PSA is crucial. However, the underlying therapeutic mechanism of neuroplasticity in PSA after acupuncture needs to be explored. Excitotoxicity after brain injury affects the activity of neurotransmitters and disrupts the transmission of normal neuron information. Thus, a helpful strategy of acupuncture might be to improve PSA by affecting the availability of these neurotransmitters and glutamate receptors at synapses. In addition, the regulation of neuroplasticity by acupuncture may also be related to the regulation of astrocytes. Considering the guiding significance of acupuncture for clinical treatment, it is necessary to carry out further study about the influence of acupuncture on the recovery of aphasia after stroke. This study summarizes the current research on the neural mechanism of acupuncture in treating PSA. It seeks to elucidate the potential effect of acupuncture on the recovery of PSA from the perspective of synaptic plasticity and integrity of gray and white matter.

Irisin at the Crossroad of Autophagy and BNDF Signaling for Neuroplasticity Regulation

Neuroplasticity is an integral feature of both the developing brain and the brain maintaining functional homeostasis and implementing adaptive changes at normal conditions and upon compensation for pathology. Support of neuroplasticity mechanisms of is one of the targets for therapeutic intervention in the treatment of neurodegenerative and stress-associated diseases. Progress in understanding the mechanisms of interaction between the muscular system and the brain points to the role of the myokine irisin in mediating the procognitive and antidepressant activity of physical exercises. Irisin being released upon myocytes activation in the periphery can cross the blood-brain barrier and is thought to stimulate cellular autophagy. Autophagy-mediated activation of protein and macromolecule recycling promotes adaptive restructuring of synaptic contacts, and the release of proteases, including matrix metalloproteinase 9, which are determining the reformatting of the extracellular matrix, maturation of brain-derived neurotrophic factor (BDNF), and, therefore, the positive regulation of BDNF signaling. Recent findings allow one to consider factors stimulating autophagy as prerequisites for successful treatment of neurological and psychiatric disorders, as well as age-related dementia. Therefore, irisin, as a physiological regulator of autophagy, appears as a prototype molecule for the creation of new therapeutic agents for the correction of neurodegenerative conditions and stress-associated brain disorders.

Involvement of miR-135a-5p Downregulation in Acute and Chronic Stress Response in the Prefrontal Cortex of Rats.

Stress is a key risk factor in the onset of neuropsychiatric disorders. The study of the mechanisms underlying stress response is important to understand the etiopathogenetic mechanisms and identify new putative therapeutic targets. In this context, microRNAs (miRNAs) have emerged as key regulators of the complex patterns of gene/protein expression changes in the brain, where they have a crucial role in the regulation of neuroplasticity, neurogenesis, and neuronal differentiation. Among them, miR-135a-5p has been associated with stress response, synaptic plasticity, and the antidepressant effect in different brain areas. Here, we used acute unavoidable foot-shock stress (FS) and chronic mild stress (CMS) on male rats to study whether miR-135a-5p was involved in stress-induced changes in the prefrontal cortex (PFC). Both acute and chronic stress decreased miR-135a-5p levels in the PFC, although after CMS the reduction was induced only in animals vulnerable to CMS, according to a sucrose preference test. MiR-135a-5p downregulation in the primary neurons reduced dendritic spine density, while its overexpression exerted the opposite effect. Two bioinformatically predicted target genes, Kif5c and Cplx1/2, were increased in FS rats 24 h after stress. Altogether, we found that miR-135a-5p might play a role in stress response in PFC involving synaptic mechanisms.

The impact of acupuncture on neuroplasticity after ischemic stroke: a literature review and perspectives.

