Bio


Ivan Soltesz received his doctorate in Budapest and conducted postdoctoral research at universities at Oxford, London, Stanford and Dallas. He established his laboratory at the University of California, Irvine, in 1995. He became full Professor in 2003, and served as department Chair from 2006 to July 2015. He returned to Stanford in 2015 as the James R. Doty Professor of Neurosurgery and Neurosciences at Stanford University School of Medicine. His major research interest is focused on neuronal microcircuits, network oscillations, cannabinoid signaling and the mechanistic bases of circuit dysfunction in epilepsy.
His laboratory employs a combination of closely integrated experimental and theoretical techniques, including closed-loop in vivo optogenetics, paired patch clamp recordings, in vivo electrophysiological recordings from identified interneurons in awake mice, 2-photon imaging, machine learning-aided 3D video analysis of behavior, video-EEG recordings, behavioral approaches, and large-scale computational modeling methods using supercomputers. He is the author of a book on GABAergic microcircuits (Diversity in the Neuronal Machine, Oxford University Press), and editor of a book on Computational Neuroscience in Epilepsy (Academic Press/Elsevier). He co-founded the first Gordon Research Conference on the Mechanisms of neuronal synchronization and epilepsy, and taught for five years in the Ion Channels Course at Cold Springs Harbor. He has over 30 years of research experience, with over 20 years as a faculty involved in the training of graduate students (total of 16, 6 of them MD/PhDs) and postdoctoral fellows (20), many of whom received fellowship awards, K99 grants, joined prestigious residency programs and became independent faculty.

Administrative Appointments


  • Assistant Professor, University of California, Irvine (1995 - 1999)
  • Associate Professor, University of California, Irvine (1999 - 2003)
  • Professor, University of California, Irvine (2003 - 2015)
  • Chair of Anatomy & Neurobiology, University of California, Irvine (2006 - 2015)
  • Chancellor's Professor, University of California, Irvine (2011 - 2015)
  • James R Doty Professor of Neurosurgery and Neurosciences, Stanford University (2015 - Present)
  • Vice Chair, Neurosurgery, Stanford University (2015 - Present)

Honors & Awards


  • Athalie Clark Research Award, University of California, Irvine (2005)
  • Javits Neuroscience Investigator Award, NINDS-NIH (2005)
  • Michael Prize in Epilepsy Research, Stiftung Michael, Germany (2009)
  • Research Recognition Award, Basic Science, American Epilepsy Society (2011)
  • Foreign Member, Hungarian Academy of Sciences (2016)

Boards, Advisory Committees, Professional Organizations


  • Co-Chair, Founder, Gordon Research Conference on Mechanisms of Epilepsy and Neuronal Synchronization (2006 - 2006)
  • Chair, Basic Science Committee, American Epilepsy Society (2006 - 2009)
  • Associate Editor, Journal of Neuroscience (2007 - 2012)
  • Member, Editorial Board, Epilepsy Research (2008 - 2015)
  • Member, Scientific Advisory Board, Citizens United in Research in Epilepsy (CURE) (2009 - 2012)
  • Co-Chair, Grants and Fellowship Review Panel, Epilepsy Foundation (2010 - 2012)
  • Chair, Clinical Neuroplasticity and Neurotransmitters (CNNT) study section, NIH (2011 - 2013)
  • Member, Professional Advisory Board, Epilepsy Foundation (2011 - Present)
  • Member, Editorial Board, Experimental Neurology (2013 - Present)
  • Chair, Research recognition Awards Committee, American Epilepsy Society (2016 - Present)

Professional Education


  • Postdoc, UT Southwestern, Neuroscience (1994)
  • Postdoc, Stanford University, Neuroscience (1993)
  • Postdoc, Universite Laval, Neuroscience (1992)
  • Postdoc, University of London, Neuroscience (1991)
  • Postdoc, Oxford University, Neuroscience (1990)
  • Ph.D., Eotvos University, Budapest, Comparative Physiology (1989)
  • University Diploma, Eotvos University, Budapest, Biology (1988)

2019-20 Courses


Stanford Advisees


Graduate and Fellowship Programs


All Publications


  • Neurological Impairments in Mice Subjected to Irradiation and Chemotherapy. Radiation research Dey, D., Parihar, V. K., Szabo, G. G., Klein, P. M., Tran, J., Moayyad, J., Ahmed, F., Nguyen, Q., Murry, A., Merriott, D., Nguyen, B., Goldman, J., Angulo, M. C., Piomelli, D., Soltesz, I., Baulch, J. E., Limoli, C. L. 2020

    Abstract

    Radiotherapy, surgery and the chemotherapeutic agent temozolomide (TMZ) are frontline treatments for glioblastoma multiforme (GBM). However beneficial, GBM treatments nevertheless cause anxiety or depression in nearly 50% of patients. To further understand the basis of these neurological complications, we investigated the effects of combined radiotherapy and TMZ chemotherapy (combined treatment) on neurological impairments using a mouse model. Five weeks after combined treatment, mice displayed anxiety-like behaviors, and at 15 weeks both anxiety- and depression-like behaviors were observed. Relevant to the known roles of the serotonin axis in mood disorders, we found that 5HT1A serotonin receptor levels were decreased by 50% in the hippocampus at both early and late time points, and a 37% decrease in serotonin levels was observed at 15 weeks postirradiation. Furthermore, chronic treatment with the selective serotonin reuptake inhibitor fluoxetine was sufficient for reversing combined treatment-induced depression-like behaviors. Combined treatment also elicited a transient early increase in activated microglia in the hippocampus, suggesting therapy-induced neuroinflammation that subsided by 15 weeks. Together, the results of this study suggest that interventions targeting the serotonin axis may help ameliorate certain neurological side effects associated with the clinical management of GBM to improve the overall quality of life for cancer patients.

