Regulation Of Synaptic Plasticity Research Articles

Systems pharmacology approach uncovers the therapeutic mechanism of medicarpin against scopolamine-induced memory loss

BackgroundMedicarpin is a natural pterocarpan-type phytoalexin widely distributed in many traditional Chinese medicines, such as Astragali Radix. A previous study showed that Astragali Radix demonstrated promising protective effects in neurons. However, there is no reported study on the neuroprotective function and the underlying mechanism of Medicarpin. PurposeThis study aimed to demonstrate the neuroprotective effect of Medicarpin on Alzheimer's disease (AD) and explore the therapeutic mechanisms. MethodFirst, we carried out animal behavioral tests and biochemical analysis to assess the anti-AD potential of Medicarpin for ameliorating spatial learning and memory and modulating cholinergic metabolism in scopolamine-induced amnesic mice. Subsequently, network proximity prediction was used to measure the network distance between the Medicarpin target network and AD-related endophenotype module. We identified Medicarpin-regulated AD pathological processes and highlighted the key disease targets via network analysis. Finally, experimental approaches including Nissl staining and Western blotting were conducted to validate our network-based findings. ResultIn this study, we first observed that Medicarpin can ameliorate cognitive and memory dysfunction and significantly modulate cholinergic metabolism in scopolamine-induced amnesic mice. We then proposed an endophenotype network-based framework to comprehensively explore the AD therapeutic mechanisms of Medicarpin by integrating 25 AD-related endophenotype modules, gold-standard AD seed genes, an experimentally validated drug-target network of Medicarpin, and a global human protein-protein interactome. In silico prediction revealed that the effect of Medicarpin is highly relevant to neuronal apoptosis and synaptic plasticity, which was validated by experimental assays. Network analysis and Western blotting further identified two key targets, GSK-3β and MAPK14 (p38), in the AD-related protein regulatory network, which play key roles in the regulation of neuronal apoptosis and synaptic plasticity by Medicarpin. ConclusionsThis study presented a powerful endophenotype network-based strategy to explore the mechanisms of action (MOAs) of new AD therapeutics, and first identified Medicarpin as a potential anti-AD candidate by targeting multiple pathways.

Sex-Specific Linear Polyubiquitination Is a Critical Regulator of Contextual Fear Memory Formation.

Strong evidence supports that protein ubiquitination is a critical regulator of fear memory formation. However, as this work has focused on protein degradation, it is currently unknown whether polyubiquitin modifications that are independent of the proteasome are involved in learning-dependent synaptic plasticity. Here, we present the first evidence that atypical linear (M1) polyubiquitination, the only ubiquitin chain that does not occur at a lysine site and is largely independent of the proteasome, is critically involved in contextual fear memory formation in the amygdala in a sex-specific manner. Using immunoblot and unbiased proteomic analyses, we found that male (49) and female (14) rats both had increased levels of linear polyubiquitinated substrates following fear conditioning, though none of these protein targets overlapped between sexes. In males, target protein functions involved cell junction and axonal guidance signaling, while in females the primary target was Adiponectin A, a critical regulator of neuroinflammation, synaptic plasticity, and memory, suggesting sex-dependent functional roles for linear polyubiquitination during fear memory formation. Consistent with these increases, in vivo siRNA-mediated knockdown of Rnf31, an essential component of the linear polyubiquitin E3 complex LUBAC, in the amygdala impaired contextual fear memory in both sexes without affecting memory retrieval. Collectively, these results provide the first evidence that proteasome-independent linear polyubiquitination is a critical regulator of fear memory formation, expanding the potential roles of ubiquitin-signaling in learning-dependent synaptic plasticity. Importantly, our data identify a novel sex difference in the functional role of, but not a requirement for, linear polyubiquitination in fear memory formation.

