Jordane Dimidschstein

Broad Institute

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Gord Fishell

Harvard University

Guoping Feng

McGovern Institute for Brain Research

Justin Balsor

University of Utah

Frederick Federer

University of Utah

Alessandra Angelucci

Politecnico di Milano

Qing Xu

New York University

Alexander Ingold

University of Utah

David P. Babcock

University of Utah

Ramesh Chittajallu

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Josselyn Vergara

Broad Institute

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Harvard University

100

Broad Institute

Massachusetts Institute of Technology

National Institutes of Health

New York University

McGovern Institute for Brain Research

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Boston VA Research Institute

Howard Hughes Medical Institute

NYU Langone Health

Author Statistics

Papers

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Alternating sources of perisomatic inhibition during behavior

Neuron (2021)

Barna Dudok Peter Klein Ernie Hwaun Brian Lee Zizhen Yao

Pyramidal cell

Interneuron

10.1016/j.neuron.2021.01.003

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Citations (114)

Reviewer #2 (Public Review): Laminar specificity and coverage of viral-mediated gene expression restricted to GABAergic interneurons and their parvalbumin subclass in marmoset primary visual cortex

Frederick Federer Justin Balsor Alexander Ingold David P. Babcock Jordane Dimidschstein

In the mammalian neocortex, inhibition is important for dynamically balancing excitation and shaping the response properties of cells and circuits. The various functions of inhibition are thought to be mediated by different inhibitory neuron types of which a large diversity exists in several species. Current understanding of the function and connectivity of distinct inhibitory neuron types has mainly derived from studies in transgenic mice. However, it is unknown whether knowledge gained from mouse studies applies to the primate, the model system closest to humans. The lack of viral tools to selectively access inhibitory neuron types has been a major impediment to studying their function in the primate. Here, we have thoroughly validated and characterized several recently-developed viral vectors designed to restrict transgene expression to GABAergic cells or their parvalbumin (PV) subtype, and identified two types that show high specificity and efficiency in marmoset V1. We show that in marmoset V1 AAV-h56D induces transgene expression in GABAergic cells with up to 91-94% specificity and 80% efficiency, depending on viral serotype and cortical layer. AAV-PHP.eB-S5E2 induces transgene expression in PV cells across all cortical layers with up to 98% specificity and 86-90% efficiency. Thus, these viral vectors represent promising tools for studying GABA and PV cell function and connectivity in the primate cortex.

Subclass

10.7554/elife.97673.1.sa1

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Citations (0)

Publisher Correction: Viral manipulation of functionally distinct interneurons in mice, non-human primates and humans

Nature Neuroscience (2022)

Douglas Vormstein-Schneider Jessica D. Lin Kenneth A. Pelkey Ramesh Chittajallu Baolin Guo

10.1038/s41593-022-01155-w

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Citations (1)

A versatile viral toolkit for functional discovery in the nervous system

Cell Reports Methods (2022)

Gabrielle Pouchelon Josselyn Vergara Justin McMahon Bram L. Gorissen Jessica D. Lin

The ability to precisely control transgene expression is essential for basic research and clinical applications. Adeno-associated viruses (AAVs) are non-pathogenic and can be used to drive stable expression in virtually any tissue, cell type, or species, but their limited genomic payload results in a trade-off between the transgenes that can be incorporated and the complexity of the regulatory elements controlling their expression. Resolving these competing imperatives in complex experiments inevitably results in compromises. Here, we assemble an optimized viral toolkit (VTK) that addresses these limitations and allows for efficient combinatorial targeting of cell types. Moreover, their modular design explicitly enables further refinements. We achieve this in compact vectors by integrating structural improvements of AAV vectors with innovative molecular tools. We illustrate the potential of this approach through a systematic demonstration of their utility for targeting cell types and querying their biology using a wide array of genetically encoded tools.

Payload (computing)

10.1016/j.crmeth.2022.100225

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Citations (17)

Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD

PMC (2020)

Qian Chen Christopher A Deister Xianhua Gao Baolin Guo Taylor Lynn-Jones

Neocortex

Stimulus (psychology)

Interneuron

Sensory stimulation therapy

Source

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Citations (4)

Viral manipulation of functionally distinct neurons from mice to humans

bioRxiv (Cold Spring Harbor Laboratory) (2019)

Douglas Vormstein-Schneider Jessica D. Lin Kenneth A. Pelkey Ramesh Chittajallu Baolin Guo

Recent success in identifying gene regulatory elements in the context of recombinant adeno-associated virus vectors have enabled cell type-restricted gene expression. However, within the cerebral cortex these tools are presently limited to broad classes of neurons. To overcome this limitation, we developed a strategy that led to the identification of multiple novel enhancers to target functionally distinct neuronal subtypes. By investigating the regulatory landscape of the disease gene Scn1a, we identified enhancers that target the breadth of its expression, including two that are selective for parvalbumin and vasoactive intestinal peptide cortical interneurons. Demonstrating the functional utility of these elements, we found that the PV-specific enhancer allowed for the selective targeting and manipulation of these neurons across species, from mice to humans. Finally, we demonstrate that our selection method is generalizable to other genes and characterize four additional PV-specific enhancers with exquisite specificity for distinct regions of the brain. Altogether, these viral tools can be used for cell-type specific circuit manipulation and hold considerable promise for use in therapeutic interventions.

