Explore the Role of Abeta in Axonal Trafficking Deficits Induced by Alpha Synuclein in Parkinson Disease Mouse Model

Alpha synuclein (ASYN) is a neuronal protein that is observed in significant amounts in the brain and is encoded for by the SNCA gene, it functions as a regulator for the trafficking of synaptic vesicles. It has been noted that the buildup of alpha synuclein has been found in the form of Lewy bodies in studies involving patients with Parkinson’s diseases (PD). Gathering an understanding for the manner in which alpha synuclein affects the synaptic structure and the movement of axonal trafficking will help further our understanding towards the formation of Lewy bodies. Experimenting with the way in which ASYN affected the intervention of Abeta was important, to see the toxicity of Abeta in axonal trafficking. The PD and SynKO mouse models treated with Abeta both showed an effect on the anterograde moving speed of both the PD and SynKO neurons. Synaptic formation was examined, and it was found that ASYN had a large negative influence on the synapse formation in PD neurons. This was due to the significantly reduced colocalization that was found in the treated neurons. It was confirmed that ASYN caused neuronal atrophy through the over expression of GFP-ASYNWT wild type or the GFP-ASYNA53T. Comprehending ASYN effect on the axonal trafficking and the synaptic structure of PD neurons can help understand the mechanism that may be present which possibly stimulates Alzheimer’s Disease in PD patients.

Dexmedetomidine Improved One-lung Ventilation-induced Cognitive Dysfunction in Rats

Background: One-lung ventilation (OLV) is widely used in thoracic surgery. However, OLV may also increase CERO2 and aggravate delayed cognitive recovery. Here, we aimed to investigate the effect of dexmedetomidine (DEX) on cognitive function in rats undergoing OLV. Methods: Sprague-Dawley rats were randomly divided into two-lung ventilation (TLV) group, OLV group and OLV treated with DEX group. Group DEX received 25 μg/kg DEX i.p. 30 min before induction. After mechanical ventilation (MV), Morris water maze (MWM) test was carried out to examine spatial memory function. Western blotting was used to detect pERK1/2, pCREB, Bcl-2 and BAX in hippocampal tissues. Transmission electron microscopy (TEM) was used to observe the hippocampal CA1 region. Results: Post-MV, compared with group OLV, group DEX showed increases in percentage of target quadrant time (P<0.05), platform crossings (P<0.05), a reduction in CERO2 (P<0.05), and pERK1/2, pCREB, and Bcl-2 significantly increased (P<0.01 or P<0.05), while BAX significantly decreased (P<0.01), besides, a less damaged synaptic structure was observed in group DEX. Conclusions: DEX improved post-MV cognitive function in rats undergoing OLV, reduced cerebral oxygen consumption, protected synaptic structure and upregulated ERK1/2-CREB anti-apoptotic signaling pathway in hippocampal CA1 region.

Peroxisomal Proliferator-Activated Receptor β/δ Deficiency Induces Cognitive Alterations

BackgroundPPARβ/δ, the most PPAR abundant isotype in the central nervous system is involved in the modulation of microglial homeostasis and metabolism. Several studies have demonstrated that people suffering from type 2 diabetes mellitus develop cognitive decline turning insulin resistance one of the best predictors of this disturbance. Although numerous investigations have studied the role of PPARb/d in metabolism, its role in neuronal and cognitive function has been underexplored. Therefore, the aim of the study is to determine the role of PPARb/d in the neuropathological pathways involved in the development of cognitive decline and as to whether a risk factor involved in cognitive loss such as obesity modulates neuropathological markers.6-month-old male PPARβ/δ-null (PPARβ/δ-/-) and wildtype (WT) littermates with the same genetic background (C57BL/6X129/SV) and exceptionally, C57BL/6 were used. After the weaning, animals were fed either with conventional chow (CT) or with a palmitic acid-enriched diet containing 45% of fat mainly from hydrogenated coconut oil (HFD). Thus, four groups were defined: WT CT, WT HFD, PPARβ/δ-/- CT and PPARβ/δ-/- HFD and several pathological mechanisms involved in cognitive decline were analyzed.ResultsOur results confirmed that C57BL/6X129/SV showed significantly increased levels of anxiety compared to C57BL/6. Therefore, to evaluate cognitive decline, behavioral tests were dismissed, and dendritic spine quantification and other biochemical biomarkers were performed.PPARβ/δ-/- mice exhibited a decrease in dendritic spine density and synaptic markers, suggesting an alteration in cognitive function and synaptic plasticity. Likewise, our study demonstrated that the lack of PPARβ/δ receptor enhances gliosis in the hippocampus, contributing to astrocyte and microglial activation and also induced an increase in neuroinflammatory biomarkers. Additionally, alterations in the hippocampal insulin receptor pathway were found. Interestingly, while some of the disturbances caused by the lack of PPARβ/δ were not affected by feeding the HFD, others were exacerbated or required the combination of both factors.ConclusionsTaken together, these findings suggest that the loss of PPARβ/δ-/- affects neuronal and synaptic structure, contributing to cognitive dysfunction and, they also present this receptor as a possible new target for the treatment of cognitive decline.

