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Matthew J During

Publications and source records attributed to Matthew J During.

At least 37 records · Page 2Linked to original sources
PubMed2004

Homer proteins regulate sensitivity to cocaine.

Drug addiction involves complex interactions between pharmacology and learning in genetically susceptible individuals. Members of the Homer gene family are regulated by acute and chronic cocaine administration. Here, we report that deletion of Homer1 or Homer2 in mice caused the same increase in sensitivity to cocaine-induced locomotion, conditioned reward, and augmented extracellular glutamate in nucleus accumbens as that elicited by withdrawal from repeated cocaine administration. Moreover, adeno-associated virus-mediated restoration of Homer2 in the accumbens of Homer2 KO mice reversed the cocaine-sensitized phenotype. Further analysis of Homer2 KO mice revealed extensive additional behavioral and neurochemical similarities to cocaine-sensitized animals, including accelerated acquisition of cocaine self-administration and altered regulation of glutamate by metabotropic glutamate receptors and cystine/glutamate exchange. These data show that Homer deletion mimics the behavioral and neurochemical phenotype produced by repeated cocaine administration and implicate Homer in regulating addiction to cocaine.

Animals↗
PubMed2004

VEGF links hippocampal activity with neurogenesis, learning and memory.

An enriched environment is associated with hippocampal plasticity, including improved cognitive performance and increased neurogenesis. Here, we show that hippocampal expression of vascular endothelial growth factor (VEGF) is increased by both an enriched environment and performance in a spatial maze. Hippocampal gene transfer of VEGF in adult rats resulted in approximately 2 times more neurogenesis associated with improved cognition. In contrast, overexpression of placental growth factor, which signals through Flt1 but not kinase insert domain protein receptors (KDRs), had negative effects on neurogenesis and inhibited learning, although it similarly increased endothelial cell proliferation. Expression of a dominant-negative mutant KDR inhibited basal neurogenesis and impaired learning. Coexpression of mutant KDR antagonized VEGF-enhanced neurogenesis and learning without inhibiting endothelial cell proliferation. Furthermore, inhibition of VEGF expression by RNA interference completely blocked the environmental induction of neurogenesis. These data support a model in which VEGF, acting through KDR, mediates the effect of the environment on neurogenesis and cognition.

Animals↗
PubMed2004

Restoration of receptor-type protein tyrosine phosphatase eta function inhibits human pancreatic carcinoma cell growth in vitro and in vivo.

DEP-1/HPTPeta, a receptor-type protein tyrosine phosphatase, is a candidate tumor suppressor gene because its expression was blocked in rat and human thyroid transformed cells, and its restoration reverted their neoplastic phenotype. In addition, loss of DEP-1/HPTPeta heterozygosity has been described in mammary, lung and colon primary tumors. We now show that DEP-1/HPTPeta is drastically reduced in several cell lines originating from human epithelial pancreatic carcinomas compared with normal pancreatic tissue. We also show that the infection of AsPC1 and PSN1 cells with a recombinant adenovirus carrying r-PTPeta cDNA (the rat homolog of DEP-1/HPTPeta) inhibits their proliferation. Flow cytometric analysis of the infected cells demonstrated that restoration of r-PTPeta activity disrupts their cell cycle and leads to apoptosis. Finally, the growth of PSN1 xenograft tumors was blocked by the intratumoral injection of a recombinant adeno-associated virus carrying r-PTPeta. The data suggest that restoration of DEP-1/HPTPeta expression could be a useful tool for the gene therapy of human pancreatic cancers.

Animals↗
PubMed2004

Over expression of ATF-3 protects rat hippocampal neurons from in vivo injection of kainic acid.

ATF-3 is a member of the ATF superfamily of transcription factors and is strongly associated with episodes of cellular stress. We demonstrate an association between increases in ATF-3 protein and resistance to exitotoxic cell death in vivo. Intra-hippocampal injection of kainic acid elicited a robust increase in endogenous ATF-3 within kainate-resistant cells of the dentate gyrus, while overexpression of exogenous ATF-3 was found to protect vulnerable CA3 neurons from the same insult. These results suggest a positive contribution to neuronal survival in the context of stress-induced death, and support an anti-apoptotic role for ATF-3 in the brain.