Ischemic stroke is common in the elderly, and is one of the main causes of long-term disability worldwide. After ischemic stroke, spontaneous recovery and functional reconstruction take place. These processes are possible thanks to neuroplasticity, which involves neurogenesis, synaptogenesis, and angiogenesis. However, the repair of ischemic damage is not complete, and neurological deficits develop eventually. The WHO recommends acupuncture as an alternative and complementary method for the treatment of stroke. Moreover, clinical and experimental evidence has documented the potential of acupuncture to ameliorate ischemic stroke-induced neurological deficits, particularly sequelae such as dyskinesia, spasticity, cognitive impairment, and dysphagia. These effects are related to the ability of acupuncture to promote spontaneous neuroplasticity after ischemic stroke. Specifically, acupuncture can stimulate neurogenesis, activate axonal regeneration and sprouting, and improve the structure and function of synapses. These processes modify the neural network and function of the damaged brain area, producing the improvement of various skills and adaptability. Astrocytes and microglia may be involved in the regulation of neuroplasticity by acupuncture, such as by the production and release of a variety of neurotrophic factors, including brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Moreover, the evidence presented indicates that acupuncture promotes neuroplasticity by modulating the functional reconstruction of the whole brain after ischemia. Therefore, the promotion of neuroplasticity is expected to become a new target for acupuncture in the treatment of neurological deficits after ischemic stroke, and research into the mechanisms responsible for these actions will be of significant clinical value.

A Study of Anxiety-Related Behavior under Conditions of Oxidative Stress Caused by Hydrogen Peroxide

Any stressful situation in the body can become the cause of intense formation of free radicals. Free radicals are molecules or individual atoms that have unpaired valence electrons in their outer orbit, which are characterized by high reactivity and damage cell proteins, nucleic acids, membrane lipids, and can lead to the development of many types of pathological processes. All possible triggering mechanisms of this process have not been fully explored. It is known that under certain conditions, in response to stressogenic factors, a biologically positive reaction _ adaptive stress response develops in the body which ensures the resistance of cells to stronger (lethal) doses of the stimulating agent of this reaction. The aim of the study was to explore the influence of the hormetic phenomenon on the psycho-emotional state of anxiety which arose from the dose-response of the oxidative stress caused by hydrogen peroxide in an experiment on rats. The experiment was conducted on white male lab rats. As an experimental model of oxidative stress caused by hydrogen peroxide, we used its 0.1% and 0.2% aqueous solutions and administered them orally to animals for different durations (10 and 25 days). The psycho-emotional state of anxiety was assayed by means of the elevated plus maze. The analysis of the obtained results was conducted using the student's t-criterion.The analysis of our results allows us to note that in the experiment under the conditions of chronic action of a low dose of stressogenic factor (hydrogen peroxide H2O2  0.1%), an improvement in the psycho-emotional state of anxiety and its stable maintenance within the maximum limits of the norm can be observed, which must be caused by the influence of the hormetic response. A further increase (doubling of the "dose") of the stressogenic factor (chronic administration of 0.2% aqueous solution of hydrogen peroxide) resulted in suppression of the hormesis. It was found that in this experimental model, oxidative stress can play a positive role in the regulation of neuroplasticity and psycho-physiological adaptation.

Hair brain-derived neurotrophic factor (BDNF) as predictor of developing psychopathological symptoms in childhood

BackgroundDysregulation in the expression of neurotrophins is implicated in the pathophysiology of several mental disorders. Peripheral brain-derived neurotrophic factor (BDNF) can be measured in hair and might represent a marker of adequate neuroplasticity regulation. In early developmental periods, neuroplasticity regulation might be particularly important, but BDNF markers have not yet been analyzed in this regard. We used the hair-BDNF concentration (HBC) to investigate the prediction of emerging symptoms of anxiety/depressive and attention-deficit hyperactivity disorder (ADHD) in the developmentally crucial period from preschool to school age. Methods117 children (58 girls, 59 boys) participated in a longitudinal study at the ages of 4–5 (T1) and 8 (T2) years. At T1, HBC was measured in a 3 cm hair segment. At T1 and T2, symptom domains were assessed using a multi-method (clinical interview, questionnaire) and multi-informant approach. ResultsT1 HBC was significantly negatively associated with T1 anxiety/depressive symptoms (r = −0.27) and predicted T2 anxiety disorder symptoms (r = −0.34) after controlling for the T1 symptoms. T1 HBC also predicted T2 depressive disorder symptoms (r = −0.18) but was not associated with ADHD symptom development. LimitationsBDNF hair analysis is a new method with a not yet large number of studies on methodological issues. Our study adds evidence to the validity of the method. ConclusionsPrediction of anxiety/depressive symptom development by HBC was shown. As this study was the first to use HBC in this context, cross-validation is necessary and worthwhile. HBC might prove to constitute a useful, non-invasive early marker of risk for anxiety/depressive disorders in childhood.

