Aging-related reduction in androgen levels may be a possible risk factor for neurodegenerative diseases and contribute to cognitive impairment. Androgens may affect synaptic function and cognition in an androgen receptor (AR)-independent manner; however, the mechanisms connecting theses effects are unknown. Therefore, we used testicular feminization mutation (Tfm) male mice, a model with AR mutation, to test the effects of testosterone on synaptic function and cognition. Our results showed that testosterone ameliorated spatial memory deficit and neuronal damage, and increased dendritic spines density and postsynaptic density protein 95 (PSD95) and glutamate receptor 1 (GluA1) expression in the hippocampus of Tfm male mice. And these effects of testosterone were not inhibited by anastrozole, which suppressed conversion of testosterone to estradiol. Mechanistically, testosterone activated the extracellular signal-related kinase 1/2 (Erk1/2) and cyclic adenosine monophosphate response element-binding protein (CREB) in the hippocampus of Tfm male mice. Meanwhile, Erk1/2 inhibitor SCH772984 blocked the upregulation of phospho-CREB, PSD95, and GluA1 induced by testosterone in HT22 cells pretreated with flutamide, an androgen antagonist. Collectively, our data indicate that testosterone may ameliorate hippocampal synaptic damage and spatial memory deficit by activating the Erk1/2-CREB signaling pathway in an AR-independent manner.

Effective preventive measures against postoperative cognitive dysfunction in older adults are urgently needed. In this study, we investigated the effect of electroacupuncture (EA) on anesthesia and surgery-induced cognitive decline in aged rats by RNA-seq analysis, behavioral testing, Golgi-Cox staining, dendritic spine analysis, immunofluorescence assay and western blot analysis. EA ameliorated anesthesia and surgery induced-cognitive decline. RNA-seq analysis identified numerous differentially-expressed genes, including 353 upregulated genes and 563 downregulated genes, after pretreatment with EA in aged rats with postoperative cognitive dysfunction. To examine the role of CREB in EA, we injected adeno-associated virus (AAV) into the CA1 region of the hippocampus bilaterally into the aged rats to downregulate the transcription factor. EA improved synaptic plasticity, structurally and functionally, by activating the MAPK/ERK/CREB signaling pathway in aged rats. Together, our findings suggest that EA protects against anesthesia and surgery-induced cognitive decline in aged rats by activating the MAPK/ERK/CREB signaling pathway and enhancing hippocampal synaptic plasticity.

In addition to amyloid and tau pathology in the central nervous system (CNS), inflammatory processes and synaptic dysfunction are highly important mechanisms involved in the development and progression of dementia diseases. In the present study, we conducted a comparative analysis of selected pro-inflammatory proteins in the CNS with proteins reflecting synaptic damage and core biomarkers in mild cognitive impairment (MCI) and early Alzheimer\'s disease (AD). To our knowledge, no studies have yet compared CXCL12 and CX3CL1 with markers of synaptic disturbance in cerebrospinal fluid (CSF) in the early stages of dementia. The quantitative assessment of selected proteins in the CSF of patients with MCI, AD, and non-demented controls (CTRL) was performed using immunoassays (single- and multiplex techniques). In this study, increased CSF concentration of CX3CL1 in MCI and AD patients correlated positively with neurogranin (r = 0.74; p < 0.001, and r = 0.40; p = 0.020, respectively), ptau181 (r = 0.49; p = 0.040), and YKL-40 (r = 0.47; p = 0.050) in MCI subjects. In addition, elevated CSF levels of CXCL12 in the AD group were significantly associated with mini-mental state examination score (r = -0.32; p = 0.040). We found significant evidence to support an association between CX3CL1 and neurogranin, already in the early stages of cognitive decline. Furthermore, our findings indicate that CXCL12 might be a useful marker for tract severity of cognitive impairment.

Excitotoxicity, a neuronal death process in neurological disorders such as stroke, is initiated by the overstimulation of ionotropic glutamate receptors. Although dysregulation of proteolytic signaling networks is critical for excitotoxicity, the identity of affected proteins and mechanisms by which they induce neuronal cell death remain unclear. To address this, we used quantitative N-terminomics to identify proteins modified by proteolysis in neurons undergoing excitotoxic cell death. We found that most proteolytically processed proteins in excitotoxic neurons are likely substrates of calpains, including key synaptic regulatory proteins such as CRMP2, doublecortin-like kinase I, Src tyrosine kinase and calmodulin-dependent protein kinase IIβ (CaMKIIβ). Critically, calpain-catalyzed proteolytic processing of these proteins generates stable truncated fragments with altered activities that potentially contribute to neuronal death by perturbing synaptic organization and function. Blocking calpain-mediated proteolysis of one of these proteins, Src, protected against neuronal loss in a rat model of neurotoxicity. Extrapolation of our N-terminomic results led to the discovery that CaMKIIα, an isoform of CaMKIIβ, undergoes differential processing in mouse brains under physiological conditions and during ischemic stroke. In summary, by identifying the neuronal proteins undergoing proteolysis during excitotoxicity, our findings offer new insights into excitotoxic neuronal death mechanisms and reveal potential neuroprotective targets for neurological disorders.