    View details for DOI 10.1667/RR15540.1

    View details for PubMedID 32134362

  • Optogenetic intervention of seizures improves spatial memory in a mouse model of chronic temporal lobe epilepsy. Epilepsia Kim, H. K., Gschwind, T., Nguyen, T. M., Bui, A. D., Felong, S., Ampig, K., Suh, D., Ciernia, A. V., Wood, M. A., Soltesz, I. 2020

    Abstract

    OBJECTIVE: To determine if closed-loop optogenetic seizure intervention, previously shown to reduce seizure duration in a well-established mouse model chronic temporal lobe epilepsy (TLE), also improves the associated comorbidity of impaired spatial memory.METHODS: Mice with chronic, spontaneous seizures in the unilateral intrahippocampal kainic acid model of TLE, expressing channelrhodopsin in parvalbumin-expressing interneurons, were implanted with optical fibers and electrodes, and tested for response to closed-loop light intervention of seizures. Animals that responded to closed-loop optogenetic curtailment of seizures were tested in the object location memory test and then given closed-loop optogenetic intervention on all detected seizures for 2 weeks. Following this, they were tested with a second object location memory test, with different objects and contexts than used previously, to assess if seizure suppression can improve deficits in spatial memory.RESULTS: Animals that received closed-loop optogenetic intervention performed significantly better in the second object location memory test compared to the first test. Epileptic controls with no intervention showed stable frequency and duration of seizures, as well as stable spatial memory deficits, for several months after the precipitating insult.SIGNIFICANCE: Many currently available treatments for epilepsy target seizures but not the associated comorbidities, thereforethere is a need to investigate new potential therapies that may be able to improve both seizure burden and associated comorbidities of epilepsy. In this study, we showed that optogenetic intervention may be able to both shorten seizure duration and improve cognitive outcomes of spatial memory.

    View details for DOI 10.1111/epi.16445

    View details for PubMedID 32072628

  • Regulation of gamma-frequency oscillation by feedforward inhibition: A computational modeling study HIPPOCAMPUS Renno-Costa, C., Teixeira, D., Soltesz, I. 2019; 29 (10): 957–70

    View details for DOI 10.1002/hipo.23093

    View details for Web of Science ID 000485902400005

  • Resolving the Micro-Macro Disconnect to Address Core Features of Seizure Networks NEURON Farrell, J. S., Quynh-Anh Nguyen, Soltesz, I. 2019; 101 (6): 1016–28
  • Ripple-related firing of identified deep CA1 pyramidal cells in chronic temporal lobe epilepsy in mice. Epilepsia open Marchionni, I., Oberoi, M., Soltesz, I., Alexander, A. 2019; 4 (2): 254–63

    Abstract

    Temporal lobe epilepsy (TLE) is often associated with memory deficits. Reactivation of memory traces in the hippocampus occurs during sharp-wave ripples (SWRs; 140-250 Hz). To better understand the mechanisms underlying high-frequency oscillations and cognitive comorbidities in epilepsy, we evaluated how rigorously identified deep CA1 pyramidal cells (dPCs) discharge during SWRs in control and TLE mice.We used the unilateral intraamygdala kainate model of TLE in video-electroencephalography (EEG) verified chronically epileptic adult mice. Local field potential and single-cell recordings were performed using juxtacellular recordings from awake control and TLE mice resting on a spherical treadmill, followed by post hoc identification of the recorded cells.Hippocampal SWRs in TLE mice occurred with increased intraripple frequency compared to control mice. The frequency of SWR events was decreased, whereas the overall frequency of SWRs, interictal epileptiform discharges, and high-frequency ripples (250-500 Hz) together was not altered. CA1 dPCs in TLE mice showed significantly increased firing during ripples as well as between the ripple events. The strength of ripple modulation of dPC discharges increased in TLE without alteration of the preferred phase of firing during the ripple waves.These juxtacellular electrophysiology data obtained from identified CA1 dPCs from chronically epileptic mice are in general agreement with recent findings indicating distortion of normal firing patterns during offline SWRs as a mechanism underlying deficits in memory consolidation in epilepsy. Because the primary seizure focus in our experiments was in the amygdala and we recorded from the CA1 region, these results are also in agreement with the presence of altered high-frequency oscillations in areas of secondary seizure spread.