Steroid Receptor Coactivator 3 Regulates Synaptic Plasticity and Hippocampus-dependent Memory

Steroid hormones play important roles in brain development and function. The signaling of steroid hormones depends on the interaction between steroid receptors and their coactivators. Although the function of steroid receptor coactivators has been extensively studied in other tissues, their functions in the central nervous system are less well investigated. In this study, we addressed the function of steroid receptor coactivator 3 (SRC3) – a member of the p160 SRC protein family that is expressed predominantly in the hippocampus. While hippocampal development was not altered in Src3+/− mice, hippocampus-dependent functions such as short-term memory and spatial memory were impaired. We further demonstrated that the deficient learning and memory in Src3+/− mice was strongly associated with the impairment of long-term potentiation (LTP) at Schaffer Collateral-CA1 synapses. Mechanistic studies indicated that Src3+/− mutation altered the composition of N-methyl-D-aspartate receptor subunits in the postsynaptic densities of hippocampal neurons. Finally, we showed that SRC3 regulated synaptic plasticity and learning mainly dependent on its lysine acetyltransferase activity. Taken together, these results reveal previously unknown functions of SRC3 in the hippocampus and thus may provide insight into how steroid hormones regulate brain function.

RGS14 Regulation of Post-Synaptic Signaling and Spine Plasticity in Brain

The regulator of G-protein signaling 14 (RGS14) is a multifunctional signaling protein that regulates post synaptic plasticity in neurons. RGS14 is expressed in the brain regions essential for learning, memory, emotion, and stimulus-induced behaviors, including the basal ganglia, limbic system, and cortex. Behaviorally, RGS14 regulates spatial and object memory, female-specific responses to cued fear conditioning, and environmental- and psychostimulant-induced locomotion. At the cellular level, RGS14 acts as a scaffolding protein that integrates G protein, Ras/ERK, and calcium/calmodulin signaling pathways essential for spine plasticity and cell signaling, allowing RGS14 to naturally suppress long-term potentiation (LTP) and structural plasticity in hippocampal area CA2 pyramidal cells. Recent proteomics findings indicate that RGS14 also engages the actomyosin system in the brain, perhaps to impact spine morphogenesis. Of note, RGS14 is also a nucleocytoplasmic shuttling protein, where its role in the nucleus remains uncertain. Balanced nuclear import/export and dendritic spine localization are likely essential for RGS14 neuronal functions as a regulator of synaptic plasticity. Supporting this idea, human genetic variants disrupting RGS14 localization also disrupt RGS14’s effects on plasticity. This review will focus on the known and unexplored roles of RGS14 in cell signaling, physiology, disease and behavior.

Roles of constitutive and signal-dependent protein phosphatase 2A docking motifs in burst attenuation of the cyclic AMP response element-binding protein

The cAMP response element-binding protein (CREB) is an important regulator of cell growth, metabolism, and synaptic plasticity. CREB is activated through phosphorylation of an evolutionarily conserved Ser residue (S133) within its intrinsically disordered kinase-inducible domain (KID). Phosphorylation of S133 in response to cAMP, Ca2+, and other stimuli triggers an association of the KID with the KID-interacting (KIX) domain of the CREB-binding protein (CBP), a histone acetyl transferase (HAT) that promotes transcriptional activation. Here we addressed the mechanisms of CREB attenuation following bursts in CREB phosphorylation. We show that phosphorylation of S133 is reversed by protein phosphatase 2A (PP2A), which is recruited to CREB through its B56 regulatory subunits. We found that a B56-binding site located at the carboxyl-terminal boundary of the KID (BS2) mediates high-affinity B56 binding, while a second binding site (BS1) located near the amino terminus of the KID mediates low affinity binding enhanced by phosphorylation of adjacent casein kinase (CK) phosphosites. Mutations that diminished B56 binding to BS2 elevated both basal and stimulus-induced phosphorylation of S133, increased CBP interaction with CREB, and potentiated the expression of CREB-dependent reporter genes. Cells from mice harboring a homozygous CrebE153D mutation that disrupts BS2 exhibited increased S133 phosphorylation stoichiometry and elevated transcriptional bursts to cAMP. These findings provide insights into substrate targeting by PP2A holoenzymes and establish a new mechanism of CREB attenuation that has implications for understanding CREB signaling in cell growth, metabolism, synaptic plasticity, and other physiologic contexts.

