Differential Levels and Phosphorylation of Type 1 Inositol 1,4,5-Trisphosphate Receptor in Four Different Murine Models of Huntington Disease.

Background: The intracellular ion channel type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) releases Ca2+ from the endoplasmic reticulum upon stimulation with IP3. Perturbation of IP3R1 has been implicated in the development of several neurodegenerative disorders, including Huntington disease (HD).

Objective: To elucidate the putative role of IP3R1 phosphorylation in HD, we investigated IP3R1 levels and protein phosphorylation state in the striatum, hippocampus and cerebellum of four murine HD models.

Presynaptic increase in IP receptor type 1 concentration in the early phase of hippocampal synaptic plasticity.

The inositol 1,4,5-trisphosphate receptor (IPR) subtype IPR1 is highly enriched in the brain, including hippocampal neurons. It plays an important function in regulating intracellular calcium concentrations. Residing on the smooth endoplasmic reticulum (sER), the IPR1 mobilizes calcium into the cytosol upon binding the intracellular signaling molecule IP, whose concentration is increased by stimulating certain metabotropic glutamate receptors.

Omega-3 fatty acids regulate plasticity in distinct hippocampal glutamatergic synapses.

Dietary omega-3 fatty acids accumulate and are actively retained in central nervous system membranes, mainly in synapses, dendrites and photoreceptors. Despite this selective enrichment, their impact on synaptic function and plasticity has not been fully determined at the molecular level. In this study, we explored the impact of omega-3 fatty acid deficiency on synaptic function in the hippocampus.

The fungal neurotoxin penitrem A induces the production of reactive oxygen species in human neutrophils at submicromolar concentrations.

Penitrem A is a fungal neurotoxin that recurrently causes intoxication in animals, and occasionally also in humans. We have previously reported that penitrem A induced the production of reactive oxygen species (ROS) in rat cerebellar granule cells, opening for a new mechanism of action for the neurotoxin. The aim of this study was to examine the potential of penitrem A to induce ROS production in isolated human neutrophil granulocytes, and to study possible mechanisms involved.

Low-Chlorinated Non-Dioxin-like Polychlorinated Biphenyls Present in Blood and Breast Milk Induce Higher Levels of Reactive Oxygen Species in Neutrophil Granulocytes than High-Chlorinated Congeners.

Despite their ban several decades ago, polychlorinated biphenyls (PCBs) still pose a health threat to human beings due to their persistent and accumulative nature and continued presence in the environment. Non-dioxin-like (NDL)-PCBs have earlier been found to have effects on the immune system, including human neutrophil granulocytes. The aim of this study was to investigate the differences between ortho-chlorinated NDL-PCBs with a low or high degree of chlorination in their capability to induce the production of reactive oxygen species (ROS) in human neutrophil granulocytes in vitro.

Gender-dependent and genotype-sensitive monoaminergic changes induced by polychlorinated biphenyl 153 in the rat brain.

Polychlorinated biphenyls (PCBs) are present as ortho- and non-ortho-substituted PCBs, with most of the ortho-substituted congeners being neurotoxic. The present study examined effects of the ortho-substituted PCB 153 on dopamine, serotonin and amino acid neurotransmitters in the neostriatum of both male and female Wistar Kyoto (WKY) and spontaneously hypertensive rat (SHR) genotypes. PCB 153 exposure at p8, p14 and p20 had no effects on levels of these transmitters when examined at p55, but led to increased levels of both homovanillic acid and 5-hydroxyindoleacetic acid, the degradation products of dopamine and serotonin, respectively, in all groups except the female SHR.

Behavioral changes following PCB 153 exposure in the spontaneously hypertensive rat - an animal model of Attention-Deficit/Hyperactivity Disorder.

Background: Attention-Deficit/Hyperactivity Disorder (ADHD) is a behavioral disorder affecting 3-5% of children. Although ADHD is highly heritable, environmental factors like exposure during early development to various toxic substances like polychlorinated biphenyls (PCBs) may contribute to the prevalence. PCBs are a group of chemical industrial compounds with adverse effects on neurobiological and cognitive functioning, and may produce behavioral impairments that share significant similarities with ADHD.

Non-dioxin-like PCBs inhibit [(3)H]WIN-35,428 binding to the dopamine transporter: a structure-activity relationship study.

Non-dioxin-like polychlorinated biphenyls (NDL-PCBs) are neurotoxic compounds with known effects at the dopaminergic system in the brain. In a previous study we demonstrated that NDL-PCBs inhibit uptake of dopamine into rat brain synaptosomes, an effect most likely mediated by inhibition of the dopamine transporter (DAT). Here, using the cocaine analogue [(3)H]WIN-35,428 binding assay and synaptosomes, we directly investigate whether NDL-PCBs act via DAT and explore the structure-activity relationship of this effect.

Mechanisms of penitrem-induced cerebellar granule neuron death in vitro: possible involvement of GABAA receptors and oxidative processes.