    View details for DOI 10.1002/epi4.12310

    View details for PubMedID 31168492

    View details for PubMedCentralID PMC6546014

  • New Concerns for Neurocognitive Function during Deep Space Exposures to Chronic, Low Dose-Rate, Neutron Radiation. eNeuro Acharya, M. M., Baulch, J. E., Klein, P. M., Baddour, A. A., Apodaca, L. A., Kramár, E. A., Alikhani, L., Garcia, C., Angulo, M. C., Batra, R. S., Fallgren, C. M., Borak, T. B., Stark, C. E., Wood, M. A., Britten, R. A., Soltesz, I., Limoli, C. L. 2019; 6 (4)

    Abstract

    As NASA prepares for a mission to Mars, concerns regarding the health risks associated with deep space radiation exposure have emerged. Until now, the impacts of such exposures have only been studied in animals after acute exposures, using dose rates ∼1.5×105 higher than those actually encountered in space. Using a new, low dose-rate neutron irradiation facility, we have uncovered that realistic, low dose-rate exposures produce serious neurocognitive complications associated with impaired neurotransmission. Chronic (6 month) low-dose (18 cGy) and dose rate (1 mGy/d) exposures of mice to a mixed field of neutrons and photons result in diminished hippocampal neuronal excitability and disrupted hippocampal and cortical long-term potentiation. Furthermore, mice displayed severe impairments in learning and memory, and the emergence of distress behaviors. Behavioral analyses showed an alarming increase in risk associated with these realistic simulations, revealing for the first time, some unexpected potential problems associated with deep space travel on all levels of neurological function.

    View details for DOI 10.1523/ENEURO.0094-19.2019

    View details for PubMedID 31383727

  • Plants come to mind: Phytocannabinoids, endocannabinoids, and the control of seizures. Addiction (Abingdon, England) Farrell, J. S., Soltesz, I. 2018

    View details for PubMedID 30589476

  • Neural stem cell lineage-specific cannabinoid type-1 receptor regulates neurogenesis and plasticity in the adult mouse hippocampus. Cerebral cortex (New York, N.Y. : 1991) Zimmermann, T., Maroso, M., Beer, A., Baddenhausen, S., Ludewig, S., Fan, W., Vennin, C., Loch, S., Berninger, B., Hofmann, C., Korte, M., Soltesz, I., Lutz, B., Leschik, J. 2018

    Abstract

    Neural stem cells (NSCs) in the adult mouse hippocampus occur in a specific neurogenic niche, where a multitude of extracellular signaling molecules converges to regulate NSC proliferation as well as fate and functional integration. However, the underlying mechanisms how NSCs react to extrinsic signals and convert them to intracellular responses still remains elusive. NSCs contain a functional endocannabinoid system, including the cannabinoid type-1 receptor (CB1). To decipher whether CB1 regulates adult neurogenesis directly or indirectly in vivo, we performed NSC-specific conditional inactivation of CB1 by using triple-transgenic mice. Here, we show that lack of CB1 in NSCs is sufficient to decrease proliferation of the stem cell pool, which consequently leads to a reduction in the number of newborn neurons. Furthermore, neuronal differentiation was compromised at the level of dendritic maturation pointing towards a postsynaptic role of CB1 in vivo. Deteriorated neurogenesis in NSC-specific CB1 knock-outs additionally resulted in reduced long-term potentiation in the hippocampal formation. The observed cellular and physiological alterations led to decreased short-term spatial memory and increased depression-like behavior. These results demonstrate that CB1 expressed in NSCs and their progeny controls neurogenesis in adult mice to regulate the NSC stem cell pool, dendritic morphology, activity-dependent plasticity, and behavior.

    View details for PubMedID 30307491

  • Proceedings of the Epilepsy Foundation's 2017 Cannabinoids in Epilepsy Therapy Workshop Huizenga, M. N., Fureman, B. E., Soltesz, I., Stella, N. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2018: 237–42

    View details for PubMedID 29908905

  • Persistent nature of alterations in cognition and neuronal circuit excitability after exposure to simulated cosmic radiation in mice EXPERIMENTAL NEUROLOGY Parihar, V. K., Maroso, M., Syage, A., Allen, B. D., Angulo, M. C., Soltesz, I., Limoli, C. L. 2018; 305: 44–55

    Abstract

    Of the many perils associated with deep space travel to Mars, neurocognitive complications associated with cosmic radiation exposure are of particular concern. Despite these realizations, whether and how realistic doses of cosmic radiation cause cognitive deficits and neuronal circuitry alterations several months after exposure remains unclear. In addition, even less is known about the temporal progression of cosmic radiation-induced changes transpiring over the duration of a time period commensurate with a flight to Mars. Here we show that rodents exposed to the second most prevalent radiation type in space (i.e. helium ions) at low, realistic doses, exhibit significant hippocampal and cortical based cognitive decrements lasting 1 year after exposure. Cosmic-radiation-induced impairments in spatial, episodic and recognition memory were temporally coincident with deficits in cognitive flexibility and reduced rates of fear extinction, elevated anxiety and depression like behavior. At the circuit level, irradiation caused significant changes in the intrinsic properties (resting membrane potential, input resistance) of principal cells in the perirhinal cortex, a region of the brain implicated by our cognitive studies. Irradiation also resulted in persistent decreases in the frequency and amplitude of the spontaneous excitatory postsynaptic currents in principal cells of the perirhinal cortex, as well as a reduction in the functional connectivity between the CA1 of the hippocampus and the perirhinal cortex. Finally, increased numbers of activated microglia revealed significant elevations in neuroinflammation in the perirhinal cortex, in agreement with the persistent nature of the perturbations in key neuronal networks after cosmic radiation exposure. These data provide new insights into cosmic radiation exposure, and reveal that even sparsely ionizing particles can disrupt the neural circuitry of the brain to compromise cognitive function over surprisingly protracted post-irradiation intervals.

