Mouse Cerebral Cortex Research Articles

The dual-functional memantine nitrate MN-08 alleviates cerebral vasospasm and brain injury in experimental subarachnoid haemorrhage models.

Cerebral vasospasm and neuronal apoptosis after subarachnoid haemorrhage (SAH) is the major cause of morbidity and mortality in SAH patients. So far, single-target agents have not prevented its occurrence. Memantine, a non-competitive NMDA re3ceptor antagonist, is known to alleviate brain injury and vasospasm in experimental models of SAH. Impairment of NO availability also contributes to vasospasm. Recently, we designed and synthesized a memantine nitrate MN-08, which has potent dual functions: neuroprotection and vasodilation. Here, we have tested the therapeutic effects of MN-08 in animal models of SAH. Binding to NMDA receptors (expressed in HEK293 cells), NO release and vasodilator effects of MN-08 were assessed in vitro. Therapeutic effects of MN-08 were investigated in vivo, using rat and rabbit SAH models. MN-08 bound to the NMDA receptor, slowly releasing NO in vitro and in vivo. Consequently, MN-08 relaxed the pre-contracted middle cerebral artery ex vivo and increased blood flow velocity in small vessels of the mouse cerebral cortex. It did not, however, lower systemic blood pressure. In an endovascular perforation rat model of SAH, MN-08 improved the neurological scores and ameliorated cerebral vasospasm. Moreover, MN-08 also alleviated cerebral vasospasm in a cisterna magna single-injection model in rabbits. MN-08 attenuated neural cell apoptosis in both rat and rabbit models of SAH. Importantly, the therapeutic benefit of MN-08 was greater than that of memantine. MN-08 has neuroprotective potential and can ameliorate vasospasm in experimental SAH models.

Metabolomic signature of mouse cerebral cortex following Toxoplasma gondii infection

BackgroundThe protozoan parasite Toxoplasma gondii infects and alters the neurotransmission in cerebral cortex and other brain regions, leading to neurobehavioral and neuropathologic changes in humans and animals. However, the molecules that contribute to these changes remain largely unknown.MethodsWe have investigated the impact of T. gondii infection on the overall metabolism of mouse cerebral cortex. Mass-spectrometry-based metabolomics and multivariate statistical analysis were employed to discover metabolomic signatures that discriminate between cerebral cortex of T. gondii-infected and uninfected control mice.ResultsOur results identified 73, 67 and 276 differentially abundant metabolites, which were involved in 25, 37 and 64 pathways at 7, 14 and 21 days post-infection (dpi), respectively. Metabolites in the unsaturated fatty acid biosynthesis pathway were upregulated as the infection progressed, indicating that T. gondii induces the biosynthesis of unsaturated fatty acids to promote its own growth and survival. Some of the downregulated metabolites were related to pathways, such as steroid hormone biosynthesis and arachidonic acid metabolism. Nine metabolites were identified as T. gondii responsive metabolites, namely galactosylsphingosine, arachidonic acid, LysoSM(d18:1), l-palmitoylcarnitine, calcitetrol, 27-Deoxy-5b-cyprinol, l-homophenylalanine, oleic acid and ceramide (d18:1/16:0).ConclusionsOur data provide novel insight into the dysregulation of the metabolism of the mouse cerebral cortex during T. gondii infection and have important implications for studies of T. gondii pathogenesis.

Dynamic imaging and quantification of subcellular motion with eigen-decomposition optical coherence tomography-based variance analysis.

The dynamic properties of subcellular organism are important biomarkers of the health. Imaging subcellular level dynamics provides effective solutions for evaluating cell metabolism and testing the responses of cells to pathogens and drugs in pharmaceutical engineering. In this paper, we demonstrate an innovative approach to contrast the subcellular motion by using eigen decomposition (ED)-based variance analysis of time-dependent complex optical coherence tomography signals. This method reveals a superior advantage of contrast to noise ratio when compared with the approach that employs intensity decorrelation. Furthermore, the eigen values derived from ED processing are calculated and applied to assess the power ratios of complex signal invariance that decreases exponentially along time dimension. The validation experiments are performed on the patterned samples of yeast powder mixed with gelatin/TiO2 water solution. Additionally, the proposed method is used to image mouse cerebral cortex in normal and pathological conditions, suggesting the practicality of variance power mapping in analyzing cortical neural activities. The technique promises efficient measurement of subcellular motions with high sensitivity and high throughput for in vivo and in situ applications.

