Tau: More than a microtubule-binding protein in neurons.

Tau protein was discovered as a microtubule-associated protein nearly 50 years ago, and our understanding of tau has revolved around that role. Even with tau's rise to stardom as a central player in neurodegenerative disease, therapeutic efforts have largely been targeted toward cytoskeletal changes. While some studies hinted toward non-cytoskeletal roles for tau, it is only fairly recently that these ideas have begun to receive considerable attention. Many new binding partners for tau have been identified, including DNA, RNA, RNA-binding proteins, some receptors, and other tau molecules. The diversity of tau binding partners coupled with the discovery of tau other than axonal compartments such as nucleus, dendrites, and synapses have led to the proposal of novel functions for tau in roles such as nuclear stability, cell signaling, transcriptional processing, and protein synthesis. Tau self-assembly in particular has made an impact, leading to the hypothesis that a prion-like function of hyperphosphorylated tau is central to tauopathies. With tau emerging as a multifaceted protein that operates in many parts of the cell and with many molecular partners, the field of tau biology is primed for discoveries that can provide new perspectives on both the unique biochemistry of tau and the nature of devastating neurological diseases.

Electrophysiological Evidence for Anti-epileptic Property of Taurine.

Taurine, 2-aminoethanesulfonic acid, is one of the most abundant free amino acids especially in excitable tissues, with wide physiological actions. Several lines of evidence suggest that taurine may function as a potent inhibitory neuromodulator that regulate neuronal activity in many cerebral areas. Parenteral injection of kainic acid (KA), a glutamate receptor agonist, causes severe and stereotyped behavioral convulsions in mice and is used as a rodent model for human temporal lobe epilepsy. In the adult brain, inhibitory GABAergic interneurons modulate the activity of principal excitatory cells via their GABAA receptors and thus adjust excitatory output of neuronal circuits. The goal of this study was to examine the potential anti-convulsive effects of the neuro-active amino acid taurine, in the mouse model of limbic seizures. We used the glutamic acid decarboxylase (GAD) inhibitor isoniazid (100 mg.kg-1, s.c.) which induces seizures by interfering with GABA synthesis through inhibition of GAD activity followed by kainic acid (5 mg.kg-1, s.c.) a glutamate receptor agonist which is commonly used to induce limbic seizures.Using intracerebral recordings of field potentials found that taurine (43 mg.kg-1, s.c.) had a significant anti-epileptic effect when injected prior to isoniazid and KA. Furthermore, injection of taurine to a mouse undergoing limbic seizure completely stopped burst population spikes and restored neuronal firing to its baseline. Therefore, taurine is potentially capable of treating seizure-associated brain damage.

In Vivo Sex-Dependent Effects of Perinatal Pb2+ Exposure on Pilocarpine-Induced Seizure Susceptibility and Taurine Neuropharmacology.

Lead (Pb2+) is a developmental neurotoxicant that disrupts the GABA-shift and subsequently causes alterations in the brain's excitation-to-inhibition (E/I) balance. This finding suggests that neurodevelopmental Pb2+ exposures may increase the risk of brain excitability and/or seizure susceptibility. Prior studies have suggested that neurodevelopmental Pb2+ exposures may cause excitotoxicity of cholinergic neurons, but little to no research has further investigated these potential relationships. The present study sought to evaluate the potential for perinatal neurodevelopmental Pb2+ exposures of 150 ppm and 1000 ppm on pilocarpine-induced seizures through the M1 receptor. The study also evaluated the potential for sex- and treatment-dependent differences in brain excitability. The study revealed that Control females have elevated cholinergic brain excitability and decreased GABAergic inhibition in response to pilocarpine-induced seizures. At low Pb2+ exposures, males exhibited more cholinergic brain excitability, whereas at higher Pb2+ exposures, females exhibited more cholinergic brain excitability. Further, taurine was able to provide neuroprotection against pilocarpine-induced seizures in males, whereas females did not reveal such observations. Thus, the present study adds new insights into the potential for cholinergic seizure susceptibility as a function of sex and the dosage ofneurodevelopmental Pb2+ exposure and how taurine may provide selective pharmacodynamics to treat or recover cholinergic system aberrations induced by neurotoxicants.

Pathological Human Tau Induces Alterations in the Brain Insulin Signaling Cascade.

