Characteristics of Brains in Autism Spectrum Disorder: Structure, Function and Connectivity across the Lifespan

Ha, Sungji,Sohn, In-Jung,Kim, Namwook,Sim, Hyeon Jeong,Cheon, Keun-Ah The Korean Society for Brain and Neural Science 2015 Experimental Neurobiology Vol.24 No.4

<P>Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by impaired social communication and restricted and repetitive behaviors (RRBs). Over the past decade, neuroimaging studies have provided considerable insights underlying neurobiological mechanisms of ASD. In this review, we introduce recent findings from brain imaging studies to characterize the brains of ASD across the human lifespan. Results of structural Magnetic Resonance Imaging (MRI) studies dealing with total brain volume, regional brain structure and cortical area are summarized. Using task-based functional MRI (fMRI), many studies have shown dysfunctional activation in critical areas of social communication and RRBs. We also describe several data to show abnormal connectivity in the ASD brains. Finally, we suggest the possible strategies to study ASD brains in the future.</P>

NOX Inhibitors - A Promising Avenue for Ischemic Stroke

Kim, Jong Youl,Park, Joohyun,Lee, Jong Eun,Yenari, Midori A. The Korean Society for Brain and Neural Science 2017 Experimental Neurobiology Vol.26 No.4

<P>NADPH-oxidase (NOX) mediated superoxide originally found on leukocytes, but now recognized in several types of cells in the brain. It has been shown to play an important role in the progression of stroke and related cerebrovascular disease. NOX is a multisubunit complex consisting of 2 membrane-associated and 4 cytosolic subunits. NOX activation occurs when cytosolic subunits translocate to the membrane, leading to transport electrons to oxygen, thus producing superoxide. Superoxide produced by NOX is thought to function in long-term potentiation and intercellular signaling, but excessive production is damaging and has been implicated to play an important role in the progression of ischemic brain. Thus, inhibition of NOX activity may prove to be a promising treatment for ischemic brain as well as an adjunctive agent to prevent its secondary complications. There is mounting evidence that NOX inhibition in the ischemic brain is neuroprotective, and targeting NOX in circulating immune cells will also improve outcome. This review will focus on therapeutic effects of NOX assembly inhibitors in brain ischemia and stroke. However, the lack of specificity and toxicities of existing inhibitors are clear hurdles that will need to be overcome before this class of compounds could be translated clinically.</P>

Dehydroascorbic Acid Attenuates Ischemic Brain Edema and Neurotoxicity in Cerebral Ischemia: An <i>in vivo</i> Study

Song, Juhyun,Park, Joohyun,Kim, Jae Hwan,Choi, Ja Yong,Kim, Jae Young,Lee, Kyoung Min,Lee, Jong Eun The Korean Society for Brain and Neural Science 2015 Experimental Neurobiology Vol.24 No.1

<P>Ischemic stroke results in the diverse phathophysiologies including blood brain barrier (BBB) disruption, brain edema, neuronal cell death, and synaptic loss in brain. Vitamin C has known as the potent anti-oxidant having multiple functions in various organs, as well as in brain. Dehydroascorbic acid (DHA) as the oxidized form of ascorbic acid (AA) acts as a cellular protector against oxidative stress and easily enters into the brain compared to AA. To determine the role of DHA on edema formation, neuronal cell death, and synaptic dysfunction following cerebral ischemia, we investigated the infarct size of ischemic brain tissue and measured the expression of aquaporin 1 (AQP-1) as the water channel protein. We also examined the expression of claudin 5 for confirming the BBB breakdown, and the expression of bcl 2 associated X protein (Bax), caspase-3, inducible nitric oxide synthase (iNOS) for checking the effect of DHA on the neurotoxicity. Finally, we examined postsynaptic density protein-95 (PSD-95) expression to confirm the effect of DHA on synaptic dysfunction following ischemic stroke. Based on our findings, we propose that DHA might alleviate the pathogenesis of ischemic brain injury by attenuating edema, neuronal loss, and by improving synaptic connection.</P>

Induction of Nerve Injury-Induced Protein 1 (Ninjurin 1) in Myeloid Cells in Rat Brain after Transient Focal Cerebral Ischemia

Lee, Hye-Kyung,Lee, Hahnbie,Luo, Lidan,Lee, Ja-Kyeong The Korean Society for Brain and Neural Science 2016 Experimental Neurobiology Vol.25 No.2

<P>Nerve injury-induced protein-1 (Ninjurin-1, Ninj1) was initially identified as a novel adhesion molecule in rat sciatic nerve and to be up-regulated in neurons and Schwann cells of distal nerve segments after nerve transection or crush injury. Recently, Ninj1 was found to act as a modulator of cell migration, angiogenesis, and apoptosis. Accumulating evidence indicates that innate immune response plays beneficial and deleterious roles in brain ischemia, and the trans-endothelial migration of blood-derived immune cells is key initiator of this response. In the present study, we examined the expression profile and cellular distribution of Ninj1 in rat brain after transient focal cerebral ischemia. Ninj1 expression was found to be significantly induced in cortical penumbras 1 day after 60 min of middle cerebral artery occlusion (MCAO) and to increase gradually for 8 days and then declined. In infarction cores of cortices, patterns of Ninj1 expression were similar to those observed in cortical penumbras, except induction was maintained for 10 days. At 1 day post-MCAO, Ninj1 inductions were detected mainly in neutrophils and endothelial cells in both infarction cores and penumbras, but reactive macrophages were the major cellular expressers of Ninj1 at 4 days post-MCAO. Expressional induction in reactive macrophages was maintained in infarction cores after 12 days post-MCAO but not in penumbras. These dynamic expressions of Ninj1 in different immune cells at different times suggest that this protein performs various, critical roles in the modulation of acute and delayed immune responses in the postischemic brain.</P>