Phosphatase and Tensin Homolog Deleted on Chromosome Ten Knockdown Attenuates Cognitive Deficits by Inhibiting Neuroinflammation in a Mouse Model of Perioperative Neurocognitive Disorder

Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a crucial regulator of neuronal development, neuronal survival, axonal regeneration, and synaptic plasticity. In this study we examined the potential role of PTEN in cognitive function in a mouse model of perioperative neurocognitive disorder (PND). Adult male C57BL/6J mice received intracerebroventricular injections of small interfering RNA (siRNA) against PTEN or control siRNA 3 days prior to exploratory laparotomy (n = 8 per group). A group of healthy mice not undergoing surgery included as additional control. Barnes maze and fear conditioning tests were conducted 7 days after surgery. Mice were then sacrificed to examine the expression of PTEN, AMP-activated protein kinase (AMPK), ionized calcium binding adaptor molecule (Iba)-1, B-cell lymphoma (Bcl)-2, Bcl2-associated X protein (Bax), interleukin (IL)-1β, and tumor necrosis factor (TNF)-α in the hippocampus. The microglial activation was examined by immunohistochemistry using Iba-1 as a microglia maker. Nissl and terminal transferase deoxyuridine triphosphate nick-end labeling (TUNEL) staining were used to measure cell death and apoptosis. In comparison to the healthy controls, surgically treated mice had longer latency to identify the target box in both training and testing sessions in the Barnes maze test and shorter freezing time in the fear conditioning test. Surgically treated mice had increased expression of PTEN, AMPK, Bax, IL-1β, and TNF-α, as well as increasing number of activated microglia and apoptosis neurons in the hippocampus. PTEN knockdown significantly attenuated the behavioral deficits in Barnes maze and fear conditioning tests, as well as over-expression of PTEN, AMPK, Bax, IL-1β, and TNF-α induced by surgery. PTEN knockdown could attenuate cognitive deficits induced by trauma, likely through inhibiting the activation of microglia.

Brain 11 C-ITMM PET to longitudinally assess type 1 metabotropic glutamate receptor availability in Alzheimer's disease.

Little evidence exists on the role of type 1 metabotropic glutamate receptor (mGluR1) in the pathophysiology of Alzheimer's disease (AD), although mGluR1 may be involved in the regulation of neuronal excitability and synaptic plasticity. We have recently reported that mGluR1 availability in the early stage of AD is equivalent to that in healthy subjects. This study aimed to address whether mGluR1 availability changes with the progression of AD. Eight patients with AD (79.1 ± 4.6 years) underwent a total of two positron emission tomography (PET) examinations using the mGluR1 radioligand during the early-to-middle stages of AD. The mean interval was 2.8 years. Volumes-of-interest were placed on the frontal, parietal, and temporal cortices, hippocampus, anterior and posterior lobes, and vermis in the cerebellum. The binding potential (BPND ) was calculated to estimate mGluR1 availability, applying partial volume correction to the BPND values. No significant difference was observed in BPND values between the first and second PET examinations in the frontal cortex (p = 0.94), parietal cortex (p = 0.67), temporal cortex (p = 0.20), hippocampus (p = 0.17), anterior lobe (p = 0.73), posterior lobe (p = 0.21), and vermis (p = 0.22). This study suggests that mGluR1 availability is unchanged in the follow-up period of a few years during the early-to-middle stages of AD.

A Computational Study on Synaptic Plasticity Regulation and Information Processing in Neuron-Astrocyte Networks.

Postsynaptic ionotropic receptors critically shape synaptic currents and underpin their activity-dependent plasticity. In recent years, regulation of expression of these receptors by slow inward and outward currents mediated by gliotransmitter release from astrocytes has come under scrutiny as a potentially important mechanism for the regulation of synaptic information transfer. In this study, we consider a model of astrocyte-regulated synapses to investigate this hypothesis at the level of layered networks of interacting neurons and astrocytes. Our simulations hint that gliotransmission sustains the transfer function across layers, although it decorrelates the neuronal activity from the signal pattern. Overall, our results make clear how astrocytes could transform neuronal activity by inducing a lowfrequency modulation of postsynaptic activity.