The process of neurodegeneration in Alzheimer's disease has been associated with a disruption of insulin signaling cascade in neurons, and to insulin resistance. T2DM correlates with Alzheimer's disease, but mechanisms of interaction are unknown. We have developed a mouse model of tau induced neurodegeneration expressing pseudo-phosphorylated tau [Pathological Human Tau (PH-Tau)] in neurons. This model (PH-Tau-Tg) recapitulated cognitive decline and neurodegeneration observed in AD. In this study we examined if expression of PH-Tau could affect neuronal excitability and insulin receptor signaling. Neuronal excitability was investigated using intracerebral recordings of extracellular field potentials from prefrontal cortex after insulin and kainic acid (KA) injection. Analysis of baseline recordings indicated an increased excitability of PH-Tau-Tg as evidenced by higher spectrum densities (PSDs) of high frequencies brain waves. Injection of insulin (1IU, s.c) led to a decrease of fast ripples PSDs, more pronounced in PH-Tau-Tg mice than controls. Subsequent injection of kainic acid (KA, 5 mg/kg, s.c) led to significant increase in firing rate, amplitude of extracellular field potentials and PSDs of high frequency brain waves in control mice only. To further investigate the role of insulin in PH-Tau-Tg mice, we subjected mice to a glucose tolerance test. We found that PH-Tau-Tg mice were significantly hyperglycemic prior to glucose injection. Interestingly, the PH-Tau-Tg mice showed a moderate increase at 30 min due to the higher baseline, indicating a low sensitivity of insulin receptor in these mice. This is consistent with increased levels of activated insulin receptors in the brain and the inhibitory effect of insulin on ictal activity post KA injection in PH-Tau-Tg mice. We suggest that these mice have reduced insulin sensitivity (hyperglycemia) and as a compensatory mechanism there is overactivation/expression of insulin receptor in the brain rendering neuronal circuits resistant to seizure induction after injection of insulin. These data indicate that insulin signal transduction pathway is altered in PH-Tau-Tg mice, and that injection of exogenous insulin reduces hypersynchronous bursting activity of field potentials recorded from cortical neuronal circuits. We propose that the appearance of abnormal tau might potentiate the toxic environment by interfering with the insulin signaling cascade in the brain of patients with Alzheimer's disease.

Hyperreflexia and enhanced ripple oscillations in the taurine-deficient mice.

In this study, we examined neuronal excitability and skeletal muscle physiology and histology in homozygous knockout mice lacking cysteine sulfonic acid decarboxylase (CSAD-KO). Neuronal excitability was measured by intracerebral recording from the prefrontal cortex. Skeletal muscle response was measured through stretch reflex in the ankle muscles. Specifically, we measured the muscle tension, amplitude of electromyogram and velocity of muscle response. Stretch reflex responses were evoked using a specialized stretching device designed for mice. The triceps surae muscle was stretched at various speeds ranging from 18 to 18,000° s-1. A transducer recorded the muscle resistance at each velocity and the corresponding EMG. We also measured the same parameter in anesthetized mice. We found that at each velocity, the CSAD-KO mice generated more tension and exhibited higher EMG responses. To evaluate if the enhanced response was due to neuronal excitability or changes in the passive properties of muscles, we anesthetize mice to eliminate the central component of the reflex. Under these conditions, CSAD-KO mice still exhibited an enhanced stretch reflex response, indicating ultrastructural alterations in muscle histology. Consistent with this, we found that sarcomeres from CSAD-KO muscles were shorter and thinner when compared to control sarcomeres. Neuronal excitability was further investigated using intracerebral recordings of brain waves from the prefrontal cortex. We found that extracellular field potentials in CSAD-KO mice were characterized by reduced amplitude of low-frequency brain waves (delta, theta, alpha, beta and gamma) and increased in the high low-frequency brain waves (slow and fast ripples). Increased slow and fast ripple rates serve as a biomarker of epileptogenic brain. We have previously shown that taurine interacts with GABAA receptors and induces biochemical changes in the GABAergic system. We suggest that taurine deficiency leads to alterations in the GABAergic system that contribute to the enhanced stretch reflex in CSAD-KO mice through biochemical mechanisms that involve alterations not only at the spinal level but also at the cortical level.

Neuroinvasion, neurotropic, and neuroinflammatory events of SARS-CoV-2: understanding the neurological manifestations in COVID-19 patients.

