Plasticity of Both Excitatory and Inhibitory Synapses Is Associated With Seizures Induced by Removal of Chronic Blockade of Activity in Cultured Hippocampus

2006 ◽  
Vol 96 (4) ◽  
pp. 2151-2167 ◽  
Author(s):  
Suzanne B. Bausch ◽  
Shuijin He ◽  
Yelena Petrova ◽  
Xiao-Min Wang ◽  
James O. McNamara
Keyword(s):  
Granule Cell ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Field Potential ◽  
Inhibitory Synapses ◽  
Current Frequency ◽  
Synaptic Circuits ◽  
Acquired Epilepsy ◽  
The Impact ◽  
Excitatory And Inhibitory Synapses

One factor common to many neurological insults that can lead to acquired epilepsy is a loss of afferent neuronal input. Neuronal activity is one cellular mechanism implicated in transducing deafferentation into epileptogenesis. Therefore the effects of chronic activity blockade on seizure susceptibility and its underlying mechanisms were examined in organotypic hippocampal slice cultures treated chronically with the sodium channel blocker, tetrodotoxin (TTX), or the N-methyl-d-aspartate receptor (NMDAR) antagonist, d-2-amino-5-phosphonovaleric acid (d-APV). Granule cell field potential recordings in physiological buffer revealed spontaneous electrographic seizures in 83% of TTX-, 9% of d-APV-, but 0% of vehicle-treated cultures. TTX-induced seizures were not associated with membrane property alterations that would elicit granule cell hyperexcitability. Seizures were blocked by glutamate receptor antagonists, suggesting that plasticity in excitatory synaptic circuits contributed to seizures. The morphology of granule cells and their mossy fiber axons remained largely unchanged, and the number of synapses onto granule cells measured immunohistochemically was not increased in TTX- or d-APV-treated cultures. However, voltage-clamp recordings revealed that miniature excitatory postsynaptic current frequency and kinetics were increased and miniature inhibitory postsynaptic current kinetics were decreased in d-APV- and TTX-treated cultures compared with vehicle. Changes were more profound and qualitatively different in TTX- compared with d-APV-treated cultures, consistent with the dramatic effects of TTX treatment on seizure expression. We propose that chronic blockade of action potentials by TTX induces homeostatic responses including plasticity of both excitatory and inhibitory synapses. Removal of TTX unmasks the impact of these synaptic plasticities on local circuit excitability, resulting in spontaneous seizures.

scholarly journals Efficient generation of reciprocal signals by inhibition

2012 ◽  
Vol 107 (9) ◽  
pp. 2453-2462 ◽  
Author(s):  
Sung-min Park ◽  
Esra Tara ◽  
Kamran Khodakhah
Keyword(s):  
Purkinje Cells ◽  
Granule Cell ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Cell Activity ◽  
Common Mechanism ◽  
Input Output ◽  
Firing Rates ◽  
Neuronal Computation ◽  
The Brain

Reciprocal activity between populations of neurons has been widely observed in the brain and is essential for neuronal computation. The different mechanisms by which reciprocal neuronal activity is generated remain to be established. A common motif in neuronal circuits is the presence of afferents that provide excitation to one set of principal neurons and, via interneurons, inhibition to a second set of principal neurons. This circuitry can be the substrate for generation of reciprocal signals. Here we demonstrate that this equivalent circuit in the cerebellar cortex enables the reciprocal firing rates of Purkinje cells to be efficiently generated from a common set of mossy fiber inputs. The activity of a mossy fiber is relayed to Purkinje cells positioned immediately above it by excitatory granule cells. The firing rates of these Purkinje cells increase as a linear function of mossy fiber, and thus granule cell, activity. In addition to exciting Purkinje cells positioned immediately above it, the activity of a mossy fiber is relayed to laterally positioned Purkinje cells by a disynaptic granule cell → molecular layer interneuron pathway. Here we show in acutely prepared cerebellar slices that the input-output relationship of these laterally positioned Purkinje cells is linear and reciprocal to the first set. A similar linear input-output relationship between decreases in Purkinje cell firing and strength of stimulation of laterally positioned granule cells was also observed in vivo. Use of interneurons to generate reciprocal firing rates may be a common mechanism by which the brain generates reciprocal signals.