Absolute Proteome Analysis of Hippocampus, Cortex and Cerebellum in Aged and Young Mice Reveals Changes in Energy Metabolism.

Aging is associated with a general decline of cognitive functions, and it is widely accepted that this decline results from changes in the expression of proteins involved in regulation of synaptic plasticity. However, several lines of evidence have accumulated that suggest that the impaired function of the aged brain may be related to significant alterations in the energy metabolism. In the current study, we employed the label-free “Total protein approach” (TPA) method to focus on the similarities and differences in energy metabolism proteomes of young (1-month-old) and aged (22-month-old) murine brains. We quantified over 7000 proteins in each of the following three analyzed brain structures: the hippocampus, the cerebral cortex and the cerebellum. To the best of our knowledge, this is the most extensive quantitative proteomic description of energy metabolism pathways during the physiological aging of mice. The analysis demonstrates that aging does not significantly affect the abundance of total proteins in the studied brain structures, however, the levels of proteins constituting energy metabolism pathways differ significantly between young and aged mice.

Venlafaxine and L-Thyroxine Treatment Combination: Impact on Metabolic and Synaptic Plasticity Changes in an Animal Model of Coexisting Depression and Hypothyroidism.

The clinical effectiveness of supportive therapy with thyroid hormones in drug-resistant depression is well-known; however, the mechanisms of action of these hormones in the adult brain have not been fully elucidated to date. We determined the effects of venlafaxine and/or L-thyroxine on metabolic parameters and markers involved in the regulation of synaptic plasticity and cell damage in an animal model of coexisting depression and hypothyroidism, namely, Wistar Kyoto rats treated with propylthiouracil. In this model, in relation to the depression model itself, the glycolysis process in the brain was weakened, and a reduction in pyruvate dehydrogenase in the frontal cortex was normalized only by the combined treatment with L-thyroxine and venlafaxine, whereas changes in pyruvate and lactate levels were affected by all applied therapies. None of the drugs improved the decrease in the expression of mitochondrial respiratory chain enzymes. No intensification of glucocorticoid action was shown, while an unfavorable change caused by the lack of thyroid hormones was an increase in the caspase-1 level, which was not reversed by venlafaxine alone. The results indicated that the combined administration of drugs was more effective in normalizing glycolysis and the transition to the Krebs cycle than the use of venlafaxine or L-thyroxine alone.

Distinct effect of prenatal and postnatal brain expression across 20 brain disorders and anthropometric social traits: a systematic study of spatiotemporal modularity.

Different spatiotemporal abnormalities have been implicated in different neuropsychiatric disorders and anthropometric social traits, yet an investigation in the temporal network modularity with brain tissue transcriptomics has been lacking. We developed a supervised network approach to investigate the genome-wide association study (GWAS) results in the spatial and temporal contexts and demonstrated it in 20 brain disorders and anthropometric social traits. BrainSpan transcriptome profiles were used to discover significant modules enriched with trait susceptibility genes in a developmental stage-stratified manner. We investigated whether, and in which developmental stages, GWAS-implicated genes are coordinately expressed in brain transcriptome. We identified significant network modules for each disorder and trait at different developmental stages, providing a systematic view of network modularity at specific developmental stages for a myriad of brain disorders and traits. Specifically, we observed a strong pattern of the fetal origin for most psychiatric disorders and traits [such as schizophrenia (SCZ), bipolar disorder, obsessive-compulsive disorder and neuroticism], whereas increased co-expression activities of genes were more strongly associated with neurological diseases [such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis] and anthropometric traits (such as college completion, education and subjective well-being) in postnatal brains. Further analyses revealed enriched cell types and functional features that were supported and corroborated prior knowledge in specific brain disorders, such as clathrin-mediated endocytosis in AD, myelin sheath in multiple sclerosis and regulation of synaptic plasticity in both college completion and education. Our study provides a landscape view of the spatiotemporal features in a myriad of brain-related disorders and traits.

GPER1 Modulates Synaptic Plasticity During the Development of Temporal Lobe Epilepsy in Rats.