Respiratory viruses are opportunistic pathogens that infect the upper respiratory tract in humans and cause severe illnesses, especially in vulnerable populations. Some viruses have neuroinvasive properties and activate the immune response in the brain. These immune events may be neuroprotective or they may cause long-term damage similar to what is seen in some neurodegenerative diseases. The new "Severe Acute Respiratory Syndrome Coronavirus 2" (SARS-CoV-2) is one of the Respiratory viruses causing highly acute lethal pneumonia coronavirus disease 2019 (COVID-19) with clinical similarities to those reported in "Severe Acute Respiratory Syndrome Coronavirus"(SARS-CoV) and the "Middle East Respiratory Syndrome Coronavirus"(MERS-CoV) including neurological manifestation. To examine the possible neurological damage induced by SARS-CoV-2, it is necessary to understand the immune reactions to viral infection in the brain, and their short- and long-term consequences. Considering the similarities between SARS-CoV and SARS-CoV-2, which will be discussed, cooperative homological and phylogenetical studies lead us to question if SARS-CoV-2 can have similar neuroinvasive capacities and neuroinflammatiory events that may lead to the same short- and long-term neuropathologies that SARS-CoV had shown in human and animal models. To explain the neurological manifestation caused by SARS-CoV-2, we will present a literature review of 765 COVID-19 patients, in which 18% had neurological symptoms and complications, including encephalopathy, encephalitis and cerebrovascular pathologies, acute myelitis, and Guillain-Barré syndrome. Clinical studies describe anosmia or partial loss of the sense of smell as the most frequent symptom in COVID19 patients, suggesting that olfactory dysfunction and the initial ultrarapid immune responses could be a prognostic factor.

Normal and Pathological Tau Uptake Mediated by M1/M3 Muscarinic Receptors Promotes Opposite Neuronal Changes.

The microtubule associated protein tau is mainly found in the cell's cytosol but recently it was also shown in the extracellular space. In neurodegenerative diseases, like Alzheimer's disease (AD), pathological tau spreads from neuron to neuron enhancing neurodegeneration. Here, we show that HEK293 cells and neurons in culture uptake extracellular normal and pathological Tau. Muscarinic receptor antagonists atropine and pirenzepine block 80% this uptake. CHO cells do not express these receptors therefore cannot uptake tau, unless transfected with M1 and/or M3 receptor. These results strongly suggest that muscarinic receptors mediate this process. Uptake of normal tau in neurons enhances neuronal process formation but a pseudophosphorylated form of tau (pathological human tau, PH-Tau) disrupts them and accumulates in the somatodendritic compartment. AD hyperphosphorylated tau (AD P-Tau) has similar effects as PH-Tau on cultured neurons. Addition of either PH-Tau or AD P-tau to neuronal cultures induced microglial activation. In conclusion, uptake of extracellular tau is mediated by muscarinic receptors with opposite effects: normal tau stabilizes neurites; whereas pathological tau disrupts this process leading to neurodegeneration.

Role of Taurine in Testicular Function in the Fragile x Mouse.

Fragile X syndrome is an X-linked dominant disorder and the most common cause of inherited mental retardation. It is caused by trinucleotide repeat expansion in the fragile X mental retardation 1 gene (FMR1) at the Xq27.3. The expansion blocks expression of the gene product, Fragile X Mental Retardation Protein (FMRP). The syndrome includes mild to moderate mental retardation and behavioral manifestations such as tactile defensiveness, gaze avoidance, repetitive motor mannerisms, perseverative (repetitive) speech, hyperarousal and it frequently includes seizures. This behavioral phenotype overlaps significantly with autism spectrum disorder. The knockout mice lack normal Fmr1 protein and show macro-orchidism, learning deficits, and hyperactivity. Consequently, this knockout mouse may serve as a valuable tool in the elucidation of the physiological role of FMR1 and the mechanisms involved in macroorchidism, abnormal behavior, abnormalities comparable to those of human fragile X patients. In this study we evaluated the effects of taurine on the testicular physiology to better understand the cellular mechanisms underlying macro-orchidism. We found that there was a significant decrease in the number of Leydig cells in the testis of fragile X mouse. Furthermore, the expression of somatostatin was drastically decreased and differential expression pattern of CDK5 in fragile X mouse testis. In the control testis, CDK is expressed in primary and secondary spermatids whereas in the Fmr1 ko mice CDK 5 is expressed mainly in spermatogonia. Taurine supplementation led to an increase in CDK5 expression in both controls and Ko mice. CDKs (Cyclin-dependent kinases) are a group of serine/threonine protein kinases activated by binding to a regulatory subunit cyclin. Over 20 functionally diverse proteins involved in cytoskeleton dynamics, cell adhesion, transport, and membrane trafficking act as CDK5 substrates elucidating the molecular mechanisms of CDK5 function. CDK5 phosphorylates a diverse list of substrates, implicating it in the regulation of a range of cellular processes. CDK5 is expressed in Leydig cells, Sertoli cells, spermatogonia and peritubular cells indicating a role in spermatogenesis. In this study we examined the expression levels of CDK5 and how it is affected by taurine supplementation in the testes and found that taurine plays an important role in testicular physiology and corrected some of the pathophysiology observed in the fragile x mouse testis.

