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Corrigendum: A viral strategy for targeting and manipulating interneurons across vertebrate species

Dimidschstein, Jordane; Chen, Qian; Tremblay, Robin; Rogers, Stephanie L; Saldi, Giuseppe-Antonio; Guo, Lihua; Xu, Qing; Liu, Runpeng; Lu, Congyi; Chu, Jianhua; Avery, Michael C; Rashid, Mohammad S; Baek, Myungin; Jacob, Amanda L; Smith, Gordon B; Wilson, Daniel E; Kosche, Georg; Kruglikov, Illya; Rusielewicz, Tomasz; Kotak, Vibhakar C; Mowery, Todd M; Anderson, Stewart A; Callaway, Edward M; Dasen, Jeremy S; Fitzpatrick, David; Fossati, Valentina; Long, Michael A; Noggle, Scott; Reynolds, John H; Sanes, Dan H; Rudy, Bernardo; Feng, Guoping; Fishell, Gord
PMID: 28653691
ISSN: 1546-1726
CID: 2782702

Addendum: A viral strategy for targeting and manipulating interneurons across vertebrate species

Dimidschstein, Jordane; Chen, Qian; Tremblay, Robin; Rogers, Stephanie L; Saldi, Giuseppe-Antonio; Guo, Lihua; Xu, Qing; Liu, Runpeng; Lu, Congyi; Chu, Jianhua; Avery, Michael C; Rashid, Mohammad S; Baek, Myungin; Jacob, Amanda L; Smith, Gordon B; Wilson, Daniel E; Kosche, Georg; Kruglikov, Illya; Rusielewicz, Tomasz; Kotak, Vibhakar C; Mowery, Todd M; Anderson, Stewart A; Callaway, Edward M; Dasen, Jeremy S; Fitzpatrick, David; Fossati, Valentina; Long, Michael A; Noggle, Scott; Reynolds, John H; Sanes, Dan H; Rudy, Bernardo; Feng, Guoping; Fishell, Gord
PMID: 28653689
ISSN: 1546-1726
CID: 3074092

A viral strategy for targeting and manipulating interneurons across vertebrate species

Dimidschstein, Jordane; Chen, Qian; Tremblay, Robin; Rogers, Stephanie L; Saldi, Giuseppe-Antonio; Guo, Lihua; Xu, Qing; Liu, Runpeng; Lu, Congyi; Chu, Jianhua; Avery, Michael C; Rashid, Mohammad S; Baek, Myungin; Jacob, Amanda L; Smith, Gordon B; Wilson, Daniel E; Kosche, Georg; Kruglikov, Illya; Rusielewicz, Tomasz; Kotak, Vibhakar C; Mowery, Todd M; Anderson, Stewart A; Callaway, Edward M; Dasen, Jeremy S; Fitzpatrick, David; Fossati, Valentina; Long, Michael A; Noggle, Scott; Reynolds, John H; Sanes, Dan H; Rudy, Bernardo; Feng, Guoping; Fishell, Gord
A fundamental impediment to understanding the brain is the availability of inexpensive and robust methods for targeting and manipulating specific neuronal populations. The need to overcome this barrier is pressing because there are considerable anatomical, physiological, cognitive and behavioral differences between mice and higher mammalian species in which it is difficult to specifically target and manipulate genetically defined functional cell types. In particular, it is unclear the degree to which insights from mouse models can shed light on the neural mechanisms that mediate cognitive functions in higher species, including humans. Here we describe a novel recombinant adeno-associated virus that restricts gene expression to GABAergic interneurons within the telencephalon. We demonstrate that the viral expression is specific and robust, allowing for morphological visualization, activity monitoring and functional manipulation of interneurons in both mice and non-genetically tractable species, thus opening the possibility to study GABAergic function in virtually any vertebrate species.
PMCID:5348112
PMID: 27798629
ISSN: 1546-1726
CID: 2297132

Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission

Karayannis, T; Au, E; Patel, J C; Kruglikov, I; Markx, S; Delorme, R; Heron, D; Salomon, D; Glessner, J; Restituito, S; Gordon, A; Rodriguez-Murillo, L; Roy, N C; Gogos, J A; Rudy, B; Rice, M E; Karayiorgou, M; Hakonarson, H; Keren, B; Huguet, G; Bourgeron, T; Hoeffer, C; Tsien, R W; Peles, E; Fishell, G
Although considerable evidence suggests that the chemical synapse is a lynchpin underlying affective disorders, how molecular insults differentially affect specific synaptic connections remains poorly understood. For instance, Neurexin 1a and 2 (NRXN1 and NRXN2) and CNTNAP2 (also known as CASPR2), all members of the neurexin superfamily of transmembrane molecules, have been implicated in neuropsychiatric disorders. However, their loss leads to deficits that have been best characterized with regard to their effect on excitatory cells. Notably, other disease-associated genes such as BDNF and ERBB4 implicate specific interneuron synapses in psychiatric disorders. Consistent with this, cortical interneuron dysfunction has been linked to epilepsy, schizophrenia and autism. Using a microarray screen that focused upon synapse-associated molecules, we identified Cntnap4 (contactin associated protein-like 4, also known as Caspr4) as highly enriched in developing murine interneurons. In this study we show that Cntnap4 is localized presynaptically and its loss leads to a reduction in the output of cortical parvalbumin (PV)-positive GABAergic (gamma-aminobutyric acid producing) basket cells. Paradoxically, the loss of Cntnap4 augments midbrain dopaminergic release in the nucleus accumbens. In Cntnap4 mutant mice, synaptic defects in these disease-relevant neuronal populations are mirrored by sensory-motor gating and grooming endophenotypes; these symptoms could be pharmacologically reversed, providing promise for therapeutic intervention in psychiatric disorders.
PMCID:4281262
PMID: 24870235
ISSN: 0028-0836
CID: 1102842