Sleep Deprivation by Exposure to Novel Objects Increases Synapse Density and Axon-Spine Interface in the Hippocampal CA1 Region of Adolescent Mice.

Sleep has been hypothesized to rebalance overall synaptic strength after ongoing learning during waking leads to net synaptic potentiation. If so, because synaptic strength and size are correlated, synapses on average should be larger after wake and smaller after sleep. This prediction was recently confirmed in mouse cerebral cortex using serial block-face electron microscopy (SBEM). However, whether these findings extend to other brain regions is unknown. Moreover, sleep deprivation by gentle handling was reported to produce hippocampal spine loss, raising the question of whether synapse size and number are differentially affected by sleep and waking. Here we applied SBEM to measure axon-spine interface (ASI), the contact area between pre-synapse and post-synapse, and synapse density in CA1 stratum radiatum. Adolescent YFP-H mice were studied after 6-8 h of sleep (S = 6), spontaneous wake at night (W = 4) or wake enforced during the day by novelty exposure (EW = 4; males/females balanced). In each animal ≥425 ASIs were measured and synaptic vesicles were counted in ~100 synapses/mouse. Reconstructed dendrites included many small, nonperforated synapses and fewer large, perforated synapses. Relative to S, ASI sizes in perforated synapses shifted toward higher values after W and more so after EW. ASI sizes in nonperforated synapses grew after EW relative to S and W, and so did their density. ASI size correlated with presynaptic vesicle number but the proportion of readily available vesicles decreased after EW, suggesting presynaptic fatigue. Thus, CA1 synapses undergo changes consistent with sleep-dependent synaptic renormalization and their number increases after extended wake.SIGNIFICANCE STATEMENT Sleep benefits learning, memory consolidation, and the integration of new with old memories, but the underlying mechanisms remain highly debated. One hypothesis suggests that sleep's cognitive benefits stem from its ability to renormalize total synaptic strength, after ongoing learning during wake leads to net synaptic potentiation. Supporting evidence for this hypothesis mainly comes from the cerebral cortex, including the observation that cortical synapses are larger after wake and smaller after sleep. Using serial electron microscopy, we find here that sleep/wake synaptic changes consistent with sleep-dependent synaptic renormalization also occur in the CA1 region. Thus, the role of sleep in maintaining synaptic homeostasis may extend to the hippocampus, a key area for learning and synaptic plasticity.

UPLC-QTOF/MS-Based Metabolomics Reveals the Protective Mechanism of Hydrogen on Mice with Ischemic Stroke.

As a reductive gas, hydrogen plays an antioxidant role by selectively scavenging oxygen free radicals. It has been reported that hydrogen has protective effects against nerve damage caused by ischemia-reperfusion in stroke, but the specific mechanism is still unclear. Therefore, this study aims to investigate the protective effects of hydrogen on stroke-induced ischemia-reperfusion injury and its detailed mechanism. Two weeks after the inhalation of high concentrations (66.7%) of hydrogen, middle cerebral artery occlusion (MCAO) was induced in mice using the thread occlusion technique to establish an animal model of the focal cerebral ischemia-reperfusion. Then, a metabolomics analysis of mouse cerebral cortex tissues was first performed by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) to study the metabolic changes and protective mechanisms of hydrogen on stroke ischemia-reperfusion injury. According to the metabolomic profiling of cortex tissues, 29 different endogenous metabolites were screened, including palmitoyl-L-carnitine, citric acid, glutathione, taurine, acetyl-L-carnitine, N-acetylaspartylglutamic acid (NAAG), L-aspartic acid, lysophosphatidylcholine (LysoPC) and lysophosphatidylethanolamine (LysoPE). Through pathway analysis, the metabolic pathways were concentrate on the glutathione pathway and the taurine pathway, mitochondrial energy metabolism and phospholipid metabolism that related to the oxidative stress process. This result reveals that hydrogen may protect against ischemic stroke by reducing oxidative stress during ischemia-reperfusion, thereby protecting nerve cells from reactive oxygen species(ROS).