Mossy Fiber–Granule Cell Synapses in the Normal and Epileptic Rat Dentate Gyrus Studied With Minimal Laser Photostimulation

1999 ◽  
Vol 82 (4) ◽  
pp. 1883-1894 ◽  
Author(s):  
Péter Molnár ◽  
J. Victor Nadler
Keyword(s):  
Status Epilepticus ◽  
Dentate Gyrus ◽  
Granule Cell ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Hippocampal Formation ◽  
Control Groups ◽  
Small Component ◽  
Fiber Growth ◽  
And Control

Dentate granule cells become synaptically interconnected in the hippocampus of persons with temporal lobe epilepsy, forming a recurrent mossy fiber pathway. This pathway may contribute to the development and propagation of seizures. The physiology of mossy fiber–granule cell synapses is difficult to characterize unambiguously, because electrical stimulation may activate other pathways and because there is a low probability of granule cell interconnection. These problems were addressed by the use of scanning laser photostimulation in slices of the caudal hippocampal formation. Glutamate was released from a caged precursor with highly focused ultraviolet light to evoke action potentials in a small population of granule cells. Excitatory synaptic currents were recorded in the presence of bicuculline. Minimal laser photostimulation evoked an apparently unitary excitatory postsynaptic current (EPSC) in 61% of granule cells from rats that had experienced pilocarpine-induced status epilepticus followed by recurrent mossy fiber growth. An EPSC was also evoked in 13–16% of granule cells from the control groups. EPSCs from status epilepticus and control groups had similar peak amplitudes (∼30 pA), 20–80% rise times (∼1.2 ms), decay time constants (∼10 ms), and half-widths (∼8 ms). The mean failure rate was high (∼70%) in both groups, and in both groups activation of N-methyl-d-aspartate receptors contributed a small component to the EPSC. The strong similarity between responses from the status epilepticus and control groups suggests that they resulted from activation of a similar synaptic population. No EPSC was recorded when the laser beam was focused in the dentate hilus, suggesting that indirect activation of hilar mossy cells contributed little, if at all, to these results. Recurrent mossy fiber growth increases the density of mossy fiber–granule cell synapses in the caudal dentate gyrus by perhaps sixfold, but the new synapses appear to operate very similarly to preexisting mossy fiber–granule cell synapses.

Optical Recording Study of Granule Cell Activities in the Hippocampal Dentate Gyrus of Kainate-Treated Rats

2000 ◽  
Vol 83 (4) ◽  
pp. 2421-2430 ◽  
Author(s):  
Yo Otsu ◽  
Eiichi Maru ◽  
Hisayuki Ohata ◽  
Ichiro Takashima ◽  
Riichi Kajiwara ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Granule Cell ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Molecular Layer ◽  
Mossy Fibers ◽  
Optical Recording ◽  
Granule Cell Layer ◽  
Gabaergic Inhibition ◽  
Mossy Fiber Sprouting

In the epileptic hippocampus, newly sprouted mossy fibers are considered to form recurrent excitatory connections to granule cells in the dentate gyrus and thereby increase seizure susceptibility. To study the effects of mossy fiber sprouting on neural activity in individual lamellae of the dentate gyrus, we used high-speed optical recording to record signals from voltage-sensitive dye in hippocampal slices prepared from kainate-treated epileptic rats (KA rats). In 14 of 24 slices from KA rats, hilar stimulation evoked a large depolarization in almost the entire molecular layer in which granule cell apical dendrites are located. The signals were identified as postsynaptic responses because of their dependence on extracellular Ca2+. The depolarization amplitude was largest in the inner molecular layer (the target area of sprouted mossy fibers) and declined with increasing distance from the granule cell layer. In the inner molecular layer, a good correlation was obtained between depolarization size and the density of mossy fiber terminals detected by Timm staining methods. Blockade of GABAergic inhibition by bicuculline enlarged the depolarization in granule cell dendrites. Our data indicate that mossy fiber sprouting results in a large and prolonged synaptic depolarization in an extensive dendritic area and that the enhanced GABAergic inhibition partly masks the synaptic depolarization. However, despite the large dendritic excitation induced by the sprouted mossy fibers, seizurelike activity of granule cells was never observed, even when GABAergic inhibition was blocked. Therefore, mossy fiber sprouting may not play a critical role in epileptogenesis.

scholarly journals High Ratio of Synaptic Excitation to Synaptic Inhibition in Hilar Ectopic Granule Cells of Pilocarpine-Treated Rats