Activating Transcription Factor 3↗
PubMed2004

Anticonvulsant and antiepileptogenic effects mediated by adeno-associated virus vector neuropeptide Y expression in the rat hippocampus.

Neuropeptide Y (NPY) inhibits seizures in experimental models and reduces excitability in human epileptic tissue. We studied the effect of long-lasting NPY overexpression in the rat hippocampus with local application of recombinant adeno-associated viral (AAV) vectors on acute kainate seizures and kindling epileptogenesis. Transgene expression was significantly increased by 7 d, reached maximal expression by 2 weeks, and persisted for at least 3 months. Serotype 2 AAV vector increased NPY expression in hilar interneurons, whereas the chimeric serotype 1/2 vector caused far more widespread expression, also including mossy fibers, pyramidal cells, and the subiculum. EEG seizures induced by intrahippocampal kainate were reduced by 50-75%, depending on the vector serotype, and seizure onset was markedly delayed. In rats injected with the chimeric serotype 1/2 vector, status epilepticus was abolished, and kindling acquisition was significantly delayed. Thus, targeted NPY gene transfer provides a potential therapeutic principle for the treatment of drug-resistant partial epilepsies.

Animals↗
PubMed2004

Gene therapy for Parkinson's disease.

Parkinson's disease (PD) is a debilitating neurodegenerative disorder arising from loss of dopaminergic neurons in the substantia nigra pars compacta and subsequent depletion of striatal dopamine levels, which results in distressing motor symptoms. The current standard pharmacological treatment for PD is direct replacement of dopamine by treatment with its precursor, levodopa (L-dopa). However, this does not significantly alter disease progression and might contribute to the ongoing pathology. Several features of PD make this disease one of the most promising targets for clinical gene therapy of any neurological disease. The confinement of the major pathology to a compact, localised neuronal population and the anatomy of the basal ganglia circuitry mean that global gene transfer is not required and there are well-defined sites for gene transfer. The multifactorial aetiology of idiopathic PD means that it is unlikely any single gene will cure the disease, and as a result at least three separate gene-transfer strategies are currently being pursued: transfer of genes for enzymes involved in dopamine production; transfer of genes for growth factors involved in dopaminergic cell survival and regeneration; and transfer of genes to reset neuronal circuitry by switching cellular phenotype. The merits of these strategies are discussed here, along with remaining hurdles that might impede transfer of gene therapy technology to the clinic as a treatment for PD.

Animals↗
PubMed2004

Brain uptake of the glucagon-like peptide-1 antagonist exendin(9-39) after intranasal administration.

Exendin, a member of the glucagon-like peptide-1 family, and its antagonist exendin(9-39) affect cognition and neuronal survival after their intranasal delivery. Here, we examined the uptake of radioactively labeled exendin(9-39) (I-Ex) by the olfactory bulbs, brain (minus pineal, pituitary, and olfactory bulb), cerebrospinal fluid, and cervical lymph nodes (C-node) as well as levels in serum after intranasal or intravenous administration. We found that olfactory bulb uptake of I-Ex after intranasal administration was rapid, much greater than after i.v. administration, and was enhanced by about 60% with cyclodextrin (CD). I-Ex was also taken up by the remainder of the brain after intranasal administration, but this uptake was not enhanced by CD, nor did it exceed uptake after i.v. administered I-Ex. Uptake by the olfactory bulb was not dependent on Brownian motion but did involve active processes. Intranasal I-Ex reached the C-node by way of the blood. About one-sixth of the intranasal dose of I-Ex entered the blood. However, the vascular route accounted for little of the intranasal I-Ex that reached the brain and even less that reached the olfactory bulb. I-Ex after intranasal administration was found in the hippocampus, cerebellum, brain stem, and cerebrospinal fluid (CSF). Distribution patterns showed that intranasal I-Ex used the extraneuronal route of CSF rather than brain parenchyma to diffuse throughout the brain. These results show that intranasal administration is an effective means of delivering peptide to the brain, especially the olfactory bulb.

