Genetic Pharmacotherapy

Gellman, Celia; Mingote, Susana; Wang, Yvonne; Gaisler‐Salomon, Inna; Rayport, Stephen

doi:10.5772/29478

Cited by 3 publications

(4 citation statements)

References 83 publications

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“…Genetic intervention to achieve a pharmacological response, which we term Genetic Pharmacotherapy (Gellman et al, 2011 ), has been used widely outside the nervous system to modulate pathogenic pathways and demonstrate therapeutic efficacy, particularly in cancer research (Ruzankina et al, 2007 ; Ventura et al, 2007 ; Higashi et al, 2009 ; Herranz et al, 2015 ), but has not been used previously for CNS disorders. The present study highlights the advantages of the approach for neuropsychiatric drug development.…”

Section: Discussionmentioning

confidence: 99%

“…Genetic pharmacotherapy—the use of genetic intervention to achieve a pharmacological effect—has been proposed as an early drug development strategy for the identification of novel CNS targets in mouse models prior to the development of specific ligands (Gellman et al, 2011 ). This strategy offers particular advantages for proof-of-concept studies for CNS disorders.…”

Section: Introductionmentioning

confidence: 99%

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Genetic Pharmacotherapy as an Early CNS Drug Development Strategy: Testing Glutaminase Inhibition for Schizophrenia Treatment in Adult Mice

Mingote

Masson

Gellman

et al. 2016

Front. Syst. Neurosci.

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Genetic pharmacotherapy is an early drug development strategy for the identification of novel CNS targets in mouse models prior to the development of specific ligands. Here for the first time, we have implemented this strategy to address the potential therapeutic value of a glutamate-based pharmacotherapy for schizophrenia involving inhibition of the glutamate recycling enzyme phosphate-activated glutaminase. Mice constitutively heterozygous for GLS1, the gene encoding glutaminase, manifest a schizophrenia resilience phenotype, a key dimension of which is an attenuated locomotor response to propsychotic amphetamine challenge. If resilience is due to glutaminase deficiency in adulthood, then glutaminase inhibitors should have therapeutic potential. However, this has been difficult to test given the dearth of neuroactive glutaminase inhibitors. So, we used genetic pharmacotherapy to ask whether adult induction of GLS1 heterozygosity would attenuate amphetamine responsiveness. We generated conditional floxGLS1 mice and crossed them with global CAGERT2cre∕+ mice to produce GLS1 iHET mice, susceptible to tamoxifen induction of GLS1 heterozygosity. One month after tamoxifen treatment of adult GLS1 iHET mice, we found a 50% reduction in GLS1 allelic abundance and glutaminase mRNA levels in the brain. While GLS1 iHET mice showed some recombination prior to tamoxifen, there was no impact on mRNA levels. We then asked whether induction of GLS heterozygosity would attenuate the locomotor response to propsychotic amphetamine challenge. Before tamoxifen, control and GLS1 iHET mice did not differ in their response to amphetamine. One month after tamoxifen treatment, amphetamine-induced hyperlocomotion was blocked in GLS1 iHET mice. The block was largely maintained after 5 months. Thus, a genetically induced glutaminase reduction—mimicking pharmacological inhibition—strongly attenuated the response to a propsychotic challenge, suggesting that glutaminase may be a novel target for the pharmacotherapy of schizophrenia. These results demonstrate how genetic pharmacotherapy can be implemented to test a CNS target in advance of the development of specific neuroactive inhibitors. We discuss further the advantages, limitations, and feasibility of the wider application of genetic pharmacotherapy for neuropsychiatric drug development.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic Pharmacotherapy as an Early CNS Drug Development Strategy: Testing Glutaminase Inhibition for Schizophrenia Treatment in Adult Mice

Mingote

Masson

Gellman

et al. 2016

Front. Syst. Neurosci.