    View details for PubMedID 29540322

  • CA1 pyramidal cell diversity enabling parallel information processing in the hippocampus NATURE NEUROSCIENCE Soltesz, I., Losonczy, A. 2018; 21 (4): 484–93

    Abstract

    Hippocampal network operations supporting spatial navigation and declarative memory are traditionally interpreted in a framework where each hippocampal area, such as the dentate gyrus, CA3, and CA1, consists of homogeneous populations of functionally equivalent principal neurons. However, heterogeneity within hippocampal principal cell populations, in particular within pyramidal cells at the main CA1 output node, is increasingly recognized and includes developmental, molecular, anatomical, and functional differences. Here we review recent progress in the delineation of hippocampal principal cell subpopulations by focusing on radially defined subpopulations of CA1 pyramidal cells, and we consider how functional segregation of information streams, in parallel channels with nonuniform properties, could represent a general organizational principle of the hippocampus supporting diverse behaviors.

    View details for PubMedID 29593317

    View details for PubMedCentralID PMC5909691

  • Plants come to mind: Phytocannabinoids, endocannabinoids, and the control of seizures Addiction Farrell, J. S., Soltesz, I. 2018: 1343–45

    View details for DOI 10.1111/add.14540

    View details for PubMedCentralID PMC6597308

  • Persistent nature of alterations in cognition and neuronal circuit excitability after exposure to simulated cosmic radiation in mice Exp Neurol Parihar, V., et al 2018
  • Single Bursts of Individual Granule Cells Functionally Rearrange Feedforward Inhibition Journal of Neuroscience Neubrandt, M., et al 2018: 1711–24

    Abstract

    The sparse single-spike activity of dentate gyrus granule cells (DG GCs) is punctuated by occasional brief bursts of 3-7 action potentials. It is well-known that such presynaptic bursts in individual mossy fibers (MFs; axons of granule cells) are often able to discharge postsynaptic CA3 pyramidal cells due to powerful short-term facilitation. However, what happens in the CA3 network after the passage of a brief MF burst, before the arrival of the next burst or solitary spike, is not understood. Because MFs innervate significantly more CA3 interneurons than pyramidal cells, we focused on unitary MF responses in identified interneurons in the seconds-long postburst period, using paired recordings in rat hippocampal slices. Single bursts as short as 5 spikes in <30 ms in individual presynaptic MFs caused a sustained, large increase (tripling) in the amplitude of the unitary MF-EPSCs for several seconds in ivy, axo-axonic/chandelier and basket interneurons. The postburst unitary MF-EPSCs in these feedforward interneurons reached amplitudes that were even larger than the MF-EPSCs during the bursts in the same cells. In contrast, no comparable postburst enhancement of MF-EPSCs could be observed in pyramidal cells or nonfeedforward interneurons. The robust postburst increase in MF-EPSCs in feedforward interneurons was associated with significant shortening of the unitary synaptic delay and large downstream increases in disynaptic IPSCs in pyramidal cells. These results reveal a new cell type-specific plasticity that enables even solitary brief bursts in single GCs to powerfully enhance inhibition at the DG-CA3 interface in the seconds-long time-scales of interburst intervals.SIGNIFICANCE STATEMENT The hippocampal formation is a brain region that plays key roles in spatial navigation and learning and memory. The first stage of information processing occurs in the dentate gyrus, where principal cells are remarkably quiet, discharging low-frequency single action potentials interspersed with occasional brief bursts of spikes. Such bursts, in particular, have attracted a lot of attention because they appear to be critical for efficient coding, storage, and recall of information. We show that single bursts of a few spikes in individual granule cells result in seconds-long potentiation of excitatory inputs to downstream interneurons. Thus, while it has been known that bursts powerfully discharge ("detonate") hippocampal excitatory cells, this study clarifies that they also regulate inhibition during the interburst intervals.

    View details for DOI 10.1523/JNEUROSCI.1595-17.2018

    View details for PubMedCentralID PMC5815453

  • Dentate gyrus mossy cells control spontaneous convulsive seizures and spatial memory Science Bui, A., et al 2018: 787–90

    Abstract

    Temporal lobe epilepsy (TLE) is characterized by debilitating, recurring seizures and an increased risk for cognitive deficits. Mossy cells (MCs) are key neurons in the hippocampal excitatory circuit, and the partial loss of MCs is a major hallmark of TLE. We investigated how MCs contribute to spontaneous ictal activity and to spatial contextual memory in a mouse model of TLE with hippocampal sclerosis, using a combination of optogenetic, electrophysiological, and behavioral approaches. In chronically epileptic mice, real-time optogenetic modulation of MCs during spontaneous hippocampal seizures controlled the progression of activity from an electrographic to convulsive seizure. Decreased MC activity is sufficient to impede encoding of spatial context, recapitulating observed cognitive deficits in chronically epileptic mice.