Serotonin Receptor 5-HT2A Regulates TrkB Receptor Function in Heteroreceptor Complexes.

Serotonin receptor 5-HT2A and tropomyosin receptor kinase B (TrkB) strongly contribute to neuroplasticity regulation and are implicated in numerous neuronal disorders. Here, we demonstrate a physical interaction between 5-HT2A and TrkB in vitro and in vivo using co-immunoprecipitation and biophysical and biochemical approaches. Heterodimerization decreased TrkB autophosphorylation, preventing its activation with agonist 7,8-DHF, even with low 5-HT2A receptor expression. A blockade of 5-HT2A receptor with the preferential antagonist ketanserin prevented the receptor-mediated downregulation of TrkB phosphorylation without restoring the TrkB response to its agonist 7,8-DHF in vitro. In adult mice, intraperitoneal ketanserin injection increased basal TrkB phosphorylation in the frontal cortex and hippocampus, which is in accordance with our findings demonstrating the prevalence of 5-HT2A–TrkB heteroreceptor complexes in these brain regions. An expression analysis revealed strong developmental regulation of 5-HT2A and TrkB expressions in the cortex, hippocampus, and especially the striatum, demonstrating that the balance between TrkB and 5-HT2A may shift in certain brain regions during postnatal development. Our data reveal the functional role of 5-HT2A–TrkB receptor heterodimerization and suggest that the regulated expression of 5-HT2A and TrkB is a molecular mechanism for the brain-region-specific modulation of TrkB functions during development and under pathophysiological conditions.

Omeprazole treatment manifests anxiolytic effects in a cysteamine hydrochloride induced mouse model of gastrointestinal disorder

Omeprazole, a proton pump inhibitor (PPI), has widely been used to treat various gastrointestinal (GI) disorders. Notably, many clinical symptoms of GI disorders have been known to be associated with anxiety. In recent years, an exponentially increased number of subjects with abnormal ageing, neurological deficits, and psychiatric problems simultaneously exhibit GI dysfunctions as well as anxiety. Considering the fact, drugs that are used to treat GI disorders can be speculated to mitigate anxiety-related symptoms, and vice versa. Although, omeprazole treatment has been reported to result in development of anxiety and neurocognitive decline, ample reports suggest that omeprazole treatment is beneficial for the positive regulation of neuroplasticity. While underlying mechanisms of omeprazole-mediated neurological alterations remain obscure, the available scientific data on the omeprazole induced adverse effects in the brain appear to be inadequate, uncertain, and controversial. Hence, this study revisited the effect of omeprazole treatment on the degree of anxiety-like behaviours in a cysteamine hydrochloride (HCl) induced mouse model of GI disorder using open field test (OFT), light-dark box (LDB) test and elevated plus maze (EPM). Results revealed that omeprazole treatment mitigates anxiety-related behaviours in the cysteamine HCl induced animal model of GI disorder. Thus, this study assuredly supports and validates the anxiolytic properties of omeprazole. However, the adverse effects associated with inappropriate intake of omeprazole may not completely be excluded. Therefore, this study advocates the future direction in determining the long-term effects of omeprazole on the brain functions.