A disinhibitory circuit mediates motor integration in the somatosensory cortex

Lee, Soohyun; Kruglikov, Illya; Huang, Z Josh; Fishell, Gord; Rudy, Bernardo
The influence of motor activity on sensory processing is crucial for perception and motor execution. However, the underlying circuits are not known. To unravel the circuit by which activity in the primary vibrissal motor cortex (vM1) modulates sensory processing in the primary somatosensory barrel cortex (S1), we used optogenetics to examine the long-range inputs from vM1 to the various neuronal elements in S1. We found that S1-projecting vM1 pyramidal neurons strongly recruited vasointestinal peptide (VIP)-expressing GABAergic interneurons, a subset of serotonin receptor-expressing interneurons. These VIP interneurons preferentially inhibited somatostatin-expressing interneurons, neurons that target the distal dendrites of pyramidal cells. Consistent with this vM1-mediated disinhibitory circuit, the activity of VIP interneurons in vivo increased and that of somatostatin interneurons decreased during whisking. These changes in firing rates during whisking depended on vM1 activity. Our results suggest previously unknown circuitry by which inputs from motor cortex influence sensory processing in sensory cortex.
PMCID:4100076
PMID: 24097044
ISSN: 1097-6256
CID: 598452

Ca 2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures

Rossignol, Elsa; Kruglikov, Illya; van den Maagdenberg, Arn M J M; Rudy, Bernardo; Fishell, Gord
OBJECTIVE: Both the neuronal populations and mechanisms responsible for generalized spike-wave absence seizures are poorly understood. In mutant mice carrying loss-of-function (LOF) mutations in Cacna1a, which encodes the alpha1 pore-forming subunit of CaV 2.1 (P/Q-type) voltage-gated Ca2+ channels, generalized spike-wave seizures have been suggested to result from excessive bursting of thalamocortical cells. However, other cellular populations including cortical inhibitory interneurons may contribute to this phenotype. We investigated how different cortical interneuron subtypes are affected by the loss of CaV 2.1 channel function and how this contributes to the onset of generalized epilepsy. METHODS: We designed genetic strategies to induce a selective Cacna1a LOF mutation in different cortical gamma-aminobutyric acidergic (GABAergic) and/or glutamatergic neuronal populations in mice. We assessed the cellular and network consequences of these mutations by combining immunohistochemical assays, in vitro physiology, optogenetics, and in vivo video electroencephalographic recordings. RESULTS: We demonstrate that selective Cacna1a LOF from a subset of cortical interneurons, including parvalbumin (PV)+ and somatostatin (SST)+ interneurons, results in severe generalized epilepsy. Loss of CaV 2.1 channel function compromises GABA release from PV+ but not SST+ interneurons. Moreover, thalamocortical projection neurons do not show enhanced bursting in these mutants, suggesting that this feature is not essential for the development of generalized spike-wave seizures. Notably, the concurrent removal of CaV 2.1 channels in cortical pyramidal cells and interneurons considerably lessens seizure severity by decreasing cortical excitability. INTERPRETATION: Our findings demonstrate that conditional ablation of CaV 2.1 channel function from cortical PV+ interneurons alters GABA release from these cells, impairs their ability to constrain cortical pyramidal cell excitability, and is sufficient to cause generalized seizures. Ann Neurol 2013.
PMCID:3849346
PMID: 23595603
ISSN: 0364-5134
CID: 425942