Taurine Regulation of Peripheral Hemodynamics.

Taurine plays an important role in the modulation of cardiovascular function by acting not only within the brain but also within peripheral tissues. We found that IV injection of taurine to male rats caused hypotension and tachycardia. A single injection of taurine significantly lowered the systolic, diastolic and mean arterial pressure blood pressure in freely moving long Evans control rats. Previousely, we found that the endothelial cells express high levels of taurine transporters and GABAA receptors and showed that taurine activates GABAA receptors. Thus we suggest that the functional implication of GABAA receptors activation is the relaxation of the arterial muscularis, vasodilation and a decrease in blood pressure. Interestingly however, the effects of acute taurine injection were very different that chronic supplementation of taurine. When rats were supplemented taurine (0.05%, 4 weeks) in their drinking water, taurine has significant hypertensive properties. The increase in blood pressure was observed however only in females, males supplemented with taurine did not show an increase in systolic, diastolic or mean arterial pressure. In both genders however, taurine supplementation caused a significant tachycardia. Thus, we suggest that acute administration of taurine may be beneficial to lowering blood pressure. However, our data indicate that supplementation of taurine to females caused a significant increase in blood pressure. It remains to be seen the effect of taurine supplementation on hypertensive rats.

Taurine Enhances Stretch Reflex Excitability.

The purpose of this study was to characterize the effects of taurine (supplementation and acute injection) on the stretch reflex in the ankle muscles, and in particular to compare the effects of chronic taurine supplementation versus acute injection on the muscle tension, amplitude of electromyogram and velocity of muscle response. Stretch reflex responses were evoked using a specialized stretching device designed for mice. The triceps surae muscle of an awake mouse was stretched at various speeds ranging from 500 to 500,000° per second. A transducer recorded the muscle resistance at each velocity and the corresponding EMG. We found that at each velocity, the taurine-fed mice generated more tension and exhibited a higher EMG response. Acute taurine injection did not affect the tension but significantly reduced the EMG. To evaluate if the enhances response was due to neuronal excitability of changes in the passive properties of the muscles, we anesthetize the mice to eliminate the central component of the reflex. Under these conditions, taurine-fed mice still exhibited an enhanced stretch reflex response. We have previously shown that taurine-fed mice have reduced expression of GABAA receptors and other biochemical changes in the GABAergic system that are consistent with hyper-excitability. GABAA receptor is a major component of the inhibitory (GABAergic) system and its reduced expression probably contributes to the enhanced stretch reflex in these mice through biochemical mechanisms that involve alterations not only at the spinal level but also at the cortical level.

Taurine Regulation of Neuroendocrine Function.

