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Dive into the research topics where John R. Huguenard is active.

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Featured researches published by John R. Huguenard.


Nature | 2011

Neocortical excitation/inhibition balance in information processing and social dysfunction

Ofer Yizhar; Lief E. Fenno; Matthias Prigge; Franziska Schneider; Thomas J. Davidson; Daniel J. O’Shea; Vikaas S. Sohal; Inbal Goshen; Joel Finkelstein; Jeanne T. Paz; Katja Stehfest; Roman Fudim; Charu Ramakrishnan; John R. Huguenard; Peter Hegemann; Karl Deisseroth

Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to direct testing. Here we design and use several novel optogenetic tools to causally investigate the cellular E/I balance hypothesis in freely moving mammals, and explore the associated circuit physiology. Elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex was found to elicit a profound impairment in cellular information processing, associated with specific behavioural impairments and increased high-frequency power in the 30–80 Hz range, which have both been observed in clinical conditions in humans. Consistent with the E/I balance hypothesis, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation. These results provide support for the elevated cellular E/I balance hypothesis of severe neuropsychiatric disease-related symptoms.


Nature | 2012

A call for transparent reporting to optimize the predictive value of preclinical research

Story C. Landis; Susan G. Amara; Khusru Asadullah; Christopher P. Austin; Robi Blumenstein; Eileen W. Bradley; Ronald G. Crystal; Robert B. Darnell; Robert J. Ferrante; Howard Fillit; Robert Finkelstein; Marc Fisher; Howard E. Gendelman; Robert M. Golub; John L. Goudreau; Robert A. Gross; Amelie K. Gubitz; Sharon E. Hesterlee; David W. Howells; John R. Huguenard; Katrina Kelner; Walter J. Koroshetz; Dimitri Krainc; Stanley E. Lazic; Michael S. Levine; Malcolm R. Macleod; John M. McCall; Richard T. Moxley; Kalyani Narasimhan; L.J. Noble

The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress.


The Journal of Neuroscience | 1992

A novel T-type current underlies prolonged Ca(2+)-dependent burst firing in GABAergic neurons of rat thalamic reticular nucleus

John R. Huguenard; David A. Prince

The inhibitory GABAergic projection of thalamic nucleus reticularis (nRt) neurons onto thalamocortical relay cells (TCs) is important in generating the normal thalamocortical rhythmicity of slow wave sleep, and may be a key element in the production of abnormal rhythms associated with absence epilepsy. Both TCs and nRt cells can generate prominent Ca(2+)-dependent low-threshold spikes, which evoke bursts of Na(+)-dependent fast spikes, and are influential in rhythm generation. Substantial differences in the pattern of burst firing in TCs versus nRt neurons led us to hypothesize that there are distinct forms of transient Ca2+ current (I(T)) underlying burst discharges in these two cell types. Using whole-cell voltage-clamp recordings, we analyzed I(T) in acutely isolated TCs and nRt neurons and found three key differences in biophysical properties. (1) The transient Ca2+ current in nRt neurons inactivated much more slowly than I(T) in TCs. This slow current is thus termed I(Ts). (2) The rate of inactivation for I(Ts) was nearly voltage independent. (3) Whole-cell I(Ts) amplitude was increased when Ba2+ was substituted for Ca2+ as the charge carrier. In addition, activation kinetics were slower for I(Ts) and the activation range was depolarized compared to that for I(T). Other properties of I(Ts) and I(T) were similar, including steady-state inactivation and sensitivities to blockade by divalent cations, amiloride, and antiepileptic drugs. Our findings demonstrate that subtypes of transient Ca2+ current are present in two different classes of thalamic neurons. The properties of I(Ts) lead to generation of long-duration calcium-dependent spike bursts in nRt cells. The resultant prolonged periods of GABA release onto TCs would play a critical role in maintaining rhythmicity by inducing TC hyperpolarization and promoting generation of low-threshold calcium spikes within relay nuclei.


The Journal of Physiology | 1989

Calcium currents in rat thalamocortical relay neurones: kinetic properties of the transient, low-threshold current.