    View details for DOI 10.1126/science.aan4074

  • Dentate gyrus mossy cells control spontaneous convulsive seizures and spatial memory. Science (New York, N.Y.) Bui, A. D., Nguyen, T. M., Limouse, C., Kim, H. K., Szabo, G. G., Felong, S., Maroso, M., Soltesz, I. 2018; 359 (6377): 787–90

    Abstract

    Temporal lobe epilepsy (TLE) is characterized by debilitating, recurring seizures and an increased risk for cognitive deficits. Mossy cells (MCs) are key neurons in the hippocampal excitatory circuit, and the partial loss of MCs is a major hallmark of TLE. We investigated how MCs contribute to spontaneous ictal activity and to spatial contextual memory in a mouse model of TLE with hippocampal sclerosis, using a combination of optogenetic, electrophysiological, and behavioral approaches. In chronically epileptic mice, real-time optogenetic modulation of MCs during spontaneous hippocampal seizures controlled the progression of activity from an electrographic to convulsive seizure. Decreased MC activity is sufficient to impede encoding of spatial context, recapitulating observed cognitive deficits in chronically epileptic mice.

    View details for PubMedID 29449490

  • Single Bursts of Individual Granule Cells Functionally Rearrange Feedforward Inhibition. The Journal of neuroscience : the official journal of the Society for Neuroscience Neubrandt, M., Oláh, V. J., Brunner, J., Marosi, E. L., Soltesz, I., Szabadics, J. 2018; 38 (7): 1711–24

    Abstract

    The sparse single-spike activity of dentate gyrus granule cells (DG GCs) is punctuated by occasional brief bursts of 3-7 action potentials. It is well-known that such presynaptic bursts in individual mossy fibers (MFs; axons of granule cells) are often able to discharge postsynaptic CA3 pyramidal cells due to powerful short-term facilitation. However, what happens in the CA3 network after the passage of a brief MF burst, before the arrival of the next burst or solitary spike, is not understood. Because MFs innervate significantly more CA3 interneurons than pyramidal cells, we focused on unitary MF responses in identified interneurons in the seconds-long postburst period, using paired recordings in rat hippocampal slices. Single bursts as short as 5 spikes in <30 ms in individual presynaptic MFs caused a sustained, large increase (tripling) in the amplitude of the unitary MF-EPSCs for several seconds in ivy, axo-axonic/chandelier and basket interneurons. The postburst unitary MF-EPSCs in these feedforward interneurons reached amplitudes that were even larger than the MF-EPSCs during the bursts in the same cells. In contrast, no comparable postburst enhancement of MF-EPSCs could be observed in pyramidal cells or nonfeedforward interneurons. The robust postburst increase in MF-EPSCs in feedforward interneurons was associated with significant shortening of the unitary synaptic delay and large downstream increases in disynaptic IPSCs in pyramidal cells. These results reveal a new cell type-specific plasticity that enables even solitary brief bursts in single GCs to powerfully enhance inhibition at the DG-CA3 interface in the seconds-long time-scales of interburst intervals.SIGNIFICANCE STATEMENT The hippocampal formation is a brain region that plays key roles in spatial navigation and learning and memory. The first stage of information processing occurs in the dentate gyrus, where principal cells are remarkably quiet, discharging low-frequency single action potentials interspersed with occasional brief bursts of spikes. Such bursts, in particular, have attracted a lot of attention because they appear to be critical for efficient coding, storage, and recall of information. We show that single bursts of a few spikes in individual granule cells result in seconds-long potentiation of excitatory inputs to downstream interneurons. Thus, while it has been known that bursts powerfully discharge ("detonate") hippocampal excitatory cells, this study clarifies that they also regulate inhibition during the interburst intervals.

    View details for PubMedID 29335356

    View details for PubMedCentralID PMC5815453

  • Optogenetics: Lighting a Path from the Laboratory to the Clinic OPTOGENETICS: A ROADMAP Kim, H. K., Alexander, A. L., Soltesz, I., Stroh, A. 2018; 133: 277–300
  • Seizing Control: From Current Treatments to Optogenetic Interventions in Epilepsy NEUROSCIENTIST Bui, A. D., Alexander, A., Soltesz, I. 2017; 23 (1): 68-81
  • Extended Interneuronal Network of the Dentate Gyrus. Cell reports Szabo, G. G., Du, X., Oijala, M., Varga, C., Parent, J. M., Soltesz, I. 2017; 20 (6): 1262–68

    Abstract

    Local interneurons control principal cells within individual brain areas, but anecdotal observations indicate that interneuronal axons sometimes extend beyond strict anatomical boundaries. Here, we use the case of the dentate gyrus (DG) to show that boundary-crossing interneurons with cell bodies in CA3 and CA1 constitute a numerically significant and diverse population that relays patterns of activity generated within the CA regions back to granule cells. These results reveal the existence of a sophisticated retrograde GABAergic circuit that fundamentally extends the canonical interneuronal network.