Taurine (2-aminoethanesulfonic acid) is a sulfur-containing amino acid. It is one of the most abundant free amino acids in many excitable tissues, including the brain, skeletal and cardiac muscles. Physiological actions of taurine are widespread and include regulation of plasma glucose levels, bile acid conjugation, detoxification, membrane stabilization, blood pressure regulation, osmoregulation, neurotransmission, and modulation of mitochondria function and cellular calcium levels. Taurine plays an important role in modulating glutamate and GABA neurotransmission and prevents excitotoxicity in vitro primarily through modulation of intracellular calcium homeostasis. Taurine supplementation prevents age-dependent decline of cognitive functions. Because of the wide spread actions of taurine, its levels are highly regulated through enzymatic biosynthesis or dietary intake. Furthermore, depletion of endogenous or dietary supplementation of exogenous taurine have been shown to induce wide spread actions on multiple organs. Cysteine sulfonic acid decarboxylase (CSAD) was first identified in the liver and is thought to be the rate-limiting enzyme in taurine biosynthesis. CSAD mRNA is expressed in the brain in astrocytes. Homozygous knockout mice lacking CSAD (CSAD-KO) have very reduced taurine content and show severe functional histopathology in the visual system, skeletal system, heart, pancreas and brain. Conversely, dietary supplementation of taurine results in significant health benefits acting through the same organ systems. Fluctuation of taurine bioavailability lead to changes in the expression levels of taurine transporters in neuronal plasma membranes, endothelial cells forming the blood-brain barrier and proximal cells of the kidneys. Suggesting a highly regulated mechanism for maintaining taurine homeostasis and organ systems function. Here we show how alterations in taurine levels directly affect the function of one organ system and through functional interaction and compensatory adaptation; these effects extend to another organ systems with focus on the nervous system.

Perinatal Pb2+ exposure alters the expression of genes related to the neurodevelopmental GABA-shift in postnatal rats.

BACKGROUND: Lead (Pb2+) is an environmental neurotoxicant that disrupts neurodevelopment, communication, and organization through competition with Ca2+ signaling. How perinatal Pb2+ exposure affects Ca2+-related gene regulation remains unclear. However, Ca2+ activates the L-Type voltage sensitive calcium channel ß-3 subunit (Ca-ß3), which autoregulates neuronal excitability and plays a role in the GABA-shift from excitatory-to-inhibitory neurotransmission. METHOD: A total of eight females (n = 4 Control and n = 4 Perinatal) and four males (n = 2 Control and n = 2 Perinatal) rats were used as breeders to serve as Dams and Sires. The Dam's litters each ranged from N = 6-10 pups per litter (M = 8, SD = 2), irrespective of Pb2+ treatment, with a majority of males over females. Since there were more males in each of the litters than females, to best assess and equally control for Pb2+- and litter-effects across all developmental time-points under study, female pups were excluded due to an insufficient sample size availability from the litter's obtained. From the included pup litters, 24 experimentally naïve male Long Evans hooded rat pups (Control N = 12; Pb2+ N = 12) were used in the present study.  Brains were extracted from rat prefrontal cortex (PFC) and hippocampus (HP) at postnatal day (PND) 2, 7, 14 and 22, were homogenized in 1 mL of TRIzol reagent per 100 mg of tissue using a glass-Teflon homogenizer. Post-centrifugation, RNA was extracted with chloroform and precipitated with isopropyl alcohol. RNA samples were then re-suspended in 100 µL of DEPC treated H2O. Next, 10 µg of total RNA was treated with RNase-free DNase (Qiagen) at 37 °C for 1 h and re-purified by a 3:1 phenol/chloroform extraction followed by an ethanol precipitation. From the purified RNA, 1 µg was used in the SYBR GreenER Two-Step qRT-PCR kit (Invitrogen) for first strand cDNA synthesis and the quantitative real-time PCR (qRT-PCR). The effects of perinatal Pb2+ exposure on genes related to early neuronal development and the GABA-shift were evaluated through the expression of: Ca-ß3, GABAAR-ß3, NKCC1, KCC2, and GAD 80, 86, 65, and 67 isoforms. RESULTS: Perinatal Pb2+ exposure significantly altered the GABA-shift neurodevelopmental GOI expression as a function of Pb2+ exposure and age across postnatal development. Dramatic changes were observed with Ca-ß3 expression consistent with a Pb2+ competition with L-type calcium channels. By PND 22, Ca-ß3 mRNA was reduced by 1-fold and 1.5-fold in PFC and HP respectively, relative to controls. All HP GABA-ß3 mRNA levels were particularly vulnerable to Pb2+ at PND 2 and 7, and both PFC and HP were negatively impacted by Pb2+ at PND 22. Additionally, Pb2+ altered both the PFC and HP immature GAD 80/86 mRNA expression particularly at PND 2, whereas mature GAD 65/67 were most significantly affected by Pb2+ at PND 22. CONCLUSIONS: Perinatal Pb2+ exposure disrupts the expression of mRNAs related to the GABA-shift, potentially altering the establishment, organization, and excitability of neural circuits across development. These findings offer new insights into the altered effects Pb2+ has on the GABAergic system preceding what is known regarding Pb2+ insults unto the glutamatergic system.