Proposed Motor Scoring System in a Porcine Model of Parkinson's Disease induced by Chronic Subcutaneous Injection of MPTP

Moon, Joon Ho,Kim, Ji Ho,Im, Hyung-Jun,Lee, Dong Soo,Park, Eun Jung,Song, Kilyoung,Oh, Hyun Ju,Hyun, Su Bin,Kang, Sang Chul,Kim, Hyunil,Moon, Hyo Eun,Park, Hyung Woo,Lee, Hong Jae,Kim, Eun Ji,Kim, Seo The Korean Society for Brain and Neural Science 2014 Experimental Neurobiology Vol.23 No.3

<P>Destruction of dopaminergic neurons in the substantia nigra pars compacta (SNpc) is a common pathophysiology of Parkinson's disease (PD). Characteristics of PD patients include bradykinesia, muscle rigidity, tremor at rest and disturbances in balance. For about four decades, PD animal models have been produced by toxin-induced or gene-modified techniques. However, in mice, none of the gene-modified models showed all 4 major criteria of PD. Moreover, distinguishing between PD model pigs and normal pigs has not been well established. Therefore, we planned to produce a pig model for PD by chronic subcutaneous administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), neurotoxin. Changes in behavioral patterns of pigs were thoroughly evaluated and a new motor scoring system was established for this porcine model that was based on the Unified Parkinson's Disease Rating Scale (UPDRS) in human PD patients. In summary, this motor scoring system could be helpful to analyze the porcine PD model and to confirm the pathology prior to further examinations, such as positron emission tomography-computed tomography (PET-CT), which is expensive, and invasive immunohistochemistry (IHC) of the brain.</P>

Ca ²⁺ Entry is Required for Mechanical Stimulation-induced ATP Release from Astrocyte

Lee, Jaekwang,Chun, Ye-Eun,Han, Kyung-Seok,Lee, Jungmoo,Woo, Dong Ho,Lee, C. Justin The Korean Society for Brain and Neural Science 2015 Experimental Neurobiology Vol.24 No.1

<P>Astrocytes and neurons are inseparable partners in the brain. Neurotransmitters released from neurons activate corresponding G protein-coupled receptors (GPCR) expressed in astrocytes, resulting in release of gliotransmitters such as glutamate, D-serine, and ATP. These gliotransmitters in turn influence neuronal excitability and synaptic activities. Among these gliotransmitters, ATP regulates the level of network excitability and is critically involved in sleep homeostasis and astrocytic Ca<SUP>2+</SUP> oscillations. ATP is known to be released from astrocytes by Ca<SUP>2+</SUP>-dependent manner. However, the precise source of Ca<SUP>2+</SUP>, whether it is Ca<SUP>2+</SUP> entry from outside of cell or from the intracellular store, is still not clear yet. Here, we performed sniffer patch to detect ATP release from astrocyte by using various stimulation. We found that ATP was not released from astrocyte when Ca<SUP>2+</SUP> was released from intracellular stores by activation of Gα<SUB>q</SUB>-coupled GPCR including PAR1, P2YR, and B2R. More importantly, mechanical stimulation (MS)-induced ATP release from astrocyte was eliminated when external Ca<SUP>2+</SUP> was omitted. Our results suggest that Ca<SUP>2+</SUP> entry, but not release from intracellular Ca<SUP>2+</SUP> store, is critical for MS-induced ATP release from astrocyte.</P>

A Critical Role of GIT1 in Vertebrate and Invertebrate Brain Development

Hong, Sung-Tae,Mah, Won The Korean Society for Brain and Neural Science 2015 Experimental Neurobiology Vol.24 No.1

<P>GIT1, a multifunctional signaling adaptor protein, is implicated in the development of dendritic spines and neuronal synapses. GIT1 forms a signaling complex with PIX, RAC, and PAK proteins that is known to play important roles in brain development. Here we found that <I>Git1</I>-knockout (<I>Git1<SUP>-/-</SUP></I>) mice show a microcephaly-like small brain phenotype, which appears to be caused by reduced neuronal size rather than number. <I>Git1<SUP>-/-</SUP></I> mice also show decreased dendritic spine number without morphological alterations in the hippocampus. Behaviorally, <I>Git1<SUP>-/-</SUP></I> mice show impaired motor coordination and learning and memory. In addition, adult <I>dGit Drosophila</I> mutants show decreased brain size and abnormal morphology of the mushroom body. These results suggest that GIT1 is important for brain development in both rodents and flies.</P>