Rapid developmental maturation of neocortical FS cell intrinsic excitability

Goldberg, Ethan M; Jeong, Hyo-Young; Kruglikov, Ilya; Tremblay, Robin; Lazarenko, Roman M; Rudy, Bernardo
Fast-spiking (FS) cells are a prominent subtype of neocortical gamma-aminobutyric acidergic interneurons that mediate feed-forward inhibition and the temporal sculpting of information transfer in neural circuits, maintain excitation/inhibition balance, and contribute to network oscillations. FS cell dysfunction may be involved in the pathogenesis of disorders such as epilepsy, autism, and schizophrenia. Mature FS cells exhibit coordinated molecular and cellular specializations that facilitate rapid responsiveness, including brief spikes and sustained high-frequency discharge. We show that these features appear during the second and third postnatal weeks driven by upregulation of K(+) channel subunits of the Kv3 subfamily. The low membrane resistance and fast time constant characteristic of FS cells also appears during this time, driven by expression of a K(+) leak current mediated by K(ir)2 subfamily inward rectifier K(+) channels and TASK subfamily 2-pore K(+) channels. Blockade of this leak produces dramatic depolarization of FS cells suggesting the possibility for potent neuromodulation. Finally, the frequency of FS cell membrane potential oscillations increases during development and is markedly slower in TASK-1/3 knockout mice, suggesting that TASK channels regulate FS cell rhythmogenesis. Our findings imply that some of the effects of acidosis and/or anesthetics on brain function may be due to blockade of TASK channels in FS cells
PMCID:3041012
PMID: 20705896
ISSN: 1460-2199
CID: 134292

Modulators of inhibitory synaptic transmission in mouse somatosensory cortex [Meeting Abstract]

Kruglikov, I; Rudy, B
ISI:000259593800167
ISSN: 0924-977x
CID: 90949

Perisomatic GABA release and thalamocortical integration onto neocortical excitatory cells are regulated by neuromodulators

Kruglikov, Illya; Rudy, Bernardo
Neuromodulators such as acetylcholine, serotonin, and noradrenaline are powerful regulators of neocortical activity. Although it is well established that cortical inhibition is the target of these modulations, little is known about their effects on GABA release from specific interneuron types. This knowledge is necessary to gain a mechanistic understanding of the actions of neuromodulators because different interneuron classes control specific aspects of excitatory cell function. Here, we report that GABA release from fast-spiking (FS) cells, the most prevalent interneuron subtype in neocortex, is robustly inhibited following activation of muscarinic, serotonin, adenosine, and GABA(B) receptors--an effect that regulates FS cell control of excitatory neuron firing. The potent muscarinic inhibition of GABA release from FS cells suppresses thalamocortical feedforward inhibition. This is supplemented by the muscarinic-mediated depolarization of thalamo-recipient excitatory neurons and the nicotinic enhancement of thalamic input onto these neurons to promote thalamocortical excitation
PMCID:2572574
PMID: 18579081
ISSN: 1097-4199
CID: 80297

Functional coupling between ryanodine receptors, mitochondria and Ca(2+) ATPases in rat submandibular acinar cells

Kopach, Olga; Kruglikov, Illya; Pivneva, Tatyana; Voitenko, Nana; Fedirko, Nataliya
Agonist stimulation of exocrine cells leads to the generation of intracellular Ca(2+) signals driven by inositol 1,4,5-trisphosphate receptors (IP(3)Rs) that rapidly become global due to propagation throughout the cell. In many types of excitable cells the intracellular Ca(2+) signal is propagated by a mechanism of Ca(2+)-induced Ca(2+) release (CICR), mediated by ryanodine receptors (RyRs). Expression of RyRs in salivary gland cells has been demonstrated immunocytochemically although their functional role is not clear. We used microfluorimetry to measure Ca(2+) signals in the cytoplasm, in the endoplasmic reticulum (ER) and in mitochondria. In permeabilized acinar cells caffeine induced a dose-dependent, transient decrease of Ca(2+) concentration in the endoplasmic reticulum ([Ca(2+)](ER)). This decrease was inhibited by ryanodine but was insensitive to heparin. Application of caffeine, however, did not elevate cytosolic Ca(2+) concentration ([Ca(2+)](i)) suggesting fast local buffering of Ca(2+) released through RyRs. Indeed, activation of RyRs produced a robust mitochondrial Ca(2+) transient that was prevented by addition of Ca(2+) chelator BAPTA but not EGTA. When mitochondrial Ca(2+) uptake was blocked, activation of RyRs evoked only a non-transient increase in [Ca(2+)](i) and substantially smaller Ca(2+) release from the ER. Upon simultaneous inhibition of mitochondrial Ca(2+) uptake and either plasmalemmal or ER Ca(2+) ATPase, activation of RyRs caused a transient rise in [Ca(2+)](i). Collectively, our data suggest that Ca(2+) released through RyRs is mostly "tunnelled" to mitochondria, while Ca(2+) ATPases are responsible for the fast initial sequestration of Ca(2+). Ca(2+) uptake by mitochondria is critical for maintaining continuous CICR. A complex interplay between RyRs, mitochondria and Ca(2+) ATPases is accomplished through strategic positioning of mitochondria close to both Ca(2+) release sites in the ER and Ca(2+) pumping sites of the plasmalemma and the ER.
PMID: 17889347
ISSN: 0143-4160
CID: 177381