0655 The Impact of Slow-Wave Sleep Disruption on Response Inhibition in Individuals with Depression

Abstract Introduction Individuals with Major Depressive Disorder (MDD) exhibit reductions in slow-wave sleep (SWS) and impairments in neuroplasticity. For example, decreased executive functioning, including poorer response inhibition compared to healthy controls, has been reported. SWS has been implicated in the homeostatic regulation of neuroplasticity, however it is unclear if the cognitive deficits seen in MDD are directly associated with SWS. In this study, we aimed to examine if disrupting SWS, thereby altering neuroplasticity, could improve response inhibition in patients with MDD. Methods Participants in this study (n=29) included 19 individuals with depression and 10 healthy controls. Data were collected after two overnight sleep studies separated by one week. During one of the two nights, participants’ slow-wave sleep was disrupted via auditory tones. In the morning following each night, participants completed a neurocognitive task battery including an auditory Go/No-Go task. Accuracy scores were calculated as the percentage of trials on which the participant responded correctly to the “Go” or “No-Go” stimulus. Repeated measures ANOVA and paired t-tests were then performed to examine changes from baseline to SWD, assessing the role of SWD on response inhibition. Results Following SWD, depressed participants’ performance on the Go/No-Go task was significantly more accurate (t=-2.067, p=.027) than following baseline sleep, while healthy controls showed no significant change between nights (t=-.231, p=.411). The interaction between group (MDD vs. healthy control) and condition (baseline vs. SWD) did not reach statistical significance (p=.175). Conclusion In a sample of individuals with depression, accuracy on the Go/No-Go task improved significantly after undergoing SWD compared to following baseline sleep, indicating improved response inhibition. However, healthy controls did not exhibit this same improvement in accuracy. These findings highlight a possible disparity in the role that SWS plays in the regulation of neuroplasticity in those with depression and those without. Support (If Any) Goldschmied: K23MH118580 (NIMH)

0263 Slow-wave Disruption Improves Irritability in Males with Major Depression: Potential Implications for Understanding the Impact of Sex Differences on Sleep and Neuroplasticity

Abstract Introduction Irritability has been proposed to be a core symptom of male-specific major depressive disorder (MDD), with a greater propensity to experiencing anger attacks and overreacting to minor annoyances compared to females with MDD. Males with MDD have also been shown to exhibit a pattern of reduced slow-wave sleep (SWS) that is not characteristic of females. Because SWS has been implicated in the homeostatic regulation of neuroplasticity, it is possible that this mood dysfunction in males is a result of SWS alterations via impairments in neuroplasticity. Therefore, in this study we aimed to manipulate SWS and examine its impact on mood. Methods 19 individuals (11 F) with MDD were recruited for an ongoing clinical trial. Participants spent two nights in the sleep laboratory one week apart: a baseline (BL) night, and a night of slow-wave sleep disruption (SWD) utilizing auditory stimulation. Irritability was assessed in the morning following each overnight visit using the 5-item Brief Irritability Test (BITe). Repeated measures ANOVA was used to evaluate the change in irritability following SWD with condition (BL, SWD) as the within-subject factor and sex (M, F) as the between-subjects factor. Results Results revealed a significant Condition x Sex interaction (F(1,17) =10.1, p=.006) for change in irritability scores, with post-hoc t-tests indicating that males with MDD showed a significant decrease in irritability following SWD, t(7)=2.22, p<.05 while women showed a significant increase in irritability, t(10)=-2.34, p<.05. Changes in irritability were not found to be associated with changes in N3. Conclusion These data demonstrate that experimentally reducing SWS decreases irritability, a core symptom of mood dysfunction, in males with MDD. As SWS has been theorized to facilitate synaptic downscaling, these results may indicate that maintaining waking levels of synaptic strength in males improves depressive symptomatology and may point to the importance of sex differences in sleep and psychopathology. Moreover, these results suggest that the modulation of neuroplasticity via sleep manipulation may be a potential therapeutic target. Support (If Any) K23MH118580 (JG)

Brain-specific deletion of GIT1 impairs cognition and alters phosphorylation of synaptic protein networks implicated in schizophrenia susceptibility.