Transmission of Synucleinopathies in the Enteric Nervous System of A53T Alpha-Synuclein Transgenic Mice

Lee, He-Jin,Suk, Ji-Eun,Lee, Kyung-Won,Park, Seung-Hwa,Blumbergs, Peter C.,Gai, Wei-Ping,Lee, Seung-Jae The Korean Society for Brain and Neural Science 2011 Experimental Neurobiology Vol.20 No.4

<P>Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are characterized by abnormal deposition of α-synuclein aggregates in many regions of the central and peripheral nervous systems. Accumulating evidence suggests that the α-synuclein pathology initiates in a few discrete regions and spreads to larger areas in the nervous system. Recent pathological studies of PD patients have raised the possibility that the enteric nervous system is one of the initial sites of α-synuclein aggregation and propagation. Here, we evaluated the induction and propagation of α-synuclein aggregates in the enteric nervous system of the A53T α-synuclein transgenic mice after injection of human brain tissue extracts into the gastric walls of the mice. Western analysis of the brain extracts showed that the DLB extract contained detergent-stable α-synuclein aggregates, but the normal brain extract did not. Injection of the DLB extract resulted in an increased deposition of α-synuclein in the myenteric neurons, in which α-synuclein formed punctate aggregates over time up to 4 months. In these mice, inflammatory responses were increased transiently at early time points. None of these changes were observed in the A53T mice injected with saline or the normal brain extract, nor were these found in the wild type mice injected with the DLB extract. These results demonstrate that pathological α-synuclein aggregates present in the brain of DLB patient can induce the aggregation of endogenous α-synuclein in the myenteric neurons in A53T mice, suggesting the transmission of synucleinopathy lesions in the enteric nervous system.</P>

Glutathione Protects Brain Endothelial Cells from Hydrogen Peroxide-Induced Oxidative Stress by Increasing Nrf2 Expression

Song, Juhyun,Kang, So Mang,Lee, Won Taek,Park, Kyung Ah,Lee, Kyoung Min,Lee, Jong Eun The Korean Society for Brain and Neural Science 2014 Experimental Neurobiology Vol.23 No.1

<P>Glutathione (GSH) protects cells against oxidative stress by playing an antioxidant role. Protecting brain endothelial cells under oxidative stress is key to treating cerebrovascular diseases and neurodegenerative diseases including Alzheimer's disease and Huntington's disease. In present study, we investigated the protective effect of GSH on brain endothelial cells against hydrogen peroxide (H<SUB>2</SUB>O<SUB>2</SUB>). We showed that GSH attenuates H<SUB>2</SUB>O<SUB>2</SUB>-induced production of nitric oxide (NO), reactive oxygen species (ROS), and 8-Oxo-2'-deoxyguanosine (8-OHdG), an oxidized form of deoxiguanosine. GSH also prevents H<SUB>2</SUB>O<SUB>2</SUB>-induced reduction of tight junction proteins. Finally, GSH increases the level of nuclear factor erythroid 2-related factor 2 (Nrf2) and activates Nrf2-mediated signaling pathways. Thus, GSH is a promising target to protect brain endothelial cells in conditions of brain injury and disease.</P>

The Unreliability of MTT Assay in the Cytotoxic Test of Primary Cultured Glioblastoma Cells

Jo, Hwa Yeon,Kim, Yona,Park, Hyung Woo,Moon, Hyo Eun,Bae, Seongtae,Kim, JinWook,Kim, Dong Gyu,Paek, Sun Ha The Korean Society for Brain and Neural Science 2015 Experimental Neurobiology Vol.24 No.3

<P>MTT assay is commonly used to assess the cellular cytotoxicity caused by anticancer drugs in glioblastomas. However, there have been some reports insisting that MTT assay exhibited non-specific intracellular reduction of tetrazolium which led to underestimated results of cytotoxicity. Here, we examine whether or not MTT assay can lead to incorrect information regarding alcohol-induced cytotoxicity on immortalized and primary glioblastoma cells. MTT assay was applied to assess the ethanol-induced cytotoxicity at various ethanol concentrations. The cellular cytotoxicity induced by different doses of ethanol was analyzed and compared through several cytotoxic assays. Ethanol-induced cytotoxicity observed through MTT assay on both cell types was shown to be ethanol dose-dependent below a 3% concentration. However, the cytotoxicity was shown to be markedly underestimated only in primary cells at a 5% concentration. RT-PCR and Western Blot showed increased expressions of pro-apoptotic proteins and decreased expressions of anti-apoptotic proteins in an ethanol dose-dependent manner in both cell types. Furthermore, we present a possible mechanism for the unreliable result of MTT assay. A high concentration of ethanol induces more severe membrane damage and increased intracellular concentration of NADH in primary cells which enhances the nonspecific reduction of tetrazolium salt. Together, our findings demonstrate that the cytotoxicity on primary cells could inaccurately be assessed when detected through MTT assay. Therefore, a careful interpretation is needed when one would analyze the cytotoxic results of MTT assay, and it is suggested that other assays must be accompanied to produce more reliable and accurate cytotoxic results on primary glioblastoma cells.</P>