UNASSIGNED: Blast induced Traumatic Brain Injury (bTBI) has become a signature casualty of military operations. Recently, military medics observed neurocognitive deficits in servicemen exposed to repeated low level blast (LLB) waves during military heavy weapons training. In spite of significant clinical and preclinical TBI research, current understanding of injury mechanisms and short- and long-term outcomes is limited. Mathematical models of bTBI biomechanics and mechanobiology of sensitive neuro-structures such as synapses may help in better understanding of injury mechanisms and in the development of improved diagnostics and neuroprotective strategies.
UNASSIGNED: In this work, we formulated a model of a single synaptic structure integrating the dynamics of the synaptic cell adhesion molecules (CAMs) with the deformation mechanics of the synaptic cleft. The model can resolve time scales ranging from milliseconds during the hyperacute phase of mechanical loading to minutes-hours acute/chronic phase of injury progression/repair. The model was used to simulate the synaptic injury responses caused by repeated blast loads.
UNASSIGNED: Our simulations demonstrated the importance of the number of exposures compared to the duration of recovery period between repeated loads on the synaptic injury responses. The paper recognizes current limitations of the model and identifies potential improvements.

Synaptic damage is one of the most prevalent pathophysiological responses to traumatic CNS injury and underlies much of the associated cognitive dysfunction; however, it is poorly understood. The D-amino acid, D-serine, serves as the primary co-agonist at synaptic NMDA receptors (NDMARs) and is a critical mediator of NMDAR-dependent transmission and synaptic plasticity. In physiological conditions, D-serine is produced and released by neurons from the enzymatic conversion of L-serine by serine racemase (SRR). However, under inflammatory conditions, glial cells become a major source of D-serine. Here, we report that D-serine synthesized by reactive glia plays a critical role in synaptic damage after traumatic brain injury (TBI) and identify the therapeutic potential of inhibiting glial D-serine release though the transporter Slc1a4 (ASCT1). Furthermore, using cell-specific genetic strategies and pharmacology, we demonstrate that TBI-induced synaptic damage and memory impairment requires D-serine synthesis and release from both reactive astrocytes and microglia. Analysis of the murine cortex and acutely resected human TBI brain also show increased SRR and Slc1a4 levels. Together, these findings support a novel role for glial D-serine in acute pathological dysfunction following brain trauma, whereby these reactive cells provide the excess co-agonist levels necessary to initiate NMDAR-mediated synaptic damage.

Synaptic and neuronal loss are major neuropathological characteristics of Parkinson\'s disease. Misfolded protein aggregates in the form of Lewy bodies, comprised mainly of α-synuclein (αSyn), are associated with disease progression, and have also been linked to other neurodegenerative diseases, including Lewy body dementia, Alzheimer\'s disease, and frontotemporal dementia. However, the effects of αSyn and its mechanism of synaptic damage remain incompletely understood. Here, we show that αSyn oligomers induce Ca2+-dependent release of glutamate from astrocytes obtained from male and female mice, and that mice overexpressing αSyn manifest increased tonic release of glutamate in vivo In turn, this extracellular glutamate activates glutamate receptors, including extrasynaptic NMDARs (eNMDARs), on neurons both in culture and in hippocampal slices of αSyn-overexpressing mice. Additionally, in patch-clamp recording from outside-out patches, we found that oligomerized αSyn can directly activate eNMDARs. In organotypic slices, oligomeric αSyn induces eNMDAR-mediated synaptic loss, which can be reversed by the drug NitroSynapsin. When we expose human induced pluripotent stem cell-derived cerebrocortical neurons to αSyn, we find similar effects. Importantly, the improved NMDAR antagonist NitroSynapsin, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from oligomeric αSyn-induced damage in our model systems, thus meriting further study for its therapeutic potential.SIGNIFICANCE STATEMENT Loss of synaptic function and ensuing neuronal loss are associated with disease progression in Parkinson\'s disease (PD), Lewy body dementia (LBD), and other neurodegenerative diseases. However, the mechanism of synaptic damage remains incompletely understood. α-Synuclein (αSyn) misfolds in PD/LBD, forming Lewy bodies and contributing to disease pathogenesis. Here, we found that misfolded/oligomeric αSyn releases excessive astrocytic glutamate, in turn activating neuronal extrasynaptic NMDA receptors (eNMDARs), thereby contributing to synaptic damage. Additionally, αSyn oligomers directly activate eNMDARs, further contributing to damage. While the FDA-approved drug memantine has been reported to offer some benefit in PD/LBD (Hershey and Coleman-Jackson, 2019), we find that the improved eNMDAR antagonist NitroSynapsin ameliorates αSyn-induced synaptic spine loss, providing potential disease-modifying intervention in PD/LBD.