2010 ◽  
Vol 104 (6) ◽  
pp. 3293-3304 ◽  
Author(s):  
Ren-Zhi Zhan ◽  
Olga Timofeeva ◽  
J. Victor Nadler
Keyword(s):  
Status Epilepticus ◽  
Granule Cell ◽  
Granule Cells ◽  
Mossy Fiber ◽  
High Ratio ◽  
Synaptic Function ◽  
Excitatory Postsynaptic Currents ◽  
Inhibitory Postsynaptic Currents ◽  
Synaptic Excitation ◽  
Postsynaptic Currents

After experimental status epilepticus, many dentate granule cells born into the postseizure environment migrate aberrantly into the dentate hilus. Hilar ectopic granule cells (HEGCs) have also been found in persons with epilepsy. These cells exhibit a high rate of spontaneous activity, which may enhance seizure propagation. Electron microscopic studies indicated that HEGCs receive more recurrent mossy fiber innervation than normotopic granule cells in the same animals but receive much less inhibitory innervation. This study used hippocampal slices prepared from rats that had experienced pilocarpine-induced status epilepticus to test the hypothesis that an imbalance of synaptic excitation and inhibition contributes to the hyperexcitability of HEGCs. Mossy fiber stimulation evoked a much smaller GABAA receptor–mediated inhibitory postsynaptic currents (IPSC) in HEGCs than in normotopic granule cells from either control rats or rats that had experienced status epilepticus. However, recurrent mossy fiber-evoked excitatory postsynaptic currents (EPSCs) of similar size were recorded from HEGCs and normotopic granule cells in status epilepticus–experienced rats. HEGCs exhibited the highest frequency of miniature excitatory postsynaptic currents (mEPSCs) and the lowest frequency of miniature inhibitory postsynaptic currents (mIPSCs) of any granule cell group. On average, both mEPSCs and mIPSCs were of higher amplitude, transferred more charge per event, and exhibited slower kinetics in HEGCs than in granule cells from control rats. Charge transfer per unit time in HEGCs was greater for mEPSCs and much less for mIPSCs than in the normotopic granule cell groups. A high ratio of excitatory to inhibitory synaptic function probably accounts, in part, for the hyperexcitability of HEGCs.

Effect of Nonlinear Summation of Synaptic Currents on the Input–Output Properties of Spinal Motoneurons

2005 ◽  
Vol 94 (5) ◽  
pp. 3465-3478 ◽  
Author(s):  
S. Cushing ◽  
T. Bui ◽  
P. K. Rose
Keyword(s):  
Synaptic Activity ◽  
Inhibitory Synapses ◽  
Excitatory Synapses ◽  
Input Output ◽  
Highly Nonlinear ◽  
Intrinsic Nonlinearity ◽  
Motoneuron Activity ◽  
The Impact ◽  
Driving Potential ◽  
Excitatory And Inhibitory Synapses

A single spinal motoneuron receives tens of thousands of synapses. The neurotransmitters released by many of these synapses act on iontotropic receptors and alter the driving potential of neighboring synapses. This interaction introduces an intrinsic nonlinearity in motoneuron input–output properties where the response to two simultaneous inputs is less than the linear sum of the responses to each input alone. Our goal was to determine the impact of this nonlinearity on the current delivered to the soma during activation of predetermined numbers and distributions of excitatory and inhibitory synapses. To accomplish this goal we constructed compartmental models constrained by detailed measurements of the geometry of the dendritic trees of three feline motoneurons. The current “lost” as a result of local changes in driving potential was substantial and resulted in a highly nonlinear relationship between the number of active synapses and the current reaching the soma. Background synaptic activity consisting of a balanced activation of excitatory and inhibitory synapses further decreased the current delivered to the soma, but reduced the nonlinearity with respect to the total number of active excitatory synapses. Unexpectedly, simulations that mimicked experimental measures of nonlinear summation, activation of two sets of excitatory synapses, resulted in nearly linear summation. This result suggests that nonlinear summation can be difficult to detect, despite the substantial “loss” of current arising from nonlinear summation. The magnitude of this “loss” appears to limit motoneuron activity, based solely on activation of iontotropic receptors, to levels that are inadequate to generate functionally meaningful muscle forces.

scholarly journals Contributions of Mossy Fiber and CA1 Pyramidal Cell Sprouting to Dentate Granule Cell Hyperexcitability in Kainic Acid–Treated Hippocampal Slice Cultures

2004 ◽  
Vol 92 (6) ◽  
pp. 3582-3595 ◽  
Author(s):  
Suzanne B. Bausch ◽  
James O. McNamara
Keyword(s):  
Dentate Gyrus ◽  
Kainic Acid ◽  
Granule Cell ◽  
Hippocampal Slice ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Mossy Fibers ◽  
Axonal Sprouting ◽  
Mossy Fiber Sprouting ◽  
Hippocampal Slice Cultures