    View details for PubMedID 28793251

    View details for PubMedCentralID PMC5576513

  • Extended Interneuronal Network of the Dentate Gyrus Cell Rep Szabo, G., et al 2017
  • Hippocampal Dentate Mossy Cells Improve Their CV and Trk into the Limelight Neuron Milstein, A., Soltesz, I. 2017
  • Involvement of fast-spiking cells in ictal sequences during spontaneous seizures in rats with chronic temporal lobe epilepsy Brain Neumann, A., et al 2017
  • Network Models of Epilepsy-Related Pathological Structural and Functional Alterations in the Dentate Gyrus REWIRING BRAIN: A COMPUTATIONAL APPROACH TO STRUCTURAL PLASTICITY IN THE ADULT BRAIN Raikov, I., Plitt, M., Soltesz, I., VanOoyen, A., ButzOstendorf, M. 2017: 485–503
  • Hippocampal Dentate Mossy Cells Improve Their CV and Trk into the Limelight. Neuron Milstein, A. D., Soltesz, I. 2017; 95 (4): 732–34

    Abstract

    The impact of dentate mossy cells on hippocampal activity remained uncertain despite a long history of investigation. In this issue of Neuron, Hashimotodani et al. (2017) discover a presynaptically expressed form of long-term potentiation at mossy cell outputs, shedding light on their mysterious function.

    View details for PubMedID 28817795

  • Involvement of fast-spiking cells in ictal sequences during spontaneous seizures in rats with chronic temporal lobe epilepsy. Brain : a journal of neurology Neumann, A. R., Raedt, R., Steenland, H. W., Sprengers, M., Bzymek, K., Navratilova, Z., Mesina, L., Xie, J., Lapointe, V., Kloosterman, F., Vonck, K., Boon, P. A., Soltesz, I., McNaughton, B. L., Luczak, A. 2017; 140 (9): 2355–69

    Abstract

    See Lenck-Santini (doi:10.1093/awx205) for a scientific commentary on this article. Epileptic seizures represent altered neuronal network dynamics, but the temporal evolution and cellular substrates of the neuronal activity patterns associated with spontaneous seizures are not fully understood. We used simultaneous recordings from multiple neurons in the hippocampus and neocortex of rats with chronic temporal lobe epilepsy to demonstrate that subsets of cells discharge in a highly stereotypical sequential pattern during ictal events, and that these stereotypical patterns were reproducible across consecutive seizures. In contrast to the canonical view that principal cell discharges dominate ictal events, the ictal sequences were predominantly composed of fast-spiking, putative inhibitory neurons, which displayed unusually strong coupling to local field potential even before seizures. The temporal evolution of activity was characterized by unique dynamics where the most correlated neuronal pairs before seizure onset displayed the largest increases in correlation strength during the seizures. These results demonstrate the selective involvement of fast spiking interneurons in structured temporal sequences during spontaneous ictal events in hippocampal and neocortical circuits in experimental models of chronic temporal lobe epilepsy.

    View details for PubMedID 29050390

    View details for PubMedCentralID PMC6248724

  • Interneuronal mechanisms of hippocampal theta oscillations in a full-scale model of the rodent CA1 circuit. eLife Bezaire, M. J., Raikov, I., Burk, K., Vyas, D., Soltesz, I. 2016; 5

    Abstract

    The hippocampal theta rhythm plays important roles in information processing; however, the mechanisms of its generation are not well understood. We developed a data-driven, supercomputer-based, full-scale (1:1) model of the rodent CA1 area and studied its interneurons during theta oscillations. Theta rhythm with phase-locked gamma oscillations and phase-preferential discharges of distinct interneuronal types spontaneously emerged from the isolated CA1 circuit without rhythmic inputs. Perturbation experiments identified parvalbumin-expressing interneurons and neurogliaform cells, as well as interneuronal diversity itself, as important factors in theta generation. These simulations reveal new insights into the spatiotemporal organization of the CA1 circuit during theta oscillations.

    View details for DOI 10.7554/eLife.18566

    View details for PubMedID 28009257

    View details for PubMedCentralID PMC5313080

  • Neurophysiology of space travel: energetic solar particles cause cell type-specific plasticity of neurotransmission. Brain structure & function Lee, S., Dudok, B., Parihar, V. K., Jung, K., Zöldi, M., Kang, Y., Maroso, M., Alexander, A. L., Nelson, G. A., Piomelli, D., Katona, I., Limoli, C. L., Soltesz, I. 2016: -?

    Abstract

    In the not too distant future, humankind will embark on one of its greatest adventures, the travel to distant planets. However, deep space travel is associated with an inevitable exposure to radiation fields. Space-relevant doses of protons elicit persistent disruptions in cognition and neuronal structure. However, whether space-relevant irradiation alters neurotransmission is unknown. Within the hippocampus, a brain region crucial for cognition, perisomatic inhibitory control of pyramidal cells (PCs) is supplied by two distinct cell types, the cannabinoid type 1 receptor (CB1)-expressing basket cells (CB1BCs) and parvalbumin (PV)-expressing interneurons (PVINs). Mice subjected to low-dose proton irradiation were analyzed using electrophysiological, biochemical and imaging techniques months after exposure. In irradiated mice, GABA release from CB1BCs onto PCs was dramatically increased. This effect was abolished by CB1 blockade, indicating that irradiation decreased CB1-dependent tonic inhibition of GABA release. These alterations in GABA release were accompanied by decreased levels of the major CB1 ligand 2-arachidonoylglycerol. In contrast, GABA release from PVINs was unchanged, and the excitatory connectivity from PCs to the interneurons also underwent cell type-specific alterations. These results demonstrate that energetic charged particles at space-relevant low doses elicit surprisingly selective long-term plasticity of synaptic microcircuits in the hippocampus. The magnitude and persistent nature of these alterations in synaptic function are consistent with the observed perturbations in cognitive performance after irradiation, while the high specificity of these changes indicates that it may be possible to develop targeted therapeutic interventions to decrease the risk of adverse events during interplanetary travel.