Multiple sclerosis (MS) is a common neurological disorder of putative autoimmune origin. Clinical and experimental studies delineate abnormal expression of specific cytokines over the course of the disease. One major cytokine that has been shown to play a pivotal role in MS is tumor necrosis factor (TNF). TNF is a pleiotropic cytokine regulating many physiological and pathological functions of both the immune system and the central nervous system (CNS). Convincing evidence from studies in human and experimental MS have demonstrated the involvement of TNF in various pathological hallmarks of MS, including immune dysregulation, demyelination, synaptopathy and neuroinflammation. However, due to the complexity of TNF signaling, which includes two-ligands (soluble and transmembrane TNF) and two receptors, namely TNF receptor type-1 (TNFR1) and type-2 (TNFR2), and due to its cell- and context-differential expression, targeting the TNF system in MS is an ongoing challenge. This review summarizes the evidence on the pathophysiological role of TNF in MS and in different MS animal models, with a special focus on pharmacological treatment aimed at controlling the dysregulated TNF signaling in this neurological disorder.

The growing number of evidences suggest that neuroinflammation and synaptic damage are closely related to the onset of depression. Bexarotene (Bex), a retinoid X receptor agonist, is an U.S. Food and Drug Administration-approved drug for the treatment of cutaneous T-cell lymphoma that has recently been reported to have anti-inflammatory and neuroprotective effects in several models of neurological disease including Parkinson\'s disease, Alzheimer\'s disease, and so forth. However, the effect of Bex on depression remains unclear. In this study, we investigated effect of Bex on depression-like behaviour in mice induced by lipopolysaccharide (LPS) or corticosterone (CORT). Our results showed that treatment with Bex for 15 days significantly improved LPS-induced depression-like behaviour in social interaction test and CORT-induced depression-like behaviour in forced swimming test and tail suspension test in mice. We found that the Bex treatment depressed the increase in the number of activated microglia and astrocytes in the frontal cortex, and the increase in the levels of inflammatory cytokines TNF-α, IL-1β and IL-6 in LPS-injected mice. Furthermore, Bex treatment also rescued the decrease in the expression of BDNF, and inhibition of CREB/BDNF/ERK pathway, and improved the expression of synaptic related protein in CORT-induced mice. Based on these results, it is possible that Bex reversed depression-like behaviour in mice by reducing neuroinflammation and protecting against synaptic damage induced by LPS or CORT.

Alzheimer\'s disease (AD) is the most common type of dementia in the elderly. It is characterized by the accumulation of amyloid-beta (Aβ) and progressive cognitive impairment. To alleviate the symptoms of AD, functional foods and nutrients have been used for centuries. In this study, we investigated whether Cuscutae Japonicae Semen (CJS), a medicinal food traditionally used in East Asia, has effects on memory improvement and synapse protection in AD. We orally administered CJS to 5x familiar AD (5xFAD) transgenic mice and performed the Morris water maze test. The results showed that CJS treatment ameliorated the decline of memory function. Then, we demonstrated that CJS attenuated the degeneration of pre- and post-synaptic proteins in the hippocampi of 5xFAD mice. To demonstrate the effects of CJS in vitro, we treated Aβ in primary neuronal culture with CJS and observed that CJS rescued the loss of functional synapses. The protective effects of CJS on the synapse were due to the inhibition of activated caspase-3 expression. Additionally, CJS inhibited the phosphorylation of glycogen synthase kinase-3β and tau proteins, which contribute to synaptic dysfunction. Taken together, our results suggest that CJS is efficient in alleviating memory loss by rescuing caspase-3-mediated synaptic damage in AD treatment.