The role of Bmal1 in neuronal radial migration and axonal projection of the embryonic mouse cerebral cortex

Normal development of the cerebral cortex is a basis for the formation and function of mammalian brains. During this process, the radial migration of cortical neurons, as well as the axon projection into specific layers, are the most important steps regulated by some transcription factors, but the underlying molecular mechanisms are still obscure. BMAL1 (brain and muscle Arnt-like protein 1) is a newly identified transcription factor that plays important roles in the circadian rhythms. It was recently found to regulate the proliferation of hippocampal neuronal progenitor/precursor cells (NPCs), implicating Bmal1 in the brain development. Here we employed both RT-RCR and real-time PCR to explore the expression pattern of the Bmal1 gene in the developing brain. We found BMAl1 is enriched in the brain cortex during the perinatal stages and peaked in P3 mouse brains. Combined with in utero electroporation and interference with RNAi, we found that reducing the expression level of Bmal1 in neurons, the radial migration of embryonic cortical neurons was largely delayed, in a gene dose-effect pattern. Moreover, reducing the level of Bmal1 expression in mouse brains, the axonal projection in the corpus callosum was also disrupted from ipsilateral to the lateral cerebral hemisphere. These findings indicate that BMAL1 is essential for the radial migration of neurons in the cerebral cortex and the axonal projection of the corpus callosum, providing insights into the molecular mechanisms of cerebral cortex development.

FGF Signaling Directs the Cell Fate Switch from Neurons to Astrocytes in the Developing Mouse Cerebral Cortex.

During mammalian neocortical development, neural precursor cells generate neurons first and astrocytes later. The cell fate switch from neurons to astrocytes is a key process generating proper numbers of neurons and astrocytes. Although the intracellular mechanisms regulating this cell fate switch have been well characterized, extracellular regulators are still largely unknown. Here, we uncovered that fibroblast growth factor (FGF) regulates the cell fate switch from neurons to astrocytes in the developing cerebral cortex using mice of both sexes. We found that the FGF signaling pathway is activated in radial glial cells of the ventricular zone at time points corresponding to the switch in cell fate. Our loss- and gain-of-function studies using in utero electroporation indicate that activation of FGF signaling is necessary and sufficient to change cell fates from neurons to astrocytes. We further found that the FGF-induced neuron-astrocyte cell fate switch is mediated by the MAPK pathway. These results indicate that FGF is a critical extracellular regulator of the cell fate switch from neurons to astrocytes in the mammalian cerebral cortex.SIGNIFICANCE STATEMENT Although the intracellular mechanisms regulating the neuron-astrocyte cell fate switch in the mammalian cerebral cortex during development have been well studied, their upstream extracellular regulators remain unknown. By using in utero electroporation, our study provides in vivo data showing that activation of FGF signaling is necessary and sufficient for changing cell fates from neurons to astrocytes. Manipulation of FGF signaling activity led to drastic changes in the numbers of neurons and astrocytes. These results indicate that FGF is a key extracellular regulator determining the numbers of neurons and astrocytes in the mammalian cerebral cortex, and is indispensable for the establishment of appropriate neural circuitry.

Characterization of binding of antipsychotics to muscarinic receptors using mouse cerebral cortex

Antipsychotics are often the first-line treatment for behavioral and psychological symptoms of dementia. However, the potential anticholinergic effects of antipsychotics could counteract the therapeutic effects of cholinesterase inhibitors used to treat dementia. We investigated the inhibitory effects of 26 antipsychotics on [N-Methyl-3H]scopolamine specific binding in mouse cerebral cortex. At 10−5 M, chlorpromazine, levomepromazine, prochlorperazine, timiperone, zotepine, pimozide, blonanserin, olanzapine, quetiapine, and clozapine inhibited [N-Methyl-3H]scopolamine binding by > 45%. Furthermore, the pKi values of chlorpromazine, levomepromazine, zotepine, olanzapine, and clozapine overlapped with their clinically achievable blood concentrations. Therefore, the anticholinergic properties of these antipsychotics could attenuate the effects of cholinesterase inhibitors.

