A tyrosine hydroxylase–neurofilament chimeric promoter enhances long-term expression in rat forebrain neurons from helper virus-free HSV-1 vectors

Zhang, Guorong; Wang, Xiaodan; Yang, Tianzhong; Sun, Minghan; Zhang, Wei; Wang, Yaming; Geller, Alfred I.

doi:10.1016/s0169-328x(00)00197-2

Cited by 51 publications

(207 citation statements)

References 42 publications

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“…Constructions were performed by standard recombinant DNA procedures (Maniatis et al, 1989). (Zhang et al, 2000). The modified neurofilament gene promoter in these vectors was isolated in two steps: addition of 5′ upstream sequences from the rat TH promoter to the mouse neurofilament heavy (NFH) gene promoter enhances long-term expression, and addition of a chicken β-globin insulator (INS) further improves long-term expression (INS-TH-NFH promoter).…”

Section: Hsv-1 Vector Constructionsmentioning

confidence: 99%

“…1B). Control vectors expressed both TH and AADC (2-gene-vector; Sun et al, 2003) or E. coli β-Gal (lacZ-vector; Zhang et al, 2000). All of these vectors contain a modified neurofilament heavy gene promoter (INS-TH-NFH promoter) that supports long-term expression in forebrain neurons (Zhang et al, 2000).…”

Section: Hsv-1 Vectors That Coexpress Multiple Dopamine Biosynthetic mentioning

confidence: 99%

“…Control vectors expressed both TH and AADC (2-gene-vector; Sun et al, 2003) or E. coli β-Gal (lacZ-vector; Zhang et al, 2000). All of these vectors contain a modified neurofilament heavy gene promoter (INS-TH-NFH promoter) that supports long-term expression in forebrain neurons (Zhang et al, 2000). A previously published time course showed that the number of expressing cells in the striatum is relatively stable between 2 weeks and 6 months after gene transfer (time points at 2 weeks, 1 month, and 2, 4, and 6 months; Zhang et al, 2000).…”

Section: Hsv-1 Vectors That Coexpress Multiple Dopamine Biosynthetic mentioning

confidence: 99%

“…All of these vectors contain a modified neurofilament heavy gene promoter (INS-TH-NFH promoter) that supports long-term expression in forebrain neurons (Zhang et al, 2000). A previously published time course showed that the number of expressing cells in the striatum is relatively stable between 2 weeks and 6 months after gene transfer (time points at 2 weeks, 1 month, and 2, 4, and 6 months; Zhang et al, 2000). Expression was observed for 6 months (Zhang et al, 2000) or 8 months (Sun et al, 2003), the longest time points examined in these studies.…”

Section: Hsv-1 Vectors That Coexpress Multiple Dopamine Biosynthetic mentioning

confidence: 99%

“…Limitations of this study included the side effects of this vector system, limited long-term expression, and expression only of TH (Isacson, 1995;Mandel et al, 1998). We subsequently developed a helper virus-free HSV-1 vector system that supports gene transfer with minimal side effects (Fraefel et al, 1996), and a modified neurofilament gene promoter that supports long-term expression in forebrain neurons (Zhang et al, 2000). Using this improved system, we reported (Sun et al, 2003) coexpression of TH and AADC for 8 months, and correction of the rat model of PD for 5 weeks.…”

Section: Introductionmentioning

confidence: 99%

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Coexpression of Tyrosine Hydroxylase, GTP Cyclohydrolase I, Aromatic Amino Acid Decarboxylase, and Vesicular Monoamine Transporter 2 from a Helper Virus-Free Herpes Simplex Virus Type 1 Vector Supports High-Level, Long-Term Biochemical and Behavioral Correction of a Rat Model of Parkinson's Disease

Sun¹,

Kong²,

Wang³

et al. 2004

Human Gene Therapy

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Parkinson's disease is due to the selective loss of nigrostriatal dopaminergic neurons. Consequently, many therapeutic strategies have focused on restoring striatal dopamine levels, including direct gene transfer to striatal cells, using viral vectors that express specific dopamine biosynthetic enzymes. The central hypothesis of this study is that coexpression of four dopamine biosynthetic and transporter genes in striatal neurons can support the efficient production and regulated, vesicular release of dopamine: tyrosine hydroxylase (TH) converts tyrosine to L-3,4-dihydroxyphenylalanine (L -DOPA), GTP cyclohydrolase I (GTP CH I) is the rate-limiting enzyme in the biosynthesis of the cofactor for TH, aromatic amino acid decarboxylase (AADC) converts L -DOPA to dopamine, and a vesicular monoamine transporter (VMAT-2) transports dopamine into synaptic vesicles, thereby supporting regulated, vesicular release of dopamine and relieving feedback inhibition of TH by dopamine. Helper virus-free herpes simplex virus type 1 vectors that coexpress the three dopamine biosynthetic enzymes (TH, GTP CH I, and AADC; 3-gene-vector) or these three dopamine biosynthetic enzymes and the vesicular monoamine transporter (TH, GTP CH I, AADC, and VMAT-2; 4-gene-vector) were compared. Both vectors supported production of dopamine in cultured fibroblasts. These vectors were microinjected into the striatum of 6-hydroxydopamine-lesioned rats. These vectors carry a modified neurofilament gene promoter, and γ-aminobutyric acid (GABA)-ergic neuronspecific gene expression was maintained for 14 months after gene transfer. The 4-gene-vector supported higher levels of correction of apomorphine-induced rotational behavior than did the 3-gene-vector, and this correction was maintained for 6 months. Proximal to the injection sites, the 4-gene-vector, but not the 3-gene-vector, supported extracellular levels of dopamine and dihydroxyphenylacetic acid (DOPAC) that were similar to those observed in normal rats, and only the 4-gene-vector supported significant K + -dependent release of dopamine. OVERVIEW SUMMARY