Taurine Recovery of Learning Deficits Induced by Developmental Pb2+ Exposure.

Lead (Pb2+) is a historically well-documented environmental neurotoxin that produces developmental cognitive learning and memory impairments. These early neurodevelopmental impairments cause increased brain excitability via disruption of Ca2+ mediated signaling during critical periods of synaptogenesis inducing competition with Ica2+ through NMDARs resulting in altered brain development and functioning across the lifespan. Interestingly, Pb2+ has been shown to decrease GABA transport and uptake, decrease spontaneous and depolarization-evoked GABA neurotransmission and lower the expression of glutamic acid decarboxylase (GAD); thereby, limiting excitatory GABAergic influences that regulate early developmental brain excitability and reducing inhibition across mature GABAergic networks. Taurine has been shown to regulate brain excitability in the mature brain through GABAAR mediated inhibition, thereby attenuating improper brain excitability. Mechanistically, taurine is developmentally a potent neuromodulator that acts as a GABAAR agonist and more recently has been reported as a partial agonist for NMDARs through glycine sites. We investigated the effects of developmental Pb2+ exposure on the rat's mature inhibitory cognitive control abilities pharmacologically through anxiety and emotional learning-related behaviors and whether taurine could recover Pb2+ induced neurodevelopmental behavioral deficits later in life. Results showed that Pb2+ increased anxiety symptoms in the open field and hole board test, increased sensitivity to context fear training with cognitive deficits in both acquisition and extinction learning while producing learning deficits and inabilities in acquiring inhibitory learned associations through the acoustic startle response and pre-pulse inhibition (ASR-PPI) test. Interestingly, taurine recovered Pb2+ developmentally induced behavioral deficits in the open field and hole board test evidenced by decreased freezing and increased exploration behaviors and facilitated inhibitory dependent ASR-PPI learning to levels higher than controls. In contrast, Baclofen, a GABABR agonist, dose dependently showed no interaction with Pb2+ effects on ASR-PPI learning. Thus, taurine may work as an important neuromodulator at both GABAARs and NMDARs glycine sites, thereby increasing inhibition, enhancing Ca2+-mediated signaling, and decreasing the altered brain excitability, which impedes learning and memory from early Pb2+ exposure. Taken together our data suggests that GABAAR dependent inhibitory learning is altered by early Pb2+ exposure and taurine was able to recover these Pb2+ induced deficits through neuromodulation of GABAARs and potentially NMDARs later in life. These findings may pave the way for further exploration of taurine as a pharmacotherapy for neurodevelopmental lead poisoning in both animal and clinical models.

Effects of Taurine Supplementation on Neuronal Excitability and Glucose Homeostasis.

In this study we examined the role of chronic taurine supplementation on plasma glucose homeostasis and brain excitability through activation of the insulin receptor. FVB/NJ male mice were supplemented with taurine in drinking water (0.05% w/v) for 4 weeks and subjected to a glucose tolerance test (7.5 mg/kg BW) after 12 h fasting. We found that taurine-fed mice were slightly hypoglycemic prior to glucose injection and showed significantly reduced plasma glucose at 30 and 60 min post-glucose injection when compared to control mice. Previously, we reported that taurine supplementation induces biochemical changes that target the GABAergic system. Those studies show that taurine-fed mice are hyperexcitable, have reduced GABAA receptors expression and increased GAD and somatostatin expression in the brain. In this study, we found that taurine-fed mice had a significant increase in insulin receptor (IR) immuno-reactivity in the pancreas and all brain regions examined. At the mRNA level, we found that the IR showed differential regional expression. Surprisingly, we found that neurons express the gene for insulin and that taurine had a significant role in regulating insulin gene expression. We propose that increased insulin production and secretion in taurine-fed mice cause an increase activation of the central IR and may be partially responsible for the increased neuronal excitability observed in taurine supplemented mice. Furthermore, the high levels of neuronal insulin expression and its regulation by taurine implicates taurine in the regulation of metabolic homeostasis.

Glucose Homeostasis and Retinal Histopathology in CSAD KO Mice.