As a Histone Deacetylase Inhibitor, γ-Aminobutyric Acid Upregulates GluR2 Expression: An In Vitro and In Vivo Study.

γ-Aminobutyric acid (GABA) possesses extensive physiological functions and can be directly obtained from foods. GABA-enriched functional foods have been developed and the commercial demands for GABA are increasing. GABA is widely recognized as a central nervous system inhibitory neurotransmitter and plays an important role in some diseases by binding to its receptors. However, some of the functions of GABA are not explained by neurotransmission or GABA receptor pathways. Therefore, this study investigates whether GABA has the potential to inhibit histone deacetylase (HDAC). It is found that GABA inhibits HDAC1/2/3 expression and upregulates histone acetylation levels (Ace-H3K9/Ace-H4K12) in SH-SY5Y cells (which express GABA receptors), 3T3-L1 cells (which do not express GABA receptors), and the cerebral cortex in mice. Glutamate receptor 2 (GluR2) is a subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor and is implicated in the pathogenesis of some neurological diseases. It is also found that GABA increases GluR2 expression by inhibiting HDAC1/2 but not HDAC3. A novel role for GABA is demonstrated in which it acts as an HDAC inhibitor. The present study expands the horizons for exploring the non-neurotransmitter functions of GABA.

Leucine-rich repeat kinase 2 (LRRK2) inhibitors differentially modulate glutamate release and Serine935 LRRK2 phosphorylation in striatal and cerebrocortical synaptosomes.

Mutations in leucine‐rich repeat kinase 2 (LRRK2) gene have been pathogenically linked to Parkinson's disease, and pharmacological inhibition of LRRK2 is being pursued to tackle nigro‐striatal dopaminergic neurodegeneration. However, LRRK2 kinase inhibitors may have manifold actions, affecting not only pathological mechanisms in dopaminergic neurons but also physiological functions in nondopaminergic neurons. Therefore, we investigated whether LRRK2 kinase inhibitors differentially modulate dopamine and glutamate release from the mouse striatum and cerebral cortex. Spontaneous and KCl‐evoked [3H]‐dopamine and glutamate release from superfused synaptosomes obtained from wild‐type and LRRK2 knock‐out, kinase‐dead or G2019S knock‐in mice was measured. Two structurally unrelated inhibitors, LRRK2‐IN‐1 and GSK2578215A, were tested. LRRK2, phosphoSerine1292 and phosphoSerine935 LRRK2 levels were measured in all genotypes, and target engagement was evaluated by monitoring phosphoSerine935 LRRK2. LRRK2‐IN‐1 inhibited striatal glutamate but not dopamine release; GSK2578215A inhibited striatal dopamine and cortical glutamate but enhanced striatal glutamate release. LRRK2‐IN‐1 reduced striatal and cortical phosphoSerine935 levels whereas GSK2578215A inhibited only the former. Neither LRRK2 inhibitor affected neurotransmitter release in LRRK2 knock‐out and kinase‐dead mice; however, they facilitated dopamine without affecting striatal glutamate in G2019S knock‐in mice. GSK2578215A inhibited cortical glutamate release in G2019S knock‐in mice. We conclude that LRRK2‐IN‐1 and GSK2578215A modulate exocytosis by blocking LRRK2 kinase activity, although their effects vary depending on the nerve terminal examined. The G2019S mutation unravels a dopamine‐promoting action of LRRK2 inhibitors while blunting their effects on glutamate release, which highlights their positive potential for the treatment of PD, especially of LRRK2 mutation carriers.

Aminophospholipids are signal-transducing TREM2 ligands on apoptotic cells

Variants of triggering receptor expressed on myeloid cells 2 (TREM2) are associated with an increased incidence of Alzheimer’s disease, as well as other neurodegenerative disorders. Using a newly developed, highly sensitive reporter cell model, consisting of Jurkat T cells stably overexpressing a reporter gene and a gene encoding TREM2DAP12 fusion protein, we show here that TREM2-dependent signal transduction in response to apoptotic Neuro2a cells is mediated by aminophospholipid ligands, phosphatidylserine and phosphatidylethanolamine, which are not exposed on the intact cell surface, but become exposed upon apoptosis. We also show that signal-transducing TREM2 ligands different from aminophospholipids, which appear to be derived from neurons, might be present in membrane fractions of mouse cerebral cortex. These results may suggest that TREM2 regulates microglial function by transducing intracellular signals from aminophospholipids on apoptotic cells, as well as unidentified ligands in the membranes of the cerebral cortex.