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Section: Hsv-1 Vector Constructionsmentioning

confidence: 99%

Section: Hsv-1 Vectors That Coexpress Multiple Dopamine Biosynthetic mentioning

confidence: 99%

Section: Hsv-1 Vectors That Coexpress Multiple Dopamine Biosynthetic mentioning

confidence: 99%

Section: Hsv-1 Vectors That Coexpress Multiple Dopamine Biosynthetic mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Coexpression of Tyrosine Hydroxylase, GTP Cyclohydrolase I, Aromatic Amino Acid Decarboxylase, and Vesicular Monoamine Transporter 2 from a Helper Virus-Free Herpes Simplex Virus Type 1 Vector Supports High-Level, Long-Term Biochemical and Behavioral Correction of a Rat Model of Parkinson's Disease

Sun¹,

Kong²,

Wang³

et al. 2004

Human Gene Therapy

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Improved spatial learning in aged rats by genetic activation of protein kinase C in small groups of hippocampal neurons

Zhang¹,

Li²,

Kong³

et al. 2008

Hippocampus

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Age-related declines in human cognition are well known, and there are correlative changes in the function of neocortical and hippocampal neurons. Similarly, age-related declines in learning have been observed in rodents, including deficits in a hippocampal-dependent learning paradigm, the Morris water maze. Furthermore, there are correlative deficits in specific signaling pathways, including protein kinase C (PKC) pathways, in cerebellar, hippocampal, or neocortical neurons. PKC pathways are strong candidates for mediating the molecular changes that underlie spatial learning, as they play critical roles in neurotransmitter release and synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), and deletion of specific PKC genes results in deficits in learning. Conversely, genetic activation of PKC pathways in small groups of hippocampal or cortical neurons enhances learning in specific paradigms. In this study, we delivered a constitutively active PKC into small groups of hippocampal dentate granule neurons in aged rats (using a Herpes Simplex Virus-1 vector). Aged two-year old rats that received the constitutively active PKC displayed improved performance in the Morris water maze relative to controls in three different measures. These results indicate that PKC pathways play an important role in mediating spatial learning in aged rats. Additionally, these results represent a system for studying the neural mechanisms underlying aging-related learning deficits, and potentially developing gene therapies for cognitive and age-related deficits.

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CaMKII, MAPK, and CREB are coactivated in identified neurons in a neocortical circuit required for performing visual shape discriminations

et al. 2012

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Current theories postulate that the essential information for specific cognitive tasks is widely dispersed in multiple forebrain areas. Nonetheless, synaptic plasticity and neural network theories hypothesize that activation of specific signaling pathways, in specific neurons, modifies synaptic strengths, thereby encoding essential information for performance in localized circuits. Consistent with these latter theories, we have shown that gene transfer of a constitutively active protein kinase C into several hundred glutamatergic and GABAergic neurons in rat postrhinal cortex enhances choice accuracy in visual shape discriminations, and the genetically‐modified circuit encodes some of the essential information for performance. However, little is known about the role of specific signaling pathways required for learning, in specific neurons within a critical circuit. Here we show that three learning‐associated signaling pathways are coactivated in the transduced neurons during both learning and performance. After gene transfer, but before learning a new discrimination, the calcium/calmodulin‐dependent protein kinase (CaMKII), MAP kinase, and CREB pathways were inactive. During learning, these three pathways were coactivated in the transduced neurons. During later performance of the discrimination, CaMKII activity declined, but MAP kinase and CREB activity persisted. Because the transduced neurons are part of a circuit that encodes essential information for performance, activation of these learning‐associated signaling pathways, in these identified neurons, is likely important for both learning and performance. © 2012 Wiley Periodicals, Inc.

show abstract

A tyrosine hydroxylase–neurofilament chimeric promoter enhances long-term expression in rat forebrain neurons from helper virus-free HSV-1 vectors

Cited by 51 publications

References 42 publications

Coexpression of Tyrosine Hydroxylase, GTP Cyclohydrolase I, Aromatic Amino Acid Decarboxylase, and Vesicular Monoamine Transporter 2 from a Helper Virus-Free Herpes Simplex Virus Type 1 Vector Supports High-Level, Long-Term Biochemical and Behavioral Correction of a Rat Model of Parkinson's Disease

Coexpression of Tyrosine Hydroxylase, GTP Cyclohydrolase I, Aromatic Amino Acid Decarboxylase, and Vesicular Monoamine Transporter 2 from a Helper Virus-Free Herpes Simplex Virus Type 1 Vector Supports High-Level, Long-Term Biochemical and Behavioral Correction of a Rat Model of Parkinson's Disease

Improved spatial learning in aged rats by genetic activation of protein kinase C in small groups of hippocampal neurons

CaMKII, MAPK, and CREB are coactivated in identified neurons in a neocortical circuit required for performing visual shape discriminations

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