Integration of quanta in cerebellar granule cells during sensory processing

Chadderton, Paul; Margrie, Troy W.; Häusser, Michael

doi:10.1038/nature02442

Cited by 610 publications

(779 citation statements)

References 32 publications

Supporting

Mentioning

708

Contrasting

Unclassified

Order By: Relevance

“…Unfortunately, the very small size of the granule cell axon and the enormity of the synaptic input to the Purkinje cell conspire to make these values very difficult to obtain experimentally and even harder to manipulate. Recent work by Hausser and his group are starting to provide important new information about the temporal response properties of individual granule cells (Chadderton et al 2004), but it is still not clear how somatic responses are translated into parallel fiber activity (Mocanu et al 2000) or how individual responses reflect the responses of large populations of granule cells to afferent input. The results presented in this paper were intended to begin to provide the basis for a new experimental approach to determining or at least constraining relative levels of cortical synaptic activity.…”

Section: Predicted Critical Parametersmentioning

confidence: 99%

“…It would therefore appear that Purkinje cells might be particularly tuned or sensitive to different temporal afferent activation patterns. Unfortunately, to date, most experimental studies of cerebellar response properties to tactile stimulation have been conducted using isolated single stimuli (Bower and Woolston 1983;Chadderton et al 2004;Morrissette and Bower 1996).…”

Section: Long-duration Modulatory Effectsmentioning

confidence: 99%

See 1 more Smart Citation

Background Synaptic Activity Modulates the Response of a Modeled Purkinje Cell to Paired Afferent Input

Santamarı́a¹,

Bower²

2005

Journal of Neurophysiology

View full text Add to dashboard Cite

Santamaria, Fidel and James M. Bower. Background synaptic activity modulates the response of a modeled Purkinje cell to paired afferent input. J Neurophysiol 93: [237][238][239][240][241][242][243][244][245][246][247][248][249][250] 2005. First published August 11, 2004; doi:10.1152/jn.00458.2004. We studied the possible effects of background excitatory and inhibitory synaptic activity on Purkinje cell responses to paired pulse inputs using a morphologically and physiologically detailed compartmental model. Paired-pulse inputs were provided via synapses associated with the ascending segment of the granule cell axon in the presence of variable amounts of background synaptic input provided by parallel fibers and inhibitory interneurons. The results predict the amplitude and dynamics of the somatic and dendritic responses to paired ascending segment inputs are modulated by the level of background synaptic activity, the basal somatic firing rate of the Purkinje cell model does not indicate the type or degree of modulation, and the modulatory effects are mediated through dendritic calcium and calcium-activated potassium currents. These results have important consequences for the functional organization of cerebellar cortex as well as the more general issue of the modulatory as distinct from driving effects of synapses now also being considered in other regions of the mammalian brain including the cerebral cortex. I N T R O D U C T I O NIn recent years, there has been a continually growing interest in the interaction between the active electrical properties of neuronal dendrites and the responses of those dendrites to synaptic input (Chance et al. 2002;Euler and Denk 2001;Hausser and Mel 2003;Migliore and Shepherd 2002). Although neuronal dendrites have traditionally most often been modeled as spatial and temporal summing devices (see London and Segev 1999;Rall 1999), it is clear that the presence of active conductances in dendrites substantially affects how these structures integrate synaptic inputs (Cook and Johnston 1999;De Schutter and Bower 1994c;London and Segev 2001;Poirazi et al. 2003;Williams and Stuart 2002). In fact, model (Chance et al. 2002)-and experimental-based (Frick et al. 2004) studies of the functional consequences of active dendritic membranes are starting to raise questions about whether all synapses are fundamentally "driving" in nature. Specifically, it is now being suggested that some synapses might be more involved in regulating dendritic dynamics than in directly influencing the spiking output of neurons (Chance et al. 2002;De Schutter and Bower 1994b;Jaeger and Bower 1999;Jaeger et al. 1997;Rhodes and Llinas 2001;Santamaria et al. 2002;Sherman and Guillery 1998).The cerebellar Purkinje cell was one of the first mammalian neurons in which experimental studies demonstrated substantial voltage-dependent dendritic conductances (Llinas and Sugimori 1980). Using an articulated set of modeling and experimental studies, we have engaged in a series of experiments intended to better understand the f...

show abstract

Section: Predicted Critical Parametersmentioning

confidence: 99%

Section: Long-duration Modulatory Effectsmentioning

confidence: 99%

Background Synaptic Activity Modulates the Response of a Modeled Purkinje Cell to Paired Afferent Input

Santamarı́a¹,

Bower²

2005

Journal of Neurophysiology

View full text Add to dashboard Cite

show abstract

“…These GABARs generate a tonic inhibitory conductance [20][21][22] that exerts strong control over granule cell firing patterns in vivo 23 .…”

