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.

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.

Subunit-specific modulation of [(3)H]MK-801 binding to NMDA receptors mediated by dopamine receptor ligands in rodent brain.

Dopamine D1 receptor (D1R) ligands may directly interact with the NMDA receptor (NMDAR), but detailed knowledge about this effect is lacking. Here we identify D1R ligands that directly modulate NMDARs and examine the contributions of NR2A and NR2B subunits to these interactions. Binding of the open channel blocker [(3)H]MK-801 in membrane preparations from rat- and mouse brain was used as a biochemical measure of the functional state of the NMDAR channel.

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)].

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.

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.

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.

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- 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.

A delayed response enhancement during hippocampal presynaptic plasticity in mice.

High frequency afferent stimulation of chemical synapses often induces short-term increases in synaptic efficacy, due to increased release probability and/or increased supply of readily releasable synaptic vesicles. This may be followed by synaptic depression, often caused by vesicle depletion. We here describe an additional, novel type of delayed and transient response enhancement phase which occurred during prolonged stimulation at 5-20 Hz frequency of excitatory glutamatergic synapses in slices from the adult mouse CA1 hippocampal region.

Synapsin utilization differs among functional classes of synapses on thalamocortical cells.

Several proteins in nerve terminals participate in synaptic transmission between neurons. The synapsins, which are synaptic vesicle-associated proteins, have widespread distribution in the brain and are assumed essential for sustained recruitment of vesicles during high rates of synaptic transmission. We compared the role of synapsins in two types of glutamatergic synapses on thalamocortical cells in the dorsal lateral geniculate nucleus of mice: retinogeniculate synapses, which transmit primary afferent input at high frequencies and show synaptic depression, and corticogeniculate synapses, which provide modulatory feedback at lower frequencies and show synaptic facilitation.

Differential development of vesicular glutamate transporters in brain: an in vitro study of cerebellar granule cells.

The cerebellar granule cells have been extensively used for studies on metabolism, neurotransmission and neurotoxicology, since they can easily be grown in cultures. However, knowledge about the development of different proteins essential for synaptic transmission in these cells is lacking. This study has characterized the developmental profiles of the vesicular glutamate transporters (VGLUTs) and the synaptic vesicle proteins synapsins and synaptophysin in cerebellar granule cells and in co-cultures containing both granule cells and astrocytes.

Absence of synapsin I and II is accompanied by decreases in vesicular transport of specific neurotransmitters.

Studies of synapsin-deficient mice have shown decreases in the number of synaptic vesicles but knowledge about the consequences of this decrease, and which classes of vesicles are being affected, has been lacking. In this study, glutamatergic, GABAergic and dopaminergic transport has been analysed in animals where the genes encoding synapsin I and II were inactivated. The levels of the vesicular glutamate transporter (VGLUT) 1, VGLUT2 and the vesicular GABA transporter (VGAT) were decreased by approximately 40% in adult forebrain from mice devoid of synapsin I and II, while vesicular monoamine transporter (VMAT) 2 and VGLUT3 were present in unchanged amounts compared with wild-type mice.

Effects on cholinergic markers in rat brain and blood after short and prolonged administration of donepezil.

Donepezil is a selective inhibitor of acetylcholinesterase (AChE) clinically used for treating Alzheimer's disease. Cholinergic effects after short-term exposure of donepezil (up to 12 h) have been extensively studied in rats, but few have addressed the potential long-term effects. After 14 days administration (1x3 mg/kg, decapitation 4 h after the last injection) the cerebral acetylcholine level was increased by 35% and the AChE activity was decreased by 66% and 32% in brain and blood, respectively.

Synapsin-regulated synaptic transmission from readily releasable synaptic vesicles in excitatory hippocampal synapses in mice.

The effects of synapsin proteins on synaptic transmission from vesicles in the readily releasable vesicle pool have been examined by comparing excitatory synaptic transmission in hippocampal slices from mice devoid of synapsins I and II and from wild-type control animals. Application of stimulus trains at variable frequencies to the CA3-to-CA1 pyramidal cell synapse suggested that, in both genotypes, synaptic responses obtained within 2 s stimulation originated from readily releasable vesicles. Detailed analysis of the responses during this period indicated that stimulus trains at 2-20 Hz enhanced all early synaptic responses in the CA3-to-CA1 pyramidal cell synapse, but depressed all early responses in the medial perforant path-to-granule cell synapse.

Thyrotrophin-releasing hormone receptor 1 and prothyrotrophin-releasing hormone mRNA expression in the central nervous system are regulated by suckling in lactating rats.

Background: The accepted function of the hypothalamic peptide, thyrotrophin-releasing hormone (TRH), is to initiate release of thyrotrophin (TSH) from the pituitary. A physiological role for TRH in lactating rats has not yet been established.

Methods: Tissues were prepared from random-cycling and lactating rats and analysed using Northern blot, real time RT-PCR and quantitative in situ hybridisation.

Targeting functional subtypes of spinal motoneurons and skeletal muscle fibers in vivo by intramuscular injection of adenoviral and adeno-associated viral vectors.

We report that functional subtypes of spinal motoneurons and skeletal muscle fibers can be selectively transduced using replication-defective adenoviral (ADV) or adeno-associated (AAV) viral vectors. After intramuscular injection in adult rodents, ADV vectors transduced both fast-twitch and slow-twitch skeletal muscle fibers. Intramuscular injection of ADV vectors also caused transduction of spinal motoneurons and dorsal root ganglion cells.