Despite tremendous effort, the molecular and cellular basis of cognitive deficits in schizophrenia remain poorly understood. Recent progress in elucidating the genetic architecture of schizophrenia has highlighted the association of multiple loci and rare variants that may impact susceptibility. One key example, given their potential etiopathogenic and therapeutic relevance, is a set of genes that encode proteins that regulate excitatory glutamatergic synapses in brain. A critical next step is to delineate specifically how such genetic variation impacts synaptic plasticity and to determine if and how the encoded proteins interact biochemically with one another to control cognitive function in a convergent manner. Towards this goal, here we study the roles of GPCR-kinase interacting protein 1 (GIT1), a synaptic scaffolding and signaling protein with damaging coding variants found in schizophrenia patients, as well as copy number variants found in patients with neurodevelopmental disorders. We generated conditional neural-selective GIT1 knockout mice and found that these mice have deficits in fear conditioning memory recall and spatial memory, as well as reduced cortical neuron dendritic spine density. Using global quantitative phospho-proteomics, we revealed that GIT1 deletion in brain perturbs specific networks of GIT1-interacting synaptic proteins. Importantly, several schizophrenia and neurodevelopmental disorder risk genes are present within these networks. We propose that GIT1 regulates the phosphorylation of a network of synaptic proteins and other critical regulators of neuroplasticity, and that perturbation of these networks may contribute specifically to cognitive deficits observed in schizophrenia and neurodevelopmental disorders.

Building Resilience with Aerobic Exercise: Role of FKBP5.

Both preclinical and clinical studies have pointed that aerobic exercise, at moderate doses, is beneficial at all stages of life by promoting a range of physiological and neuroplastic adaptations that reduce the anxiety response. Previous research about this topic has repeatedly described how the regular practice of aerobic exercise induces a positive regulation of neuroplasticity and neurogenesis-related genes, as well as a better control of the HPA axis function. However, limited progress has been carried out in the integration of neuroendocrine and neuroplastic changes, as well as in introducing new factors to understand how aerobic exercise can promote resilience to future stressful conditions. Resilience is defined as the ability to adapt to stress while maintaining healthy mental and physical performance. Consistent findings point to an important role of FKBP5, the gene expressing FK506-binding protein 51 (FKBP51), as a strong inhibitor of the glucocorticoid receptor (GR), and thus, an important regulator of the stress response. We propose that aerobic exercise could contribute to modulate FKBP5 activity acting as a potential therapeutic approach for mood disorders. In this sense, aerobic exercise is well known for increasing the growth factor BDNF, which by downstream pathways could affect the FKBP5 activity. Therefore, our manuscript has the aim of analyzing how FKBP5 could constitute a promising target of aerobic exercise promoting resilient-related phenotypes.

Effect of Tetramethylpyrazine on Neuroplasticity after Transient Focal Cerebral Ischemia Reperfusion in Rats.

Tetramethylpyrazine (TMP) has been widely used in ischemic stroke in China. The regulation of neuroplasticity may underlie the recovery of some neurological functions in ischemic stroke. Middle cerebral artery occlusion (MCAO) model was established in this study. Rats were divided into three groups: sham group, model group, and TMP group. The neurological function was evaluated using modified neurological severity score (mNSS). Following the neurological function test, expression of synaptophysin (SYP) and growth-associated protein 43 (GAP-43) were analyzed through immunohistochemistry at 3 d, 7 d, 14 d, and 28 d after MCAO. Finally, the synaptic structural plasticity was investigated using transmission electron microscopy (TEM). The TMP group showed better neurological function comparing to the model group. SYP levels increased gradually in ischemic penumbra (IP) in the model group and could be enhanced by TMP treatment at 7 d, 14 d, and 28 d, whereas GAP-43 levels increased from 3 d to 7 d and thereafter decreased gradually from 14 d to 28 d in the model group, which showed no significant improvement in the TMP group. The results of TEM showed a flatter synaptic interface, a thinner postsynaptic density (PSD), and a wider synaptic cleft in the model group, and the first two alterations could be ameliorated by TMP. Then, a Pearson's correlation test revealed mNSS markedly correlated with SYP and synaptic ultrastructures. Taken together, TMP is capable of promoting functional outcome after ischemic stroke, and the mechanisms may be partially associated with regulation of neuroplasticity.