G-protein coupled estrogen receptor 1 (GPER1) is a novel type of estrogen receptor. Several studies have shown that it has an anti-inflammatory action,which plays an important role in remyelination and cognitive ability adjustment. However, whether it is involved in the development of temporal lobe epilepsy (TLE) is still unknown. The present study established a TLE model by intraperitoneal injection of lithium chloride (3 mmol/kg) and pilocarpine (50mg/kg) in rats to study the effect of GPER1 in the synaptic plasticity during the development of temporal lobe epilepsy. A microinjection cannula was implanted into the lateral ventricle region of rats via a stereotaxic instrument. G-1 is the specific GPER1 agonist and G15 is the specific GPER1 antagonist. The G1 or G15 and Dimethyl sulfoxide were injected into the rat brains in the intervention groups and control group, respectively. After G1 intervention, the learning and memory abilities and hippocampal neuron damage in epileptic rats were significantly improved, while G15 weakened the neuroprotective effect of GPER1. Meanwhile, G1 controlled the abnormal formation of hippocampal mossy fiber sprouting caused by seizures, and participated in the regulation of synaptic plasticity by reducing the expression of Synapsin I and increasing the expression of gephyrin. Inhibitory synapse gephyrin may play a significant role in synaptic plasticity.

172-OR: Perinatal Exposure to a Western Diet Alters Hypothalamic Gene Expression and Predisposes to Diabetes in Adult Male Mice

Cardiometabolic diseases are among the most prevalent diseases worldwide. Maternal epigenetic imprinting affects gene expression in offspring, leading to increased disease susceptibility later in life. We showed previously that perinatal exposure to high fat diet (HFD) leads to obesity, fasting hyperglycemia, glucose intolerance, elevated heart rate and hypertension, exclusively in male mice. Here, we hypothesize that epigenetic maternal programming alters gene expression in the hypothalamus to promote the cardiometabolic disturbances seen in male offspring. To investigate this, C57BL6/J dams were fed a HFD or regular diet (RD) for 1 month and mated with RD-fed males. All offspring were maintained on RD after weaning. At 3 months of age, hypothalami from programmed (HFD-RD) and control (RD-RD) offspring were harvested for mRNA sequencing (Illumina NextSeq). Results show 11 differentially expressed genes (DEG) in HFD-RD males in comparison to RD-RD males. Using iPathway analysis, some of the DEGs were involved in insulin secretion and synaptic vesicle cycle pathways. Among the DEG, Snap25, coding a protein of the exocytosis machinery important for neurotransmitters, and insulin release was upregulated (p= 2.31E-06). Additionally, Nnat gene, involved in appetite suppression and regulation of synaptic plasticity in the hypothalamus, as well as insulin secretion was downregulated (p= 0.04955). MiRNA6236 (p= 2.28E-09) and Rn45s (p= 0.002), whose deficiency in islets is known to be associated with prediabetes in mice, were both downregulated in programmed males. Interestingly, with exception of Nnat gene downregulation (p= 0.001), all the male DEGs were unaltered in HFD-RD females compared to RD-RD females. In conclusion, perinatal exposure to HFD programs sex-specific alterations in gene expression in the hypothalamus, possibly impairing the central metabolic regulation and predisposing to type 2 diabetes. Disclosure M. Elgazzaz: None. E. D. Lazartigues: None. F. Mauvais-jarvis: None. Funding American Diabetes Association (1-19-IBS-291 to E.D.L.); U.S. Department of Veterans Affairs (BX004294)

Subchronic nonylphenol exposure induced anxiety-like behavior and decreased expressions of regulators of synaptic plasticity in rats