    View details for PubMedID 27905022

  • Target-Selectivity of Parvalbumin-Positive Interneurons in Layer II of Medial Entorhinal Cortex in Normal and Epileptic Animals HIPPOCAMPUS Armstrong, C., Wang, J., Lee, S. Y., Broderick, J., Bezaire, M. J., Lee, S., Soltesz, I. 2016; 26 (6): 779-793

    Abstract

    The medial entorhinal cortex layer II (MEClayerII ) is a brain region critical for spatial navigation and memory, and it also demonstrates a number of changes in patients with, and animal models of, temporal lobe epilepsy (TLE). Prior studies of GABAergic microcircuitry in MEClayerII revealed that cholecystokinin-containing basket cells (CCKBCs) select their targets on the basis of the long-range projection pattern of the postsynaptic principal cell. Specifically, CCKBCs largely avoid reelin-containing principal cells that form the perforant path to the ipsilateral dentate gyrus and preferentially innervate non-perforant path forming calbindin-containing principal cells. We investigated whether parvalbumin containing basket cells (PVBCs), the other major perisomatic targeting GABAergic cell population, demonstrate similar postsynaptic target selectivity as well. In addition, we tested the hypothesis that the functional or anatomic arrangement of circuit selectivity is disrupted in MEClayerII in chronic TLE, using the repeated low-dose kainate model in rats. In control animals, we found that PVBCs innervated both principal cell populations, but also had significant selectivity for calbindin-containing principal cells in MEClayerII . However, the magnitude of this preference was smaller than for CCKBCs. In addition, axonal tracing and paired recordings showed that individual PVBCs were capable of contacting both calbindin and reelin-containing principal cells. In chronically epileptic animals, we found that the intrinsic properties of the two principal cell populations, the GABAergic perisomatic bouton numbers, and selectivity of the CCKBCs and PVBCs remained remarkably constant in MEClayerII . However, miniature IPSC frequency was decreased in epilepsy, and paired recordings revealed the presence of direct excitatory connections between principal cells in the MEClayerII in epilepsy, which is unusual in normal adult MEClayerII . Taken together, these findings advance our knowledge about the organization of perisomatic inhibition both in control and in epileptic animals. © 2015 Wiley Periodicals, Inc.

    View details for DOI 10.1002/hipo.22559

    View details for Web of Science ID 000383272000009

    View details for PubMedCentralID PMC4866882

  • Target-selectivity of parvalbumin-positive interneurons in layer II of medial entorhinal cortex in normal and epileptic animals. Hippocampus Armstrong, C., Wang, J., Yeun Lee, S., Broderick, J., Bezaire, M. J., Lee, S., Soltesz, I. 2016; 26 (6): 779-793

    Abstract

    The medial entorhinal cortex layer II (MEClayerII ) is a brain region critical for spatial navigation and memory, and it also demonstrates a number of changes in patients with, and animal models of, temporal lobe epilepsy (TLE). Prior studies of GABAergic microcircuitry in MEClayerII revealed that cholecystokinin-containing basket cells (CCKBCs) select their targets on the basis of the long-range projection pattern of the postsynaptic principal cell. Specifically, CCKBCs largely avoid reelin-containing principal cells that form the perforant path to the ipsilateral dentate gyrus and preferentially innervate non-perforant path forming calbindin-containing principal cells. We investigated whether parvalbumin containing basket cells (PVBCs), the other major perisomatic targeting GABAergic cell population, demonstrate similar postsynaptic target selectivity as well. In addition, we tested the hypothesis that the functional or anatomic arrangement of circuit selectivity is disrupted in MEClayerII in chronic TLE, using the repeated low-dose kainate model in rats. In control animals, we found that PVBCs innervated both principal cell populations, but also had significant selectivity for calbindin-containing principal cells in MEClayerII . However, the magnitude of this preference was smaller than for CCKBCs. In addition, axonal tracing and paired recordings showed that individual PVBCs were capable of contacting both calbindin and reelin-containing principal cells. In chronically epileptic animals, we found that the intrinsic properties of the two principal cell populations, the GABAergic perisomatic bouton numbers, and selectivity of the CCKBCs and PVBCs remained remarkably constant in MEClayerII . However, miniature IPSC frequency was decreased in epilepsy, and paired recordings revealed the presence of direct excitatory connections between principal cells in the MEClayerII in epilepsy, which is unusual in normal adult MEClayerII . Taken together, these findings advance our knowledge about the organization of perisomatic inhibition both in control and in epileptic animals. © 2015 Wiley Periodicals, Inc.