Cell type

10.1101/808170

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Citations (6)

Laminar specificity and coverage of viral-mediated gene expression restricted to GABAergic interneurons and their parvalbumin subclass in marmoset primary visual cortex

Frederick Federer Justin Balsor Alexander Ingold David P. Babcock Jordane Dimidschstein

In the mammalian neocortex, inhibition is important for dynamically balancing excitation and shaping the response properties of cells and circuits. The various computational functions of inhibition are thought to be mediated by different inhibitory neuron types of which a large diversity exists in several species. Current understanding of the function and connectivity of distinct inhibitory neuron types has mainly derived from studies in transgenic mice. However, it is unknown whether knowledge gained from mouse studies applies to the non-human primate, the model system closest to humans. The lack of viral tools to selectively access inhibitory neuron types has been a major impediment to studying their function in the primate. Here, we have thoroughly validated and characterized several recently-developed viral vectors designed to restrict transgene expression to GABAergic cells or their parvalbumin (PV) subtype, and identified two types that show high specificity and efficiency in marmoset V1. We show that in marmoset V1 AAV-h56D induces transgene expression in GABAergic cells with up to 91-94% specificity and 79% efficiency, but this depends on viral serotype and cortical layer. AAV-PHP.eB-S5E2 induces transgene expression in PV cells across all cortical layers with up to 98% specificity and 86-90% efficiency, depending on layer. Thus, these viral vectors are promising tools for studying GABA and PV cell function and connectivity in the primate cortex.

Neocortex

Interneuron

10.7554/elife.97673.2

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Citations (1)

Nova proteins direct synaptic integration of somatostatin interneurons through activity-dependent alternative splicing

bioRxiv (Cold Spring Harbor Laboratory) (2019)

Leena A. Ibrahim Brie Wamsley Norah Alghamdi Nusrath Yusuf Elaine Sevier

Abstract Somatostatin interneurons are the earliest born population of cortical inhibitory cells. They are crucial to support normal brain development and function; however, the mechanisms underlying their integration into nascent cortical circuitry are not well understood. In this study, we begin by demonstrating that the maturation of somatostatin interneurons is activity dependent. We then investigated the relationship between activity, alternative splicing and synapse formation within this population. Specifically, we discovered that the Nova family of RNA-binding proteins are activity-dependent and are essential for the maturation of somatostatin interneurons, as well as their afferent and efferent connectivity. Within this population, Nova2 preferentially mediates the alternative splicing of genes required for axonal formation and synaptic function independently from its effect on gene expression. Hence, our work demonstrates that the Nova family of proteins through alternative splicing are centrally involved in coupling developmental neuronal activity to cortical circuit formation.

Interneuron

10.1101/845230

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Citations (2)

Ripple-selective GABAergic projection cells in the hippocampus

Neuron (2022)

Gergely Szabó Jordan S. Farrell Barna Dudok Wen‐Hsien Hou Anna L. Ortiz

Ripples are brief high-frequency electrographic events with important roles in episodic memory. However, the in vivo circuit mechanisms coordinating ripple-related activity among local and distant neuronal ensembles are not well understood. Here, we define key characteristics of a long-distance projecting GABAergic cell group in the mouse hippocampus that selectively exhibits high-frequency firing during ripples while staying largely silent during theta-associated states when most other GABAergic cells are active. The high ripple-associated firing commenced before ripple onset and reached its maximum before ripple peak, with the signature theta-OFF, ripple-ON firing pattern being preserved across awake and sleep states. Controlled by septal GABAergic, cholinergic, and CA3 glutamatergic inputs, these ripple-selective cells innervate parvalbumin and cholecystokinin-expressing local interneurons while also targeting a variety of extra-hippocampal regions. These results demonstrate the existence of a hippocampal GABAergic circuit element that is uniquely positioned to coordinate ripple-related neuronal dynamics across neuronal assemblies.

10.1016/j.neuron.2022.04.002

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Citations (38)

Divergent Opioid-Mediated Suppression of Inhibition between Hippocampus and Neocortex Across Species and Development

Adam Caccavano Sarah Kimmel Anna Vlachos Vivek Mahadevan June Hoan Kim

Opioid receptors within the CNS regulate pain sensation and mood and are key targets for drugs of abuse. Within the adult rodent hippocampus (HPC), μ-opioid receptor agonists suppress inhibitory parvalbumin-expressing interneurons (PV-INs), thus disinhibiting the circuit. However, it is uncertain if this disinhibitory motif is conserved in other cortical regions, species, or across development. We observed that PV-IN mediated inhibition is robustly suppressed by opioids in HPC but not neocortex in mice and nonhuman primates, with spontaneous inhibitory tone in resected human tissue also following a consistent dichotomy. This hippocampal disinhibitory motif was established in early development when PV-INs and opioids were found to regulate primordial network rhythmogenesis. Acute opioid-mediated modulation was partially occluded with morphine pretreatment, with implications for the effects of opioids on hippocampal network activity important for learning and memory. Together, these findings demonstrate that PV-INs exhibit a divergence in opioid sensitivity across brain regions that is remarkably conserved across evolution and highlights the underappreciated role of opioids acting through immature PV-INs in shaping hippocampal development.

Neocortex

10.2139/ssrn.4706902

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Citations (0)