Studies have shown that there were associations between endocrine disrupting chemicals (EDCs) and anxiety. Nonylphenol (NP) is an EDC with weak estrogen activity. This study aimed to clarify whether subchronic exposure of NP at environmental concentrations induces anxiety-like behavior, and effects of NP on the regulators (NMDAR2B, PSD-95, Synapsin1) expressions of synaptic plasticity in vivo and in vitro experiments. In vivo, 40 male SD rats were randomly divided into 4 groups (each with 10 rats): low dose (0.4 mg/kg/day, L-NP), middle-dose (4 mg/kg/day, M − NP), high-dose (40 mg/kg/day, H-NP) and corn oil (Control) groups. In vitro, HT22 cells were divided into a control group (Control), NP group (NP, 20 μM), glutamine acid receptor inhibitor group (MK-801, 10 μM) and MK-801 + NP group. The concentration of NP in the hippocampus rised with the increase of NP exposure concentration in the treatment groups (F = 7.542, P = 0.001). Compared with the control group, the residence time in the dark box after NP exposure had extended (F = 117.927, P < 0.01). The duration (F = 112.054, P < 0.01) and the number of times (F = 13.514, P < 0.01) to enter the closed arm in the NP exposure group significantly increased. There were more neurons degeneration and nuclear shrinkage in the M − and H– NP groups, while the average number of shrinked neurons increased with the increasing dose of NP exposure. The protein expressions of PSD-95 (F = 97.723, P < 0.01), Synapsin1 (F = 41.797, P < 0.01) and NMDAR2B (F = 3.440, P = 0.036) in the NP group were lower than those of the control. Simultaneously, the expressions of PSD-95, Synapsin1 and NMDAR2B in the hippocampus were down-regulated; the mRNA expression of PSD-95 (F = 19.950, P < 0.01), Synapsin1 (F = 3.498, P = 0.035) and NMDAR2B (F = 9.293, P < 0.01) genes in the hippocampus decreased in the M − and H-NP groups. In vitro, the trend of the fluorescence intensity expressed by PSD-95 (F = 2.606, P = 0.124) and Synapsin1 (F = 20.573, P < 0.01) among the groups was: MK-801 + NP group < MK-801 < NP group. The protein expressions of PSD-95 (F = 5.699, P = 0.022), Synapsin1 (F = 10.820, P = 0.003) and NMDAR2B (F = 6.041, P = 0.019) were down-regulated. These results suggested that subchronic exposure to environmental concentrations of NP induced anxiety, and reduced the protein and/or mRNA expressions of regulators of synaptic plasticity (PSD-95, Synapsin1, NMDAR2B).

Inactivation of Presenilin in inhibitory neurons results in decreased GABAergic responses and enhanced synaptic plasticity

Mutations in the Presenilin genes are the major genetic cause of Alzheimer's disease (AD). Presenilin (PS) is highly expressed in the hippocampus, which is particularly vulnerable in AD. Previous studies of PS function in the hippocampus, however, focused exclusively on excitatory neurons. Whether PS regulates inhibitory neuronal function remained unknown. In the current study, we investigate PS function in GABAergic neurons by performing whole-cell and field-potential electrophysiological recordings using acute hippocampal slices from inhibitory neuron-specific PS conditional double knockout (IN-PS cDKO) mice at 2 months of age, before the onset of age-dependent loss of interneurons. We found that the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) is reduced in hippocampal CA1 neurons of IN-PS cDKO mice, whereas the amplitude of sIPSCs is normal. Moreover, the efficacy of inhibitory neurotransmission as assessed with synaptic input/output relations for evoked mono- and di-synaptic IPSCs is markedly lowered in hippocampal CA1 neurons of IN-PS cDKO mice. Consistent with these findings, IN-PS cDKO mice display enhanced paired-pulse facilitation, frequency facilitation and long-term potentiation in the Schaffer collateral-CA1 pathway. Interestingly, depletion of intracellular Ca2+ stores by inhibition of sarcoendoplasmic reticulum Ca2+ ATPase results in a reduction of IPSC amplitude in control hippocampal neurons but not in IN-PS cDKO neurons, suggesting that impaired intracellular calcium homeostasis in the absence of PS may contribute to the deficiencies in inhibitory neurotransmission. Furthermore, the amplitude of IPSCs induced by short trains of presynaptic stimulation and paired-pulse ratio are decreased in IN-PS cDKO mice. These findings show that inactivation of PS in interneurons results in decreased GABAergic responses and enhanced synaptic plasticity in the hippocampus, providing additional evidence for the importance of PS in the regulation of synaptic plasticity and calcium homeostasis.