Arhgap22 Disruption Leads to RAC1 Hyperactivity Affecting Hippocampal Glutamatergic Synapses and Cognition in Mice

Rho GTPases are a class of G-proteins involved in several aspects of cellular biology, including the regulation of actin cytoskeleton. The most studied members of this family are RHOA and RAC1 that act in concert to regulate actin dynamics. Recently, Rho GTPases gained much attention as synaptic regulators in the mammalian central nervous system (CNS). In this context, ARHGAP22 protein has been previously shown to specifically inhibit RAC1 activity thus standing as critical cytoskeleton regulator in cancer cell models; however, whether this function is maintained in neurons in the CNS is unknown. Here, we generated a knockout animal model for arhgap22 and provided evidence of its role in the hippocampus. Specifically, we found that ARHGAP22 absence leads to RAC1 hyperactivity and to an increase in dendritic spine density with defects in synaptic structure, molecular composition, and plasticity. Furthermore, arhgap22 silencing causes impairment in cognition and a reduction in anxiety-like behavior in mice. We also found that inhibiting RAC1 restored synaptic plasticity in ARHGAP22 KO mice. All together, these results shed light on the specific role of ARHGAP22 in hippocampal excitatory synapse formation and function as well as in learning and memory behaviors.

Molecular Mechanisms of Environmental Metal Neurotoxicity: A Focus on the Interactions of Metals with Synapse Structure and Function

Environmental exposure to neurotoxic metals and metalloids such as arsenic, cadmium, lead, mercury, or manganese is a global health concern affecting millions of people worldwide. Depending on the period of exposure over a lifetime, environmental metals can alter neurodevelopment, neurobehavior, and cognition and cause neurodegeneration. There is increasing evidence linking environmental exposure to metal contaminants to the etiology of neurological diseases in early life (e.g., autism spectrum disorder) or late life (e.g., Alzheimer’s disease). The known main molecular mechanisms of metal-induced toxicity in cells are the generation of reactive oxygen species, the interaction with sulfhydryl chemical groups in proteins (e.g., cysteine), and the competition of toxic metals with binding sites of essential metals (e.g., Fe, Cu, Zn). In neurons, these molecular interactions can alter the functions of neurotransmitter receptors, the cytoskeleton and scaffolding synaptic proteins, thereby disrupting synaptic structure and function. Loss of synaptic connectivity may precede more drastic alterations such as neurodegeneration. In this article, we will review the molecular mechanisms of metal-induced synaptic neurotoxicity.

Effects of general anesthetics on synaptic transmission and plasticity

: General anesthetics depress excitatory and/or enhance inhibitory synaptic transmission principally by modulating the function of glutamatergic or GABAergic synapses, respectively, with relative anesthetic agent-specific mechanisms. Synaptic signaling proteins, including ligand- and voltage-gated ion channels, are targeted by general anesthetics to modulate various synaptic mechanisms including presynaptic neurotransmitter release, postsynaptic receptor signaling, and dendritic spine dynamics to produce their characteristic acute neurophysiological effects. As synaptic structure and plasticity mediate higher-order functions such as learning and memory, long-term synaptic dysfunction following anesthesia may lead to undesirable neurocognitive consequences depending on specific anesthetic agent and the vulnerability of population. Here we review the cellular and molecular mechanisms of transient and persistent general anesthetic alterations of synaptic transmission and plasticity.