Douglas A. Coulter; John R. Huguenard; David A. Prince

1. Calcium currents were recorded with whole‐cell voltage‐clamp procedures in relay neurones of the rat thalamus which had been acutely isolated by an enzymatic dissociation procedure. 2. Low‐threshold and high‐threshold Ca2+ currents were elicited by depolarizing voltage steps from holding potentials more negative than ‐60 mV. A transient current, analogous to the T‐current in sensory neurones, was activated at low threshold near ‐65 mV and was completely inactivating at command steps up to ‐35 mV. Voltage steps to more depolarized levels activated a high‐threshold current that inactivated slowly and incompletely during a 200 ms step depolarization. 3. The high‐threshold current contained both non‐inactivating and slowly inactivating components which were insensitive and sensitive to holding potential, respectively. 4. A ‘T‐type’ current was prominent in relay neurones, in both absolute terms (350 pA peak current average) and in relation to high‐threshold currents. The average ratio of maximum transient to maximum sustained current was greater than 2. 5. T‐current could be modelled in a manner analogous to that employed for the fast Na+ current underlying action potential generation, using the m3h format. The rate of activation of T‐current was voltage dependent, with a time constant (tau m) varying between 8 and 2 ms at command potentials of ‐60 to ‐10 mV at 23 degrees C. The rate of inactivation was also voltage dependent, and the time constant tau h varied between 50 and 20 ms over the same voltage range. With command potentials more positive than ‐35 mV, the inactivation of Ca2+ current could no longer be fitted by a single exponential. 6. Steady‐state inactivation of T‐current could be well fitted by a Boltzman equation with slope factor of 6.3 and half‐inactivated voltage of ‐83.5 mV. 7. Recovery from inactivation of T‐current was not exponential. The major component of recovery (70‐80% of total) was not very voltage sensitive at potentials more negative than ‐90 mV, with tau r of 251 ms at ‐92 mV and 23 degrees C, compared to 225 ms at ‐112 mV. A smaller, voltage‐sensitive component accounted for the remainder of recovery. 8. All kinetic properties, including rates of activation, inactivation, and recovery from inactivation, as well as the amplitude of T‐current, were temperature sensitive with Q10 (temperature coefficient) values of greater than 2.5.(ABSTRACT TRUNCATED AT 400 WORDS)


Neuron | 1995

A Model of Spike Initiation in Neocortical Pyramidal Neurons

Zachary F. Mainen; Jasdan Joerges; John R. Huguenard; Terrence J. Sejnowski

Neocortical pyramidal cells possess voltage-dependent dendritic sodium channels that promote propagation of action potentials into the dendritic tree but paradoxically may fail to originate dendritic spikes. A biophysical model was constructed to reconcile these observations with known anatomical and physiological properties. When dendritic and somatic sodium channel densities compatible with electrophysiological measurements were combined with much higher densities in the axon initial segment then, regardless of the site of stimulation, spikes initiated at the initial segment and subsequently invaded the dendrites. The lower initial segment threshold arose from high current density and electrical isolation from the soma. Failure of dendritic channels to initiate spikes was due to inactivation and source-load considerations, which were more favorable for conduction of back-propagated spikes.


Nature Neuroscience | 2013

Closed-loop optogenetic control of thalamus as a tool for interrupting seizures after cortical injury

Jeanne T. Paz; Thomas J. Davidson; Eric S. Frechette; Bruno Delord; Isabel Parada; Kathy Peng; Karl Deisseroth; John R. Huguenard

Cerebrocortical injuries such as stroke are a major source of disability. Maladaptive consequences can result from post-injury local reorganization of cortical circuits. For example, epilepsy is a common sequela of cortical stroke, but the mechanisms responsible for seizures following cortical injuries remain unknown. In addition to local reorganization, long-range, extra-cortical connections might be critical for seizure maintenance. In rats, we found that the thalamus, a structure that is remote from, but connected to, the injured cortex, was required to maintain cortical seizures. Thalamocortical neurons connected to the injured epileptic cortex underwent changes in HCN channel expression and became hyperexcitable. Targeting these neurons with a closed-loop optogenetic strategy revealed that reducing their activity in real-time was sufficient to immediately interrupt electrographic and behavioral seizures. This approach is of therapeutic interest for intractable epilepsy, as it spares cortical function between seizures, in contrast with existing treatments, such as surgical lesioning or drugs.