Administration, Intranasal↗
PubMed2004

AAV-mediated gene delivery of BDNF or GDNF is neuroprotective in a model of Huntington disease.

Huntington disease (HD) is a neurodegenerative disorder that results in the progressive loss of GABAergic medium spiny projection neurons in the striatum. Neurotrophic factors have demonstrated neuroprotective actions on striatal neurons, suggesting that increased neurotrophic factor expression may prevent or reduce neuronal loss in the HD brain. We investigated whether enhanced expression of brain-derived neurotrophic factor (BDNF) or glial cell line-derived neurotrophic factor (GDNF), achieved by adeno-associated viral (AAV) vector-mediated gene delivery, could protect striatal neurons in the quinolinic acid (QA) rodent model of HD. Adult Wistar rats received unilateral intrastriatal injections of AAV-BDNF, AAV-GDNF, AAV-GFP, or PBS. Three weeks later, the rats were lesioned with QA, a toxin that induces striatal neuron death by an excitotoxic process. Both AAV-BDNF and AAV-GDNF significantly reduced the loss of both NeuN- and calbindin-immunopositive striatal neurons 2 weeks after lesion compared to controls. AAV-BDNF also provided significant neurotrophic support to NOS-immunopositive striatal interneurons, while AAV-GDNF-treated rats demonstrated significant protection of parvalbumin-immunopositive striatal interneurons compared to controls. These results indicate that AAV-mediated gene transfer of BDNF or GDNF into the striatum provides neuronal protection in a rodent model of HD.

Animals↗
PubMed2003

ATF3 enhances c-Jun-mediated neurite sprouting.

The AP-1 transcription factor c-Jun is induced in axotomized neurons of the peripheral and central nervous systems, and in both cases upregulation of c-Jun expression has been correlated with axonal regeneration. More recently there has been interest in the c-Jun-related bZIP transcription factor, ATF3, and its function in neurons. ATF3 is also induced in nerve cells in response to axotomy and there is a correlation between increased ATF3 expression and upregulation of c-Jun in surviving neurons. Moreover, c-Jun is able to induce expression of ATF3. We investigated the effect of co-expressing c-Jun and ATF3 in two neuronal-like cell lines to model transcriptional events occurring in axotomized neurons undergoing regeneration. We show that expression of ATF3 with c-Jun significantly enhances c-Jun-mediated neurite sprouting, and that this phenotype is most likely mediated by a physical association of these two transcription factors. Our results suggest that a program of axonal regeneration is initiated when both c-Jun and ATF3 are upregulated in neurons in response to axotomy.

Activating Transcription Factor 3↗
PubMed2003

Disulfiram facilitates the development and expression of locomotor sensitization to cocaine in rats.

BACKGROUND: Disulfiram (DS; Antabuse) inhibits dopamine-beta-hydroxylase leading to increased brain dopamine levels and shows treatment efficacy for cocaine addiction. Yet few preclinical studies have been performed. This study establishes the effects of DS on locomotor sensitization to cocaine in rats. METHODS: Rats were administered vehicle, cocaine (10 mg/kg; intraperitoneally [IP]), or DS (50 or 100 mg/kg; IP) alone or in combination for 5 days (development phase). Locomotor activity was measured for 60-min each day. After a 10-day drug washout, rats were administered cocaine, and locomotor activity was measured (expression phase). Plasma cocaine levels were assessed in separate groups of rats administered one of two cocaine doses (0 or 10 mg/kg) and one of two DS doses (0 or 100 mg/kg) for 5 days. Ten days later, blood was collected 60-min postcocaine injection. RESULTS: The development of cocaine locomotor sensitization was facilitated by DS even though DS alone had minimal effect on activity levels. Furthermore, expression of sensitization was greatest in rats previously administered DS, an effect that cannot be attributed to altered plasma cocaine levels. CONCLUSIONS: Because DS shows treatment efficacy for cocaine addiction, results from this study suggest potential treatment agents should enhance, not attenuate, locomotor sensitization in rats.