In this study we examined glucose homeostasis and retinal histology in homozygous knockout mice lacking CSAD (CSAD-KO). Two-month-old male mice were used including wild type (WT), homozygotes with without supplementation of taurine in the drinking water (1% w/v). Mice were sacrificed and the eyes processed for histology and immunohistochemistry. Additional mice were subjected to a glucose tolerance test (7.5 mg/kg BW) after 12 h fasting. We found that CSAD-KO and CSAD-KO treated with taurine were slightly hypoglycemic prior to glucose injection and showed a significantly reduced plasma glucose at 30, 60 and 120 min post-glucose injection, compared to WT. While glucose homeostasis in CSAD-KO was significantly different compared to WT, CSAD-KO supplemented with taurine was without effect. Analysis of retinas by electron microscopy showed that CSAD-KO without taurine supplementation exhibited substantial retinal degeneration. Remaining photoreceptor outer and inner segments were disorganized. Retinal nuclear and synaptic layers were largely absent and there was apparent reorganization of the pigmented epithelial cells. The choroid and sclera were intact. These histological aberrations were largely rectified by taurine supplementation in the drinking water.These data indicate that taurine deficiency alters glucose homeostasis and retinal structure and taurine supplementation improves these retinal abnormalities, but not in hypoglycemia.

Neuroprotective role of taurine during aging.

Aging of the brain is characterized by several neurochemical modifications involving structural proteins, neurotransmitters, neuropeptides and related receptors. Alterations of neurochemical indices of synaptic function are indicators of age-related impairment of central functions, such as locomotion, memory and sensory performances. Several studies demonstrate that ionotropic GABA receptors, glutamate decarboxylase (GAD), and somatostatinergic subpopulations of GABAergic neurons are markedly decreased in experimental animal brains during aging. Additionally, levels of several neuropeptides co-expressed with GAD decrease during aging. Thus, the age-related decline in cognitive functions could be attributable, at least in part, to decrements in GABA inhibitory neurotransmission. In this study, we showed that chronic supplementation of taurine to aged mice significantly ameliorated the age-dependent decline in spatial memory acquisition and retention. We also demonstrated that concomitant with the amelioration in cognitive function, taurine caused significant alterations in the GABAergic and somatostatinergic system. These changes included (1) increased levels of the neurotransmitters GABA and glutamate, (2) increased expression of both isoforms of GAD (65 and 67) and the neuropeptide somatostatin, (3) decreased hippocampal expression of the ß3 subunits of the GABAA receptor, (4) increased expression in the number of somatostatin-positive neurons, (5) increased amplitude and duration of population spikes recorded from CA1 in response to Schaefer collateral stimulation and (6) enhanced paired pulse facilitation in the hippocampus. These specific alterations of the inhibitory system caused by taurine treatment oppose those naturally occurring in the aging brain, suggesting a protective role of taurine in this process. An increased understanding of age-related neurochemical changes in the GABAergic system will be important in elucidating the underpinnings of the functional changes of aging. Taurine supplementation might help forestall the age-related decline in cognitive functions through interaction with the GABAergic system.

Changes in gene expression at inhibitory synapses in response to taurine treatment.

We have previously shown that chronic supplementation of taurine to mice significantly ameliorated the age-dependent decline in memory acquisition and retention. We also showed that concomitant with the amelioration in cognitive function, taurine caused significant alterations in the GABAergic and somatonergic system. These changes include increased levels of the neurotransmitters GABA and glutamate, increased expression of both isoforms of GAD and the neuropeptide somatostatin, decreased hippocampal expression of the beta (ß) 2/3 subunits of the GABA(A) receptor, an increase in the number of somatostatin-positive neurons, and an increase in the amplitude and duration of population spikes recorded from CA1 in response to Schaefer collateral stimulation and enhanced paired pulse facilitation in the hippocampus. These specific alterations of the inhibitory system caused by taurine treatment oppose those naturally induced by aging, suggesting a protective role of taurine in this process. In this study, we further investigated the effects of taurine on gene expression of relevant proteins of the inhibitory synapses using qRT-PCR method and found that taurine affects gene expression of various subunits of the GABA(A) receptors and GAD. Increased understanding the effects of taurine on gene expression will increase our understanding of age-related taurine-mediated neurochemical changes in the GABAergic system and will be important in elucidating the underpinnings of the functional changes of aging. Taurine might help forestall the age-related decline in cognitive functions through interaction with the GABAergic system.