Trends in Neurosciences | 2007

Thalamic synchrony and dynamic regulation of global forebrain oscillations

John R. Huguenard; David A. McCormick

The circuitry within the thalamus creates an intrinsic oscillatory unit whose function depends critically on reciprocal synaptic connectivity between excitatory thalamocortical relay neurons and inhibitory thalamic reticular neurons along with a robust post-inhibitory rebound mechanism in relay neurons. Feedforward and feedback connections between cortex and thalamus reinforce the thalamic oscillatory activity into larger thalamocortical networks to generate sleep spindles and spike-wave discharge of generalized absence epilepsy. The degree of synchrony within the thalamic network seems to be crucial in determining whether normal (spindle) or pathological (spike-wave) oscillations occur, and recent studies show that regulation of excitability in the reticular nucleus leads to dynamical modulation of the state of the thalamic circuit and provide a basis for explaining how a variety of unrelated genetic alterations might lead to the spike-wave phenotype. In addition, given the central role of the reticular nucleus in generating spike-wave discharge, these studies have suggested specific interventions that would prevent seizures while still allowing normal spindle generation to occur. This review is part of the INMED/TINS special issue Physiogenic and pathogenic oscillations: the beauty and the beast, based on presentations at the annual INMED/TINS symposium (http://inmednet.com).


Nature | 2004

Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids

Alberto Bacci; John R. Huguenard; David A. Prince

Neocortical GABA-containing interneurons form complex functional networks responsible for feedforward and feedback inhibition and for the generation of cortical oscillations associated with several behavioural functions. We previously reported that fast-spiking (FS), but not low-threshold-spiking (LTS), neocortical interneurons from rats generate a fast and precise self-inhibition mediated by inhibitory autaptic transmission. Here we show that LTS cells possess a different form of self-inhibition. LTS, but not FS, interneurons undergo a prominent hyperpolarization mediated by an increased K+-channel conductance. This self-induced inhibition lasts for many minutes, is dependent on an increase in intracellular [Ca2+] and is blocked by the cannabinoid receptor antagonist AM251, indicating that it is mediated by the autocrine release of endogenous cannabinoids. Endocannabinoid-mediated slow self-inhibition represents a powerful and long-lasting mechanism that alters the intrinsic excitability of LTS neurons, which selectively target the major site of excitatory connections onto pyramidal neurons; that is, their dendrites. Thus, modulation of LTS networks after their sustained firing will lead to long-lasting changes of glutamate-mediated synaptic strength in pyramidal neurons, with consequences during normal and pathophysiological cortical network activities.


Neuron | 2009

Neurons that fire together also conspire together: is normal sleep circuitry hijacked to generate epilepsy?

Mark P. Beenhakker; John R. Huguenard

Brain circuits oscillate during sleep. The same circuits appear to generate pathological oscillations. In this review, we discuss recent advances in our understanding of how epilepsy co-opts normal, sleep-related circuits to generate seizures.


The Journal of Neuroscience | 2006

Barrel cortex microcircuits: thalamocortical feedforward inhibition in spiny stellate cells is mediated by a small number of fast-spiking interneurons.

Qian-Quan Sun; John R. Huguenard; David A. Prince

Inhibitory and excitatory neurons located in rodent barrel cortex are known to form functional circuits mediating vibrissal sensation. Excitatory neurons located in a single barrel greatly outnumber interneurons, and form extensive reciprocal excitatory synaptic contacts. Inhibitory and excitatory networks must interact to shape information ascending to cortex. The details of these interactions, however, have not been completely explored. Using paired intracellular recordings, we studied the properties of synaptic connections between spiny neurons (i.e., spiny stellate and pyramidal cells) and interneurons, as well as integration of thalamocortical (TC) input, in layer IV barrels of rat thalamocortical slices. Results show the following: (1) the strength of unitary excitatory connections of spiny neurons is similar among different targets; (2) although inhibition from regular-spiking nonpyramidal interneurons to spiny neurons is comparable in strength to excitatory connections, inhibition mediated by fast-spiking (FS) interneurons is 10 times more powerful; (3) TC EPSPs elicit reliable and precisely timed action potentials in FS neurons; and (4) a small number of FS neurons mediate thalamocortical feedforward inhibition in each spiny neuron and can powerfully shunt TC-mediated excitation. The ready activation of FS cells by TC inputs, coupled with powerful feedforward inhibition from these neurons, would profoundly influence sensory processing and constrain runaway excitation in vivo.

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Douglas A. Coulter

Children's Hospital of Philadelphia

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Alain Destexhe

Centre national de la recherche scientifique

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