    View details for DOI 10.1002/hipo.22559

    View details for PubMedID 26663222

  • Hippogate: a break-in from entorhinal cortex. Nature neuroscience Alexander, A., Soltesz, I. 2016; 19 (4): 530-532

    View details for DOI 10.1038/nn.4253

    View details for PubMedID 26878673

  • Cannabinoid Control of Learning and Memory through HCN Channels NEURON Maroso, M., Szabo, G. G., Kim, H. K., Alexander, A., Bui, A. D., Lee, S., Lutz, B., Soltesz, I. 2016; 89 (5): 1059-1073

    Abstract

    The mechanisms underlying the effects of cannabinoids on cognitive processes are not understood. Here we show that cannabinoid type-1 receptors (CB1Rs) control hippocampal synaptic plasticity and spatial memory through the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that underlie the h-current (Ih), a key regulator of dendritic excitability. The CB1R-HCN pathway, involving c-Jun-N-terminal kinases (JNKs), nitric oxide synthase, and intracellular cGMP, exerts a tonic enhancement of Ih selectively in pyramidal cells located in the superficial portion of the CA1 pyramidal cell layer, whereas it is absent from deep-layer cells. Activation of the CB1R-HCN pathway impairs dendritic integration of excitatory inputs, long-term potentiation (LTP), and spatial memory formation. Strikingly, pharmacological inhibition of Ih or genetic deletion of HCN1 abolishes CB1R-induced deficits in LTP and memory. These results demonstrate that the CB1R-Ih pathway in the hippocampus is obligatory for the action of cannabinoids on LTP and spatial memory formation.

    View details for DOI 10.1016/j.neuron.2016.01.023

    View details for PubMedID 26898775

  • Organization and control of epileptic circuits in temporal lobe epilepsy. Progress in brain research Alexander, A., Maroso, M., Soltesz, I. 2016; 226: 127-154

    Abstract

    When studying the pathological mechanisms of epilepsy, there are a seemingly endless number of approaches from the ultrastructural level-receptor expression by EM-to the behavioral level-comorbid depression in behaving animals. Epilepsy is characterized as a disorder of recurrent seizures, which are defined as "a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain" (Fisher et al., 2005). Such abnormal activity typically does not occur in a single isolated neuron; rather, it results from pathological activity in large groups-or circuits-of neurons. Here we choose to focus on two aspects of aberrant circuits in temporal lobe epilepsy: their organization and potential mechanisms to control these pathological circuits. We also look at two scales: microcircuits, ie, the relationship between individual neurons or small groups of similar neurons, and macrocircuits, ie, the organization of large-scale brain regions. We begin by summarizing the large body of literature that describes the stereotypical anatomical changes in the temporal lobe-ie, the anatomical basis of alterations in microcircuitry. We then offer a brief introduction to graph theory and describe how this type of mathematical analysis, in combination with computational neuroscience techniques and using parameters obtained from experimental data, can be used to postulate how microcircuit alterations may lead to seizures. We then zoom out and look at the changes which are seen over large whole-brain networks in patients and animal models, and finally we look to the future.

    View details for DOI 10.1016/bs.pbr.2016.04.007

    View details for PubMedID 27323941

  • Brain State Is a Major Factor in Preseizure Hippocampal Network Activity and Influences Success of Seizure Intervention JOURNAL OF NEUROSCIENCE Ewell, L. A., Liang, L., Armstrong, C., Soltesz, I., Leutgeb, S., Leutgeb, J. K. 2015; 35 (47): 15635-15648

    View details for DOI 10.1523/JNEUROSCI.5112-14.2015

    View details for PubMedID 26609157

  • Pass-Through Code of Synaptic Integration. Neuron Szabo, G. G., Soltesz, I. 2015; 87 (6): 1124-1126

    Abstract

    How do the components of neuronal circuits collaborate to select combinations of synaptic inputs from multiple pathways? In this issue of Neuron, Milstein et al. (2015) uncover mechanisms of synaptic facilitation and dendritic inhibition that cooperate to provide filtering for co-active inputs of distinct origins.

    View details for DOI 10.1016/j.neuron.2015.09.006

    View details for PubMedID 26402596

  • Optogenetics: 10 years after ChR2 in neurons-views from the community NATURE NEUROSCIENCE Adamantidis, A., Arber, S., Bains, J. S., Bamberg, E., Bonci, A., Buzsaki, G., Cardin, J. A., Costa, R. M., Dan, Y., Goda, Y., Graybiel, A. M., Haeusser, M., Hegemann, P., Huguenard, J. R., Insel, T. R., Janak, P. H., Johnston, D., Josselyn, S. A., Koch, C., Kreitzer, A. C., Luescher, C., Malenka, R. C., Miesenboeck, G., Nagel, G., Roska, B., Schnitzer, M. J., Shenoy, K. V., Soltesz, I., Sternson, S. M., Tsien, R. W., Tsien, R. Y., Turrigiano, G. G., Tye, K. M., Wilson, R. I. 2015; 18 (9): 1202–12

    View details for PubMedID 26308981

  • Regulation of fast-spiking basket cell synapses by the chloride channel ClC-2 NATURE NEUROSCIENCE Foldy, C., Lee, S., Morgan, R. J., Soltesz, I. 2010; 13 (9): 1047-1049

    Abstract

    Parvalbumin-expressing, fast-spiking basket cells are important for the generation of synchronous, rhythmic population activities in the hippocampus. We found that GABAA receptor-mediated synaptic inputs from murine parvalbumin-expressing basket cells were selectively modulated by the membrane voltage- and intracellular chloride-dependent chloride channel ClC-2. Our data reveal a previously unknown cell type-specific regulation of intracellular chloride homeostasis in the perisomatic region of hippocampal pyramidal neurons.

    View details for DOI 10.1038/nn.2609

    View details for Web of Science ID 000281332600006

    View details for PubMedID 20676104

    View details for PubMedCentralID PMC2928876