The fungal neurotoxin penitrem A has previously been found to cause neurological disorders in animals and humans after ingestion of contaminated food and/or feed. It penetrates the blood-brain-barrier and causes cerebellar pathology in rats, including mild effects on granule neurons. The aim of the current study was to investigate the potential toxicity of penitrem A in rat cerebellar granule neurons in vitro, and to examine the involvement of the GABAA, AMPA and NMDA receptors, intracellular signalling pathways as well as the role of oxidative stress in penitrem A-induced neuronal death.

Marine Ο-3 polyunsaturated fatty acids induce sex-specific changes in reinforcer-controlled behaviour and neurotransmitter metabolism in a spontaneously hypertensive rat model of ADHD.

Background: Previous reports suggest that omega-3 (n-3) polyunsaturated fatty acids (PUFA) supplements may reduce ADHD-like behaviour. Our aim was to investigate potential effects of n-3 PUFA supplementation in an animal model of ADHD.

Methods: We used spontaneously hypertensive rats (SHR).

Plasma Norepinephrine in Hypertensive Rats Reflects α(2)-Adrenoceptor Release Control Only When Re-Uptake is Inhibited.

Unlabelled: α(2)-adrenoceptors (AR) lower central sympathetic output and peripheral catecholamine release, thereby protecting against sympathetic hyperactivity and hypertension. Norepinephrine re-uptake-transporter effectively (NET) removes norepinephrine from the synapse. Overflow to plasma will therefore not reflect release.

Synapsins I and II are not required for insulin secretion from mouse pancreatic β-cells.

Synapsins are a family of phosphoproteins that modulate the release of neurotransmitters from synaptic vesicles. The release of insulin from pancreatic β-cells has also been suggested to be regulated by synapsins. In this study, we have utilized a knock out mouse model with general disruptions of the synapsin I and II genes [synapsin double knockout (DKO)].

Neuroethologically delineated differences in the seizure behavior of synapsin 1 and synapsin 2 knock-out mice.

The highly homologous nerve terminal phosphoproteins synapsin I and synapsin II have been linked to the pathogenesis of epilepsy through associations between synapsin gene mutations and epileptic disease in humans and to the observation of handling induced seizures in mice genetically depleted of one or both of these proteins. Whereas seizure behavior in mice lacking both synapsin I and synapsin II is well characterized, the seizure behavior in mice lacking either is less well studied. Through so called neuroethologically based analyses of fully established seizure behavior in Synapsin 1 and 2 knock-out mice (Syn1KO and Syn2KO mice) aged 4 1/2 months, this study reveals significant differences in the seizure behavior of the two genotypes: whereas Syn1KO mice show both partial and generalized forebrain seizure activity, Syn2KO mice show only fully generalized forebrain seizures.

In vitro neuropharmacological evaluation of penitrem-induced tremorgenic syndromes: importance of the GABAergic system.

The effects of the fungal neurotoxin penitrem A on the GABAergic and glutamatergic systems in rat brain were evaluated. Penitrem A inhibited binding of the GABA(A)-receptor ligand [³H]TBOB to rat forebrain and cerebellar membrane preparations with IC₅₀ (half maximal inhibitory concentration) values of 11 and 9 μM, respectively. Furthermore, penitrem A caused a concentration-dependent increase of [³H]flunitrazepam and [³H]muscimol binding in rat forebrain, but not in cerebellar preparations.

Beyond the dopamine receptor: regulation and roles of serine/threonine protein phosphatases.

Dopamine plays an important modulatory role in the central nervous system, helping to control critical aspects of motor function and reward learning. Alteration in normal dopaminergic neurotransmission underlies multiple neurological diseases including schizophrenia, Huntington's disease, and Parkinson's disease. Modulation of dopamine-regulated signaling pathways is also important in the addictive actions of most drugs of abuse.

Glutamatergic neurotransmission in the synapsin I and II double knock-out mouse.

The synaptic vesicle-associated synapsin proteins may participate in synaptic transmission, but their exact functional role(s) here remain(s) uncertain. We here briefly describe the important characteristics of the synapsin proteins, and review recent studies on transgenic mice devoid of the gene products encoded by the synapsin I and II genes, where both neurochemical, cell biological and electrophysiological methods have been employed. We present evidence for synapsin effects on both neurotransmitter synthesis and homeostasis, as well as on synaptic vesicle development and functions.

Decreased α4β2 nicotinic receptor number in the absence of mRNA changes suggests post-transcriptional regulation in the spontaneously hypertensive rat model of ADHD.

The spontaneously hypertensive rat (SHR) is widely used as a model of attention-deficit/hyperactivity disorder (ADHD). Deficits in central nicotinic receptors (nAChRs) have been previously observed in SHRs, which is interesting since epidemiological studies have identified an association between smoking and ADHD symptoms in humans. Here, we examine whether nAChR deficits in SHRs compared with Wistar Kyoto rat (WKY) controls are nAChR subtype-specific and whether these deficits correlate with changes at the level of mRNA transcription in specific brain regions.

Postnatal exposure to PCB 153 and PCB 180, but not to PCB 52, produces changes in activity level and stimulus control in outbred male Wistar Kyoto rats.