mentioning

confidence: 99%

Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity

et al. 2005

View full text Add to dashboard Cite

Neuronal mechanisms underlying alcohol intoxication are unclear. We find that alcohol impairs motor coordination by enhancing tonic inhibition mediated by a specific subtype of extrasynaptic GABA A receptor (GABAR), α6β3δ, expressed exclusively in cerebellar granule cells. In recombinant studies, we characterize a naturally occurring single-nucleotide polymorphism that causes a single amino acid change (R100Q) in α6 (encoded in rats by the Gabra6 gene). We show that this change selectively increases alcohol sensitivity of α6β3δ GABARs. Behavioral and electrophysiological comparisons of Gabra6 100R/100R and Gabra6 100Q/100Q rats strongly suggest that alcohol impairs motor coordination by enhancing granule cell tonic inhibition. These findings identify extrasynaptic GABARs as critical targets underlying low-dose alcohol intoxication and demonstrate that subtle changes in tonic inhibition in one class of neurons can alter behavior.Humans have been consuming alcohol for thousands of years, and the use of alcoholic beverages pervades human culture and society and can have substantial health effects 1 . Different mechanisms by which ethanol might depress brain function have been proposed based on ethanol's ability to modulate a wide variety of ion channels 2-4 , neurotransmitter receptors 5-10 and transporters 11 . Among these diverse targets, however, GABARs are arguably the most attractive candidates. This is in part because other classes of known GABAR modulators such as benzodiazepines, barbiturates and certain anesthetics lead to behavioral effects that closely resemble ethanol intoxication. Yet despite strong evidence implicating GABARs in ethanol's action, critical details remain unclear. For instance, although it is known that native GABARs are heteropentamers assembled from 19 possible subunits 12,13 , it has not been possible to link the activity of particular GABAR subunits to changes in behavioral sensitivity to ethanol.Recent studies suggest that specific combinations of GABAR subunits (those containing α4β3δ and α6β3δ) are uniquely sensitive to ethanol, showing dose dependencies that mirror blood alcohol levels associated with intoxication in humans 9,10 . GABARs containing α4 and δ subunits are expressed in many brain regions 14,15 , but α6 is found in only two types of neurons (cerebellar granule cells and granule cells in the cochlear nucleus) and is expressed together with δ only in cerebellar granule cells 14,16,17 . In granule cells α6 and δ combine with β subunits Correspondence should be addressed to M.W. (mwallner@mednet.ucla.edu) or T.S.O. (otist@ucla.edu). 3 These authors contributed equally to this work. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. We set out to examine whether such extrasynaptic GABARs containing α6 and δ subunits account for behavioral effects of ethanol at moderately intoxicating doses. To link these particular GABARs to behavioral sensitivity, we first characterized a naturally occurring single-nucleotide polymo...

show abstract

“…T he waveform of rapid synaptic responses shapes the temporal domain of signal integration in the brain (1,2). In turn, the kinetics of synaptic receptor currents is constrained by diffusion of neurotransmitter in the synaptic cleft (3,4).…”

mentioning

confidence: 99%

The optimal height of the synaptic cleft

Savtchenko

Rusakov

2007

Proc. Natl. Acad. Sci. U.S.A.

142

181

View full text Add to dashboard Cite

Signal integration in the brain is determined by the size and kinetics of rapid synaptic responses. The latter, in turn, depends on the concentration profile of neurotransmitter in the synaptic cleft. According to a traditional view, narrower clefts should correspond to higher intracleft concentrations of neurotransmitter, and therefore to the enhanced activation of synaptic receptors. Here, we argue that narrowing the cleft also increases electrical resistance of the intracleft medium and therefore reduces local receptor currents. We employ detailed theoretical analyses and Monte Carlo simulations to propose that these two contrasting phenomena result in a relatively narrow range of cleft heights at which the synaptic receptor current reaches its maximum. Over a physiological range of synaptic parameters, the ''optimum'' height falls between Ϸ12 and 20 nm. This range is consistent with the structure of central synapses reported by electron microscopy. Therefore, our results suggest that a simple fundamental principle may underlie the synaptic cleft architecture: to maximize synaptic strength.T he waveform of rapid synaptic responses shapes the temporal domain of signal integration in the brain (1, 2). In turn, the kinetics of synaptic receptor currents is constrained by diffusion of neurotransmitter in the synaptic cleft (3, 4). This relationship, however, remains poorly understood, mainly because events inside the cleft are beyond the powers of direct experimental observation. There is little doubt, however, that synaptic cleft geometry is an important factor in shaping synaptic currents (3, 5-7). The straightforward logic of physics predicts that decreasing the cleft height should increase the intracleft concentration of neurotransmitter and therefore enhance activation of synaptic receptors (8). In turn, increasing the lateral cleft size could generally slow down neurotransmitter escape from the cleft and thus prolong synaptic responses (9). Indeed, faster AMPA receptor-mediated EPSCs have recently been associated with smaller synaptic apposition zones in the developing cerebellar synapses (10). However, lateral dimensions of synapses fluctuate considerably (even within homogeneous synaptic populations), whereas the cleft height remains remarkably stable. For instance, at the common excitatory synapses in hippocampal area CA1, the lateral cleft area varies several-fold (11) whereas the cleft height shows the coefficient of variation (an upper estimate) of only Ϸ26% (12). Interestingly, osmotic challenge or other physiological manipulations that affect dramatically the overall extracellular space dimensions (13, 14) do not appear to modify the synaptic cleft height (15). This parameter also remains virtually unchanged during development (16-18). Remarkably, in electron micrographs of synaptosomes (a preparation obtained using strong mechanical forces of centrifugal separation), the distance between the apposing synaptic membranes is indistinguishable from that in the intact neuropil. Across many synaptic type...

show abstract

Integration of quanta in cerebellar granule cells during sensory processing

Cited by 610 publications

References 32 publications

Background Synaptic Activity Modulates the Response of a Modeled Purkinje Cell to Paired Afferent Input

Background Synaptic Activity Modulates the Response of a Modeled Purkinje Cell to Paired Afferent Input

Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity

The optimal height of the synaptic cleft

Contact Info

Product

Resources

About