This laboratory reported the first virus vector-mediated gene transfer into neurons, and we pioneered a helper virus-free Herpes Simplex Virus (HSV-1) plasmid vector system. More recently, we have developed large vectors to coexpress multiple genes, promoters that support long-term expression in forebrain neurons, and modified HSV-1 vector particles for improved gene transfer and expression. Using this vector system, we have begun to explore gene therapy approaches to specific neurological disorders, and we are studying learning. We authored one of the first reports that used direct gene transfer to neurons to correct a rat model of Parkinson's Disease (PD), by expressing tyrosine hydroxylase (TH). Recently, we showed that coexpression of TH, GTP cyclohydrolase I, aromatic amino acid decarboxylase, and vesicular monoamine transporter-2 supported regulated release of dopamine, high levels of behavioral correction, and long-term expression (~11,000 expressing cells at 6 months). Moreover, we showed that expressing a constitutively active protein kinase C (PKC) in cortical or hippocampal neurons enhanced visual or auditory learning, respectively. In 2 year old rats, expressing this PKC in hippocampal neurons improved spatial learning. Targeted gene transfer to a specific type of neuron is critical for specific gene therapy treatments and neuroscience studies. We targeted gene transfer to nigrostriatal neurons using HSV-1 vector particles that contained chimeric HSV-1 glycoprotein C (gC)-glial cell line-derived neurotrophic factor or gC~brain-derived neurotrophic factor proteins. This study represents the first example of targeted gene transfer to a specific type of neuron in the brain. The goal of this proposal is to systematically develop targeted gene transfer to specific types of neurons, for neural gene therapy and neuroscience. The first specific aim will systematically optimize the parameters that control targeted gene transfer. The second specific aim will develop a general procedure for targeted gene transfer, using antibodies, and develop targeting to specific types of striatal or cortical neurons. The third specific aim will develop a targeting procedure to deliver different genes to paired presynaptic and postsynaptic neurons, that together form a synapse, for studies on synaptic plasticity and learning, and for gene therapy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZRG1-BDCN-A (11))
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Sieber, Beth-Anne
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Harvard University
Schools of Medicine
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Zhang, Guo-Rong; Zhao, Hua; Cook, Nathan et al. (2017) Characteristic and intermingled neocortical circuits encode different visual object discriminations. Behav Brain Res 331:261-275
Zhang, Guo-Rong; Zhao, Hua; Abdul-Muneer, P M et al. (2015) Neurons can be labeled with unique hues by helper virus-free HSV-1 vectors expressing Brainbow. J Neurosci Methods 240:77-88
Zhang, Guo-rong; Zhao, Hua; Cao, Haiyan et al. (2012) Targeted gene transfer of different genes to presynaptic and postsynaptic neocortical neurons connected by a glutamatergic synapse. Brain Res 1473:173-84
Zhang, Guo-Rong; Zhao, Hua; Choi, Eui M et al. (2012) CaMKII, MAPK, and CREB are coactivated in identified neurons in a neocortical circuit required for performing visual shape discriminations. Hippocampus 22:2276-89
Zhang, Guo-Rong; Zhao, Hua; Cao, Haiyan et al. (2012) Overexpression of either lysine-specific demethylase-1 or CLOCK, but not Co-Rest, improves long-term expression from a modified neurofilament promoter, in a helper virus-free HSV-1 vector system. Brain Res 1436:157-67
Zhang, Guo-Rong; Zhao, Hua; Li, Xu et al. (2011) A 16 bp upstream sequence from the rat tyrosine hydroxylase promoter supports long-term expression from a neurofilament promoter, in a helper virus-free HSV-1 vector system. Brain Res 1415:109-18
Cao, Haiyan; Zhang, Guo-rong; Geller, Alfred I (2011) Antibody-mediated targeted gene transfer of helper virus-free HSV-1 vectors to rat neocortical neurons that contain either NMDA receptor 2B or 2A subunits. Brain Res 1415:127-35
Zhang, Guo-rong; Li, Xu; Cao, Haiyan et al. (2011) The vesicular glutamate transporter-1 upstream promoter and first intron each support glutamatergic-specific expression in rat postrhinal cortex. Brain Res 1377:1-12
Zhang, Guo-rong; Cao, Haiyan; Kong, Lingxin et al. (2010) Identified circuit in rat postrhinal cortex encodes essential information for performing specific visual shape discriminations. Proc Natl Acad Sci U S A 107:14478-83
Zhang, Guo-rong; Geller, Alfred I (2010) A helper virus-free HSV-1 vector containing the vesicular glutamate transporter-1 promoter supports expression preferentially in VGLUT1-containing glutamatergic neurons. Brain Res 1331:12-9

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