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“…One such approach is Genetic Pharmacotherapy, which is defined as the use of genetic interventions in mouse models to elucidate potential drug targets prior to the development of specific ligands ( Gellman et al, 2011 ). This strategy enables the evaluation of therapeutic potential for target gene modification without costly and time-consuming development of specific ligands that may lack regional specificity and face issues regarding blood-brain barrier permeability.…”

Section: Potential Directions For Circuit-based Pharmacotherapymentioning

confidence: 99%

Dopamine Neurons That Cotransmit Glutamate, From Synapses to Circuits to Behavior

Eskenazi

Malave

Mingote

et al. 2021

Front. Neural Circuits

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Discovered just over 20 years ago, dopamine neurons have the ability to cotransmit both dopamine and glutamate. Yet, the functional roles of dopamine neuron glutamate cotransmission and their implications for therapeutic use are just emerging. This review article encompasses the current body of evidence investigating the functions of dopamine neurons of the ventral midbrain that cotransmit glutamate. Since its discovery in dopamine neuron cultures, further work in vivo confirmed dopamine neuron glutamate cotransmission across species. From there, growing interest has led to research related to neural functioning including roles in synaptic signaling, development, and behavior. Functional connectome mapping reveals robust connections in multiple forebrain regions to various cell types, most notably to cholinergic interneurons in both the medial shell of the nucleus accumbens and the lateral dorsal striatum. Glutamate markers in dopamine neurons reach peak levels during embryonic development and increase in response to various toxins, suggesting dopamine neuron glutamate cotransmission may serve neuroprotective roles. Findings from behavioral analyses reveal prominent roles for dopamine neuron glutamate cotransmission in responses to psychostimulants, in positive valence and cognitive systems and for subtle roles in negative valence systems. Insight into dopamine neuron glutamate cotransmission informs the pathophysiology of neuropsychiatric disorders such as addiction, schizophrenia and Parkinson Disease, with therapeutic implications.

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“…There are precedents for constitutive mutations affecting emotional and cognitive behavior that show phenotypes opposite to the corresponding pharmacological effects in adulthood [149,150], while others have the same effect as the pharmacological treatment [151]. This potential confound can be addressed using a genetic pharmacotherapy approach in which an inducible global deletor mouse is crossed with a mouse bearing a conditional version of the targeted allele to enable induction of the knockdown or KO in adulthood [152]. …”

Section: Expert Commentarymentioning

confidence: 99%

Modeling resilience to schizophrenia in genetically modified mice: a novel approach to drug discovery

Mihali

Subramani²,

Kaunitz³

et al. 2012

Expert Review of Neurotherapeutics

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Complex psychiatric disorders, such as schizophrenia, arise from a combination of genetic, developmental, environmental and social factors. These vulnerabilities can be mitigated by adaptive factors in each of these domains engendering resilience. Modeling resilience in mice using transgenic approaches offers a direct path to intervention, as resilience mutations point directly to therapeutic targets. As prototypes for this approach, we discuss the three mouse models of schizophrenia resilience, all based on modulating glutamatergic synaptic transmission. This motivates the broader development of schizophrenia resilience mouse models independent of specific pathophysiological hypotheses as a strategy for drug discovery. Three guiding validation criteria are presented. A resilience-oriented approach should identify pharmacologically tractable targets and in turn offer new insights into pathophysiological mechanisms.

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Genetic Pharmacotherapy

Cited by 3 publications

References 83 publications

Genetic Pharmacotherapy as an Early CNS Drug Development Strategy: Testing Glutaminase Inhibition for Schizophrenia Treatment in Adult Mice

Genetic Pharmacotherapy as an Early CNS Drug Development Strategy: Testing Glutaminase Inhibition for Schizophrenia Treatment in Adult Mice

Dopamine Neurons That Cotransmit Glutamate, From Synapses to Circuits to Behavior

Modeling resilience to schizophrenia in genetically modified mice: a novel approach to drug discovery

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