Frontal cortex genetic ablation of metabotropic glutamate receptor subtype 3 (mGlu3) impairs postsynaptic plasticity and modulates affective behaviors.

Clinical and translational studies suggest that prefrontal cortex (PFC) dysregulation is a hallmark feature of several affective disorders. Thus, investigating the mechanisms involved in the regulation of PFC function and synaptic plasticity could aid in developing new medications. In recent years, the mGlu2 and mGlu3 subtypes of metabotropic glutamate (mGlu) receptors have emerged as exciting potential targets for the treatment of affective disorders, as mGlu2/3 antagonists exert antidepressant-like effects across many rodent models. Several recent studies suggest that presynaptic mGlu2 receptors may contribute to these effects by regulating excitatory transmission at synapses from the thalamus to the PFC. Interestingly, we found that mGlu3 receptors also inhibit excitatory drive to the PFC but act by inducing long-term depression (LTD) at amygdala-PFC synapses. It remains unclear, however, whether blockade of presynaptic, postsynaptic, or glial mGlu3 receptors contribute to long-term effects on PFC circuit function and antidepressant-like effects of mGlu2/3 antagonists. To address these outstanding questions, we leveraged transgenic Grm3fl/fl mice and viral-mediated gene transfer to genetically ablate mGlu3 receptors from pyramidal cells in the frontal cortex of adult mice of all sexes. Consistent with a role for mGlu3 in PFC pyramidal cells, mGlu3-dependent amygdala-cortical LTD was eliminated following mGlu3 receptor knockdown. Furthermore, knockdown mice displayed a modest, task-specific anxiolytic phenotype and decreased passive coping behaviors. These studies reveal that postsynaptic mGlu3 receptors are critical for mGlu3-dependent LTD and provide convergent genetic evidence suggesting that modulating cortical mGlu3 receptors may provide a promising new approach for the treatment of mood disorders.

Instructive roles of astrocytes in hippocampal synaptic plasticity: neuronal activity-dependent regulatory mechanisms.

In the adult hippocampus, synaptic plasticity is important for information processing, learning, and memory encoding. Astrocytes, the most common glial cells, play a pivotal role in the regulation of hippocampal synaptic plasticity. While astrocytes were initially described as a homogenous cell population, emerging evidence indicates that in the adult hippocampus, astrocytes are highly heterogeneous and can differentially respond to changes in neuronal activity in a subregion‐dependent manner to actively modulate synaptic plasticity. In this review, we summarize how local neuronal activity changes regulate the interactions between astrocytes and synapses, either by modulating the secretion of gliotransmitters and synaptogenic proteins or via contact‐mediated signaling pathways. In turn, these specific responses induced in astrocytes mediate the interactions between astrocytes and neurons, thus shaping synaptic communication in the adult hippocampus. Importantly, the activation of astrocytic signaling is required for memory performance including memory acquisition and recall. Meanwhile, the dysregulation of this signaling can cause hippocampal circuit dysfunction in pathological conditions, resulting in cognitive impairment and neurodegeneration. Indeed, reactive astrocytes, which have dysregulated signaling associated with memory, are induced in the brains of patients with Alzheimer's disease (AD) and transgenic mouse model of AD. Emerging technologies that can precisely manipulate and monitor astrocytic signaling in vivo enable the examination of the specific actions of astrocytes in response to neuronal activity changes as well as how they modulate synaptic connections and circuit activity. Such findings will clarify the roles of astrocytes in hippocampal synaptic plasticity and memory in health and disease.

Amyloid-Beta Mediates Homeostatic Synaptic Plasticity.

The physiological role of the amyloid-precursor protein (APP) is insufficiently understood. Recent work has implicated APP in the regulation of synaptic plasticity. Substantial evidence exists for a role of APP and its secreted ectodomain APPsα in Hebbian plasticity. Here, we addressed the relevance of APP in homeostatic synaptic plasticity using organotypic tissue cultures prepared from APP−/− mice of both sexes. In the absence of APP, dentate granule cells failed to strengthen their excitatory synapses homeostatically. Homeostatic plasticity is rescued by amyloid-β and not by APPsα, and it is neither observed in APP+/+ tissue treated with β- or γ-secretase inhibitors nor in synaptopodin-deficient cultures lacking the Ca2+-dependent molecular machinery of the spine apparatus. Together, these results suggest a role of APP processing via the amyloidogenic pathway in homeostatic synaptic plasticity, representing a function of relevance for brain physiology as well as for brain states associated with increased amyloid-β levels.