Animals↗
PubMed2003

Molecular mechanisms of learning and memory.

Memory is the process by which organisms are able to record their experiences, and use this information to adapt their responses to the environment. As such, it is vital for survival. In recent years, the development of spatially and temporally selective techniques for the regulation of gene expression has allowed the molecular details of this process to emerge. Here we review the molecular mechanisms thought to underlie memory acquisition and storage, as well as discuss recent evidence regarding the mechanisms of subsequent memory consolidation.

Animals↗
PubMed2003

Identification and distribution of aspartoacylase in the postnatal rat brain.

Aspartoacylase metabolizes N-acetylaspartic acid to produce L-aspartate and acetate. An aspartoacylase deficiency in humans is responsible for Canavan disease, a lethal autosomal recessive leukodystrophy. The role of aspartoacylase in the mammalian brain is unclear. Here we have generated and characterized a highly specific polyclonal antibody against aspartoacylase which recognizes a 37 kDa monomer and a dimer in normal but not in aspartoacylase-deficient rat tissue. Aspartoacylase protein expression sharply increases at P14, peaks at P28 and plateaus thereafter. Biochemical analysis reveals immunoreactivity in cytosolic but not in membrane fractions. Histologically, most abundant expression was observed in white matter tracts and thalamus. On the cellular level, aspartoacylase immunoreactivity is restricted to oligodendrocyte somata in both white and gray matter.

Aging↗
PubMed2003

Glucagon-like peptide-1 receptor is involved in learning and neuroprotection.

Glucagon-like peptide-1 (GLP-1) is a gut peptide that, together with its receptor, GLP-1R, is expressed in the brain. Here we show that intracerebroventricular (i.c.v.) GLP-1 and [Ser(2)]exendin(1-9) (HSEGTFTSD; homologous to a conserved domain in the glucagon/GLP-1 family) enhance associative and spatial learning through GLP-1R. [Ser(2)]exendin(1-9), but not GLP-1, is also active when administered peripherally. GLP-1R-deficient mice have a phenotype characterized by a learning deficit that is restored after hippocampal Glp1r gene transfer. In addition, rats overexpressing GLP-1R in the hippocampus show improved learning and memory. GLP-1R-deficient mice also have enhanced seizure severity and neuronal injury after kainate administration, with an intermediate phenotype in heterozygotes and phenotypic correction after Glp1r gene transfer in hippocampal somatic cells. Systemic administration of [Ser(2)]exendin(1-9) in wild-type animals prevents kainate-induced apoptosis of hippocampal neurons. Brain GLP-1R represents a promising new target for both cognitive-enhancing and neuroprotective agents.

Administration, Intranasal↗
PubMed2003

Viral restoration of dopamine to the nucleus accumbens is sufficient to induce a locomotor response to amphetamine.

Administration of amphetamine to mice evokes hyperlocomotion. Dopamine deficient (DD) mice, in which tyrosine hydroxylase (TH) has been specifically inactivated in dopaminergic neurons, have a blunted response to amphetamine, indicating that the hyperlocomotive response requires dopamine. Dopamine production can be restored to specific brain regions by using adeno-associated viruses expressing TH and GTP cyclohydrolase 1 (GTPCH1). Restoration of dopamine specifically to the nucleus accumbens (NAc) of DD mice completely restores the ability of these mice to respond to amphetamine. This response is specific to the dopamine production in the NAc, as restoration of dopamine production to the caudate putamen (CPu) does not fully restore the hyperlocomotive response to amphetamine. These data support previous studies in which accumbal dopamine is required for producing a normal locomotor response to amphetamine and further show that release of dopamine restricted to the NAc is sufficient for this response

Amphetamine↗
PubMed2003

Regression of upper gastric cancer in mice by FHIT gene delivery.