Background: Polychlorinated biphenyls (PCBs) are a class of organic compounds that bioaccumulate due to their chemical stability and lipophilic properties. Humans are prenatally exposed via trans-placental transfer, through breast milk as infants, and through fish, seafood and fatty foods as adolescents and adults. Exposure has several reported effects ranging from developmental abnormalities to cognitive and motor deficiencies.

Methylphenidate normalizes elevated dopamine transporter densities in an animal model of the attention-deficit/hyperactivity disorder combined type, but not to the same extent in one of the attention-deficit/hyperactivity disorder inattentive type.

The spontaneously hypertensive rat (SHR/NCrl) is a validated model of attention-deficit/hyperactivity disorder (ADHD) combined subtype, whereas a recently identified substrain of the Wistar Kyoto rat (WKY/NCrl) is a model of ADHD inattentive subtype. In this study, we first examined the expression of genes involved in dopamine signaling and metabolism in the dorsal striatum and ventral mesencephalon of these two rat strains, as well as three reference control strains (WKY/NHsd, WK/HanTac, and SD/NTac) using quantitative real time RT-PCR. Next, striatal dopamine transporter (DAT) density was determined by ligand binding assay in the two ADHD-like strains at different developmental stages and after methylphenidate treatment.

Synapsin-dependent vesicle recruitment modulated by forskolin, phorbol ester and ca in mouse excitatory hippocampal synapses.

Repeated release of transmitter from presynaptic elements depends on stimulus-induced Ca(2+) influx together with recruitment and priming of synaptic vesicles from different vesicle pools. We have compared three different manipulations of synaptic strength, all of which are known to increase short-term synaptic efficacy through presynaptic mechanisms, in the glutamatergic CA3-to-CA1 stratum radiatum synapse in the mouse hippocampal slice preparation. Synaptic responses elicited from the readily releasable vesicle pool during low-frequency synaptic activation (0.

The spontaneously hypertensive rat model of ADHD--the importance of selecting the appropriate reference strain.

Although several molecular and genetic manipulations may produce hyperactive animals, hyperactivity alone is insufficient for the animal to qualify as a model of ADHD. Based on a wider range of criteria - behavioral, genetic and neurobiological - the spontaneously hypertensive rat (SHR) obtained from Charles River, Germany (SHR/NCrl) at present constitutes the best validated animal model of ADHD combined subtype (ADHD-C), and the Wistar Kyoto substrain obtained from Harlan, UK (WKY/NHsd) is its most appropriate control. Although other rat strains may behave like WKY/NHsd rats, genetic results indicate significant differences when compared to the WKY/NHsd substrain, making them less suitable controls for the SHR/NCrl.

The importance of synapsin I and II for neurotransmitter levels and vesicular storage in cholinergic, glutamatergic and GABAergic nerve terminals.

The aim of this study was to examine the importance of the vesicle-associated synapsin I and II phosphoproteins for the accumulation of neurotransmitters in central cholinergic as compared to central glutamatergic and GABAergic nerve terminals. In brain homogenate samples from mice devoid of synapsin I and II, the levels of vesicular transporters for glutamate (VGLUT1-2) and GABA (VGAT) were decreased by 35-40% in striatum and cortex, while no change was apparent for the vesicular acetylcholine transporter (VAChT). The severe decrease in the levels of amino acid vesicular transporters caused only minor changes in the concentrations of the respective neurotransmitters in homogenates of the three selected brain areas from synapsin I- and II-deficient mice.

Synapsin-dependent development of glutamatergic synaptic vesicles and presynaptic plasticity in postnatal mouse brain.

Inactivation of the genes encoding the neuronal, synaptic vesicle-associated proteins synapsin I and II leads to severe reductions in the number of synaptic vesicles in the CNS. We here define the postnatal developmental period during which the synapsin I and/or II proteins modulate synaptic vesicle number and function in excitatory glutamatergic synapses in mouse brain. In wild-type mice, brain levels of both synapsin I and synapsin IIb showed developmental increases during synaptogenesis from postnatal days 5-20, while synapsin IIa showed a protracted increase during postnatal days 20-30.

Synapsin- and actin-dependent frequency enhancement in mouse hippocampal mossy fiber synapses.

The synapsin proteins have different roles in excitatory and inhibitory synaptic terminals. We demonstrate a differential role between types of excitatory terminals. Structural and functional aspects of the hippocampal mossy fiber (MF) synapses were studied in wild-type (WT) mice and in synapsin double-knockout mice (DKO).

Distinct changes in neuronal and astrocytic amino acid neurotransmitter metabolism in mice with reduced numbers of synaptic vesicles.

The relations between glutamate and GABA concentrations and synaptic vesicle density in nerve terminals were examined in an animal model with 40-50% reduction in synaptic vesicle numbers caused by inactivation of the genes encoding synapsin I and II. Concentrations and synthesis of amino acids were measured in extracts from cerebrum and a crude synaptosomal fraction by HPLC and (13)C nuclear magnetic resonance spectroscopy (NMRS), respectively. Analysis of cerebrum extracts, comprising both neurotransmitter and metabolic pools, showed decreased concentration of GABA, increased concentration of glutamine and unchanged concentration of glutamate in synapsin I and II double knockout (DKO) mice.