Recording and neural circuit-based manipulation of the maternal oxytocin pulses in mice

For mammals, successful parturition and breastfeeding are critical to the survival of offspring. Pulsatile release of the hormone oxytocin mediates uterine contraction during parturition and milk ejection during lactation. These oxytocin pulses are generated by unique activity patterns of the central neuroendocrine oxytocin neurons located in the paraventricular and supraoptic hypothalamus. However, the maternal activities of oxytocin neurons remain elusive because most classical electrophysiological studies in anesthetized rats have lacked the genetically defined cell identity of oxytocin neurons. We herein introduce viral genetic approaches in mice to characterize the maternal pulsatile activities of oxytocin neurons by fiber-photometry-based chronic in vivo Ca2+ imaging. We also demonstrate the pharmaco-genetic manipulation of oxytocin pulses during lactation via activating a prominent pre-synaptic structure of oxytocin neurons defined by retrograde trans-synaptic tracing. Collectively, our study opens a new avenue for the neuroscience of maternal neuroendocrine functions.

AAV Delivery of shRNA Against TRPC6 in Mouse Hippocampus Impairs Cognitive Function

Transient Receptor Potential Canonical 6 (TRPC6) has been suggested to be involved in synapse function and contribute to hippocampal-dependent cognitive processes. Gene silencing of TRPC6 was performed by injecting adeno-associated virus (AAV) expressing TRPC6-specific shRNA (shRNA-TRPC6) into the hippocampal dentate gyrus (DG). Spatial learning, working memory and social recognition memory were impaired in the shRNA-TRPC6 treated mice compared to control mice after 4 weeks. In addition, gene ontology (GO) analysis of RNA-sequencing revealed that viral intervention of TRPC6 expression in DG resulted in the enrichment of the process of synaptic transmission and cellular compartment of synaptic structure. KEGG analysis showed PI3K-Akt signaling pathway were significantly down-regulated. Furthermore, the shRNA-TRPC6 treatment reduced dendritic spines of DG granule neurons, in terms of spine loss, the thin and mushroom types predominated. Accompanying the spine loss, the levels of PSD95, pAkt and CREB in the hippocampus were decreased in the shRNA-TRPC6 treated animals. Taken together, our results suggest that knocking down TRPC6 in the DG have a disadvantageous effect on cognitive processes.

Acute MPTP Treatment Impairs Dendritic Spine Density in the Mouse Hippocampus

Among the animal models of Parkinson’s disease (PD), the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model has shown both dopaminergic (DA) damage and related motor control defects, as observed in patients with PD. Recent studies have suggested that the DA system interacts with the synaptic plasticity of the hippocampus in PD. However, little is known about how alterations in the hippocampal structural plasticity are affected by the DA damage in MPTP-lesioned models. In the present study, we investigated alterations in dendritic complexity and spine density in the mouse hippocampus following acute MPTP treatment (22 mg/kg, intraperitoneally, four times/day, 2-h intervals). We confirmed that acute MPTP treatment significantly decreased initial motor function and persistently reduced the number of tyrosine hydroxylase-positive DA neurons in the substantia nigra. Golgi staining showed that acute MPTP treatment significantly reduced the spine density of neuronal dendrites in the cornu ammonis 1 (CA1) apical/basal and dentate gyrus (DG) subregions of the mouse hippocampus at 8 and 16 days after treatment, although it did not affect dendritic complexity (e.g., number of crossing dendrites, total dendritic length, and branch points per neuron) in both CA1 and DG subregions at all time points after treatment. Therefore, the present study provides anatomical evidence that acute MPTP treatment affects synaptic structure in the hippocampus during the late phase after acute MPTP treatment in mice, independent of any changes in the dendritic arborization of hippocampal neurons. These findings offer data for the ability of the acute MPTP-lesioned mouse model to replicate the non-nigrostriatal lesions of clinical PD.

Brain Symptoms of Tuberous Sclerosis Complex: Pathogenesis and Treatment

The mammalian target of the rapamycin (mTOR) system plays multiple, important roles in the brain, regulating both morphology, such as cellular size, shape, and position, and function, such as learning, memory, and social interaction. Tuberous sclerosis complex (TSC) is a congenital disorder caused by a defective suppressor of the mTOR system, the TSC1/TSC2 complex. Almost all brain symptoms of TSC are manifestations of an excessive activity of the mTOR system. Many children with TSC are afflicted by intractable epilepsy, intellectual disability, and/or autism. In the brains of infants with TSC, a vicious cycle of epileptic encephalopathy is formed by mTOR hyperactivity, abnormal synaptic structure/function, and excessive epileptic discharges, further worsening epilepsy and intellectual/behavioral disorders. Molecular target therapy with mTOR inhibitors has recently been proved to be efficacious for epilepsy in human TSC patients, and for autism in TSC model mice, indicating the possibility for pharmacological treatment of developmental synaptic disorders.