The role and mechanism of dl-3-n-butylphthalide in inflammatory response after traumatic brain injury in mice

Objective To investigate whether butylphthalide (NBP) can protect neurons by inhibiting microglial activation and inflammation after traumatic brain injury in mice. Methods One hundred and forty-four mice were randomly assigned to four experimental groups: sham, traumatic brain injury (TBI), TBI+ vehicle (V) and TBI+ NBP. Neurological score, Nissl staining were performed in each group of mice, immunofluorescence staining was used to localize the distribution of ionized calcium binding adapter molecule 1 (IBA-1) in the cerebral cortex of mice, and enzyme-linked immunosorbent assay (ELISA) was used to detect the contents of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the contusion and laceration brain tissue of mice. Statisticalanalysis of data using the statistical product and service solutions 22.0 software. Results NBP could improve the neurological function score, relieve neurodegeneration after brain injury in mice (t=6.320, 5.440, P<0.05). NBP can inhibit the expression of IBA-1 protein and the inflammatory factors TNF-α [(7.21±1.21) pg/mg] and IL-1β [(3.52±1.13) pg/mg] after brain injury in mice (t=3.370, 3.420, 3.350, 3.400, P<0.05). Conclusion NBP can inhibit the activation of microglia in mice after TBI, which is related to the decrease of the release of pro-inflammatory cytokines. Key words: Traumatic brain injury; Butylphthalide; Neuroprotection; Inflammatory factors

Multicolor multiscale brain imaging with chromatic multiphoton serial microscopy

Large-scale microscopy approaches are transforming brain imaging, but currently lack efficient multicolor contrast modalities. We introduce chromatic multiphoton serial (ChroMS) microscopy, a method integrating one‐shot multicolor multiphoton excitation through wavelength mixing and serial block-face image acquisition. This approach provides organ-scale micrometric imaging of spectrally distinct fluorescent proteins and label-free nonlinear signals with constant micrometer-scale resolution and sub-micron channel registration over the entire imaged volume. We demonstrate tridimensional (3D) multicolor imaging over several cubic millimeters as well as brain-wide serial 2D multichannel imaging. We illustrate the strengths of this method through color-based 3D analysis of astrocyte morphology and contacts in the mouse cerebral cortex, tracing of individual pyramidal neurons within densely Brainbow-labeled tissue, and multiplexed whole-brain mapping of axonal projections labeled with spectrally distinct tracers. ChroMS will be an asset for multiscale and system-level studies in neuroscience and beyond.

Role of Per3, a circadian clock gene, in embryonic development of mouse cerebral cortex

Per3 is one of the primary components of circadian clock system. While circadian dysregulation is known to be involved in the pathogenesis of several neuropsychiatric diseases. It remains largely unknown whether they participate in embryonic brain development. Here, we examined the role of clock gene Per3 in the development of mouse cerebral cortex. In situ hybridization analysis revealed that Per3 is expressed in the developing mouse cortex. Acute knockdown of Per3 with in utero electroporation caused abnormal positioning of cortical neurons, which was rescued by RNAi-resistant Per3. Per3-deficient cells showed abnormal migration phenotypes, impaired axon extension and dendritic arbor formation. Taken together, Per3 was found to play a pivotal role in corticogenesis via regulation of excitatory neuron migration and synaptic network formation.

Zinc Uptake and Storage During the Formation of the Cerebral Cortex in Mice.