Long-term depression at hippocampal mossy fiber-CA3 synapses involves BDNF but is not mediated by p75NTR signaling

BDNF plays a crucial role in the regulation of synaptic plasticity. It is synthesized as a precursor (proBDNF) that can be proteolytically cleaved to mature BDNF (mBDNF). Previous studies revealed a bidirectional mode of BDNF actions, where long-term potentiation (LTP) was mediated by mBDNF through tropomyosin related kinase (Trk) B receptors whereas long-term depression (LTD) depended on proBDNF/p75 neurotrophin receptor (p75NTR) signaling. While most experimental evidence for this BDNF dependence of synaptic plasticity in the hippocampus was derived from Schaffer collateral (SC)-CA1 synapses, much less is known about the mechanisms of synaptic plasticity, in particular LTD, at hippocampal mossy fiber (MF) synapses onto CA3 neurons. Since proBDNF and mBDNF are expressed most abundantly at MF-CA3 synapses in the rodent brain and we had shown previously that MF-LTP depends on mBDNF/TrkB signaling, we now explored the role of proBDNF/p75NTR signaling in MF-LTD. Our results show that neither acute nor chronic inhibition of p75NTR signaling impairs MF-LTD, while short-term plasticity, in particular paired-pulse facilitation, at MF-CA3 synapses is affected by a lack of functional p75NTR signaling. Furthermore, MF-CA3 synapses showed normal LTD upon acute inhibition of TrkB receptor signaling. Nonetheless, acute inhibition of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of both intracellular and extracellular proBDNF cleavage, impaired MF-LTD. This seems to indicate that LTD at MF-CA3 synapses involves BDNF, however, MF-LTD does not depend on p75NTRs. Altogether, our experiments demonstrate that p75NTR signaling is not warranted for all glutamatergic synapses but rather needs to be checked separately for every synaptic connection.

Out-of-Field Hippocampus from Partial-Body Irradiated Mice Displays Changes in Multi-Omics Profile and Defects in Neurogenesis.

The brain undergoes ionizing radiation exposure in many clinical situations, particularly during radiotherapy for brain tumors. The critical role of the hippocampus in the pathogenesis of radiation-induced neurocognitive dysfunction is well recognized. The goal of this study is to test the potential contribution of non-targeted effects in the detrimental response of the hippocampus to irradiation and to elucidate the mechanisms involved. C57Bl/6 mice were whole body (WBI) or partial body (PBI) irradiated with 0.1 or 2.0 Gy of X-rays or sham irradiated. PBI consisted of the exposure of the lower third of the mouse body, whilst the upper two thirds were shielded. Hippocampi were collected 15 days or 6 months post-irradiation and a multi-omics approach was adopted to assess the molecular changes in non-coding RNAs, proteins and metabolic levels, as well as histological changes in the rate of hippocampal neurogenesis. Notably, at 2.0 Gy the pattern of early molecular and histopathological changes induced in the hippocampus at 15 days following PBI were similar in quality and quantity to the effects induced by WBI, thus providing a proof of principle of the existence of out-of-target radiation response in the hippocampus of conventional mice. We detected major alterations in DAG/IP3 and TGF-β signaling pathways as well as in the expression of proteins involved in the regulation of long-term neuronal synaptic plasticity and synapse organization, coupled with defects in neural stem cells self-renewal in the hippocampal dentate gyrus. However, compared to the persistence of the WBI effects, most of the PBI effects were only transient and tended to decrease at 6 months post-irradiation, indicating important mechanistic difference. On the contrary, at low dose we identified a progressive accumulation of molecular defects that tended to manifest at later post-irradiation times. These data, indicating that both targeted and non-targeted radiation effects might contribute to the pathogenesis of hippocampal radiation-damage, have general implications for human health.