Fhit expression is reduced in most cancers, and Fhit replacement by FHIT expression viruses in lung, esophageal, pancreatic, and cervical cancers induces apoptosis in the cancer cells. Mice carrying one or two inactivated Fhit alleles are hypersensitive to development of N-nitrosomethylbenzylamine (NMBA)-induced forestomach tumors. In the present study, we investigated the kinetics and mechanism of tumor reversal and intervention by oral delivery of FHIT expression viruses. Tumor analysis showed that: a) by 37 days post-NMBA, control mice showed approximately 7 tumors and by 84 days approximately 10 tumors/forestomach; b) mice receiving FHIT virus at 2 or 42 days post-NMBA showed significantly reduced tumor burdens; c) Fhit was still expressed at 82 days postinfection; d) control viral infection had no effect on tumor development; and e) reduced Bcl2, increased Bax expression, and increased TUNEL-positive apoptotic nuclei characterized the restored epithelia of FHIT transduced forestomachs. Thus, FHIT viral gene delivery prevents or retards development of carcinogen-induced forestomach tumors and reverses development of established tumors by 60-70% through an apoptotic pathway. This dramatic reduction in tumor burden emphasizes the efficacy of targeting the FHIT apoptotic pathway for tumor eradication.

Acid Anhydride Hydrolases↗
PubMed2003

Structural and functional neuroprotection in a rat model of Huntington's disease by viral gene transfer of GDNF.

Huntington's disease (HD) is an autosomal dominant disorder caused by an expanded polyglutamine (CAG) tract at the IT15 locus on chromosome 4. These excessive repeats lead to the degeneration of striatal and cortical neurons resulting in a devastating cognitive, psychiatric, and motor disorder for which no treatments are available. Neurotrophic factors support the viability of striatal neurons suggesting that they might prevent the inevitable neural degeneration and its accompanying functional decline associated with HD. The present study investigated whether glial cell line-derived neurotrophic factor (GDNF) delivered by an adeno associated virus could provide structural and functional neuroprotection in a rat model of HD. Lewis rats received bilateral injections of either AAV-GDNF (n = 12) or AAV-green fluorescence protein (AAV-GFP, n = 12) into the striatum followed 2 weeks later by chronic subcutaneous infusions of the mitochondrial toxin, 3-nitropropionic acid (3-NP, 38 mg/kg). All rats underwent 4 weeks of behavioral testing and were then sacrificed. Following 3-NP, the performance by AAV-GFP-treated rats on a raised platform motor task deteriorated while the performance by AAV-GDNF-treated rats was near normal (P < 0.001). AAV-GDNF-treated rats also received better scores on a blinded semi-quantitative neurological scale compared to rats receiving AAV-GFP (P < 0.001). Histological analyses supported our behavioral findings. 3-NP-treated rats receiving AAV-GDNF displayed 70% more NeuN-immunoreactive neurons compared to 3-NP-treated rats receiving AAV-GFP (P = 0.002). Similar findings were seen with dopamine-and-adenosine-3'5'-monophosphate-regulated phosphoprotein (DARPP-32) staining. These data indicate that the viral-mediated gene transfer of GDNF into the striatum provides neuroanatomical and behavioral protection in a rodent model of HD.

Animals↗
PubMed2003

Molecular investigation of TBP allele length: a SCA17 cellular model and population study.

Recently, an inherited spinocerebellar ataxia (SCA17) has been attributed to polyglutamine coding expansions within the gene coding for human TATA-box binding protein (TBP). The normal repeat range is 25-42 units with patients having as few as 46 repeats. We undertook a TBP repeat length population study showing its relative stability, skewed distribution, and substantial population specific differences. To investigate the mechanism of neurodegeneration in SCA17 we have developed a cellular model expressing full-length TBP with a range of polyQ expansions. As has been found with other polyQ cellular models, insoluble intracellular inclusions form in a repeat-length-dependent manner. In addition, we have shown that the expanded TBP polyQ tract is able to interact with other overexpressed polyQ-containing proteins. Importantly, overexpression of expanded TBP results in increased Cre-dependent transcriptional activity. As TBP is required for transcription by all RNA polymerases, this may indicate a mechanism for aberrant polyQ gain of function.

Animals↗