The cerebral cortex (or neocortex) is a brain structure formed during embryogenesis. The present study seeks to provide a detailed characterization of the Zn homeostatic mechanisms during cerebral cortex formation and development. To reach that goal, we have combined high-throughput RNA-sequencing analysis of the whole murine genome, X-ray fluorescence nanoimaging (XRF), inductively coupled plasma-atomic emission spectrometry (ICP-AES), and live-cell imaging of dissociated cortical neurons loaded with the Zn fluorescent probe FluoZin-3. The transcriptomic analysis was conducted from mRNAs isolated from cortices collected at embryonic (E) days 11 (E11), E13, and E17 and on postnatal day 1 (PN1) pups. This permitted to characterize the temporal pattern of expression of the main genes participating in the cellular transport, storage, and release of Zn during corticogenesis. It appears that cells of the immature cortex express a wide diversity of actors involved in Zn homeostasis with Zip7, SOD1, and metallothioneins being the most abundant transcripts throughout corticogenesis. The quantification of total Zn with XRF and ICP-AES reveals a reduction of Zn levels. Moreover, this is accompanied by a diminution of the size of the internal pools of mobilizable Zn. This study illustrates the tight temporal and spatial regulation of Zn homeostasis during cerebral brain development.

Long-Term Social Isolation Changes the Sensitivity of Monoaminergic Brain Systems to Acute Hypoxia with Hypercapnia

The experiments were performed in male albino mice kept in a group or under conditions of long-term social isolation. Changes in the monoaminergic systems of the left and right hemispheres of the brain have been investigated after acute hypoxia with hypercapnia. The levels of dopamine (DA), serotonin (5-HT) and their metabolites, dioxyphenylacetic (DOPAC), homovanillic (HVA), and 5-hydroxyindoleacetic (5‑HIAA) acids, were determined by HPLC in the cerebral cortex, hippocampus, and striatum of the right and left sides of the brain. Control mice kept both in the group and under conditions of social isolation had a higher DA content in the left cerebral cortex. In the other brain structures the monoamine content was symmetric. In the cerebral cortex of mice kept in the group, acute hypoxia with hypercapnia resulted in a right-sided increase in the DA and 5-HT levels. At the same time, the DOPAC content decreased in the left cortex. In mice kept in the group hypoxia with hypercapnia conditions increased the DA level in the left hippocampus. In the striatum, the content of monoamines and their metabolites remained insignificantly changed. In animals kept for a long time under the conditions of social isolation, hypoxia with hypercapnia did not cause any statistically significant changes in the monoamines and their metabolites levels. It has been concluded that the preliminary maintenance under conditions of prolonged social isolation changes the reaction of central monoaminergic systems to acute hypoxia with hypercapnia.

Genotoxicity of the vegetables juice grown in garden built on the tailings coal deposits

The aim of the present study was to evaluate the genotoxic effect of lettuce (Lactuca sativa L.), beet (Beta vulgaris L.), broccoli (Brassica oleracea var. italica), and kale (Brassica oleracea var. acephala) grown in vegetable garden built on the deposits of coal tailings. For this, we used 72 healthy male Swiss albino mice that received juice from the vegetables in an acute or chronic treatment. Using comet assay, we determined that acute administration of the juices of all vegetables from the coal-mining area was genotoxic, and increased the DNA damage in the blood, liver, and cerebral cortex of mice. Therefore, the present data suggest that intake of vegetables cultivated over coal waste results in an increase in DNA damage in some organs; this situation may pose a risk to health.

Effect of glycine transporter 1 inhibitor on epileptic seizures and cognitive dysfunction in epilepsy mice

Objective To study the effect of glycine transporter 1 inhibitor M22 on epileptic seizures and cognitive dysfunction in epilepsy mice. Methods A total of 110 C57BL/6 mice were randomly divided into Normal control group (CON group, n=10), Model group (Mod group n=20), M22-1 group (n=20), M22-2 group (n=20), M22-3 group (n=20), M22-4 group (n=20) according to weight.The chronic epileptic model was established by intraperitoneal injection of PTZ(30 mg/kg). The mice in CON group was injected with normal saline(10 mg/kg). The mice in Mod group were intraperitoneally injected with normal saline (10 ml/kg) and were injected with PT2 30 min later.The mice in M22-1 group, M22-2 group, M22-3 group, M22-4 group were intraperitoneally injected with M22 of corresponding dose(10 mg/kg, 20 mg/kg, 40 mg/kg, 80 mg/kg)respectively, lasting for 2 weeks.Epilepsy seizures of mice in each group were recorded.The learning and memory function of epilepsy mice were evaluated by Morris water maze test .Then the mice were sacrificed and the apoptosis related proteins Bcl-2, Bax, Cyt-c in the cerebral cortex of mice were measured by Western blot. Results (1)The mortality kindling rate, epileptic seizure grade and rate of tonic clonus in M22-2 and M22-3 group were significantly lower than those in Mod, M22-1 and M22-4 group(all P 0.05). Conclusion M22 (40 mg/kg) has significant anti-epileptic effect and can effectively improve the cognitive dysfunction of epileptic mice, which may be related to the inhibition of neuronal apoptosis in mice. Key words: Epilepsy; Glycine transporter 1 inhibitor; M22; Cognitive function; Pentylenetetrazole

A role for polycystin-1 and polycystin-2 in neural progenitor cell differentiation.

Polycystin-1 (PC1) and polycystin-2 (PC2) are transmembrane proteins encoded by the Pkd1 and Pkd2 genes, respectively. Mutations in these genes are causative for the development of autosomal-dominant polycystic kidney disease. A prominent feature of this disease is an unbalanced cell proliferation. PC1 and PC2 physically interact to form a complex, which localizes to the primary cilia of renal epithelial cells. Recently, PC1 and PC2 have also been described to be present in primary cilia of radial glial cells (RGCs) and to contribute to the planar cell polarity of late RGCs and E1 ependymal cells. As neural progenitor cells (NPCs), early RGCs have to balance proliferation for expansion, or for self-renewal and differentiation to generate neurons. It is not known whether the polycystins play a role in this process. Here, we show that PC1 and PC2 are expressed in RGCs of the developing mouse cerebral cortex during neurogenesis. Loss-of-function analysis and cell-based assays reveal that a reduction of PC1 or PC2 expression leads to increased NPC proliferation, while the differentiation to neurons becomes impaired. The increased NPC proliferation is preceded by enhanced Notch signaling and accompanied by a rise in the number of symmetric cell divisions. The transcription factor STAT3 seems to be mechanistically important for polycystin signaling in NPCs as either STAT3 knockdown or inhibition of STAT3 function abrogates the increased proliferation driven by reduced polycystin expression. Our findings indicate that PC1 and PC2 are critical for maintaining a balance between proliferation and differentiation of NPCs.

Neurotoxic effects of MPTP on mouse cerebral cortex: Modulation of neuroinflammation as a neuroprotective strategy

Parkinson's disease (PD) is a progressive neurological disorder, mainly characterized by the progressive loss of dopaminergic neurons in the Substantia nigra pars compacta (SNpc) and by the presence of intracellular inclusions, known as Lewy bodies. Despite SNpc being considered the primary affected region in PD, the neuropathological features are confined solely to the nigro-striatal axis. With disease progression other brain regions are also affected, namely the cerebral cortex, although the spreading of the neurologic damage to this region is still not completely unraveled.Tauroursodeoxycholic acid (TUDCA) is an endogenous bile acid that has been shown to have antioxidant properties and to exhibit a neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model of PD. Moreover, TUDCA anti-inflammatory properties have been reported in glial cells, making it a prominent therapeutic agent in PD.Here, we used C57BL/6 mice injected with MPTP in a sub-acute paradigm aiming to investigate if the neurotoxic effects of MPTP could be extended to the cerebral cortex. In parallel, we evaluated the anti-oxidant, neuroprotective and anti-inflammatory effects of TUDCA. The anti-inflammatory mechanisms elicited by TUDCA were further dissected in microglia cells.Our results show that MPTP leads to a decrease of ATP and activated AMP-activated protein kinase levels in mice cortex, and to a transient increase in the expression of antioxidant downstream targets of nuclear factor erythroid 2 related factor 2 (Nrf-2), and parkin. Notably, MPTP increases pro-inflammatory markers, while down-regulating the expression of the anti-inflammatory protein Annexin-A1 (ANXA1). Importantly, we show that TUDCA treatment prevents the deleterious effects of MPTP, sustains increased levels of antioxidant enzymes and parkin, and most of all negatively modulates neuroinflammation and up-regulates ANXA1 expression. Additionally, results from cellular models using microglia corroborate TUDCA modulation of ANXA1 synthesis, linking inhibition of neuroinflammation and neuroprotection by TUDCA.