Axonal sprouting like that of the mossy fibers is commonly associated with temporal lobe epilepsy, but its significance remains uncertain. To investigate the functional consequences of sprouting of mossy fibers and alternative pathways, kainic acid (KA) was used to induce robust mossy fiber sprouting in hippocampal slice cultures. Physiological comparisons documented many similarities in granule cell responses between KA- and vehicle-treated cultures, including: seizures, epileptiform bursts, and spontaneous excitatoty postsynaptic currents (sEPSCs) >600pA. GABAergic control and contribution of glutamatergic synaptic transmission were similar. Analyses of neurobiotin-filled CA1 pyramidal cells revealed robust axonal sprouting in both vehicle- and KA-treated cultures, which was significantly greater in KA-treated cultures. Hilar stimulation evoked an antidromic population spike followed by variable numbers of postsynaptic potentials (PSPs) and population spikes in both vehicle- and KA-treated cultures. Despite robust mossy fiber sprouting, knife cuts separating CA1 from dentate gyrus virtually abolished EPSPs evoked by hilar stimulation in KA-treated but not vehicle-treated cultures, suggesting a pivotal role of functional afferents from CA1 to dentate gyrus in KA-treated cultures. Together, these findings demonstrate striking hyperexcitability of dentate granule cells in long-term hippocampal slice cultures after treatment with either vehicle or KA. The contribution to hilar-evoked hyperexcitability of granule cells by the unexpected axonal projection from CA1 to dentate in KA-treated cultures reinforces the idea that axonal sprouting may contribute to pathologic hyperexcitability of granule cells.

Modest Increase in Extracellular Potassium Unmasks Effect of Recurrent Mossy Fiber Growth

2000 ◽  
Vol 84 (5) ◽  
pp. 2380-2389 ◽  
Author(s):  
Jeremy L. Hardison ◽  
Maxine M. Okazaki ◽  
J. Victor Nadler
Keyword(s):  
Granule Cell ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Epileptiform Activity ◽  
Mossy Fibers ◽  
Fiber Growth ◽  
Antidromic Stimulation ◽  
Frequency Facilitation ◽  
Mossy Fiber Pathway ◽  
Stimulation Of

The recurrent mossy fiber pathway of the dentate gyrus expands dramatically in many persons with temporal lobe epilepsy. The new connections among granule cells provide a novel mechanism of synchronization that could enhance the participation of these cells in seizures. Despite the presence of robust recurrent mossy fiber growth, orthodromic or antidromic activation of granule cells usually does not evoke repetitive discharge. This study tested the ability of modestly elevated [K+]o, reduced GABAA receptor-mediated inhibition and frequency facilitation to unmask the effect of recurrent excitation. Transverse slices of the caudal hippocampal formation were prepared from pilocarpine-treated rats that either had or had not developed status epilepticus with subsequent recurrent mossy fiber growth. During superfusion with standard medium (3.5 mM K+), antidromic stimulation of the mossy fibers evoked epileptiform activity in 14% of slices with recurrent mossy fiber growth. This value increased to ∼50% when [K+]o was raised to either 4.75 or 6 mM. Addition of bicuculline (3 or 30 μM) to the superfusion medium did not enhance the probability of evoking epileptiform activity but did increase the magnitude of epileptiform discharge if such activity was already present. (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine (1 μM), which selectively activates type II metabotropic glutamate receptors present on mossy fiber terminals, strongly depressed epileptiform responses. This result implies a critical role for the recurrent mossy fiber pathway. No enhancement of the epileptiform discharge occurred during repetitive antidromic stimulation at frequencies of 0.2, 1, or 10 Hz. In fact, antidromically evoked epileptiform activity became progressively attenuated during a 10-Hz train. Antidromic stimulation of the mossy fibers never evoked epileptiform activity in slices from control rats under any condition tested. These results indicate that even modest changes in [K+]o dramatically affect granule cell epileptiform activity supported by the recurrent mossy fiber pathway. A small increase in [K+]o reduces the amount of recurrent mossy fiber growth required to synchronize granule cell discharge. Block of GABAA receptor-mediated inhibition is less efficacious and frequency facilitation may not be a significant factor.

scholarly journals Morphological constraints on cerebellar granule cell combinatorial diversity

2017 ◽  
Author(s):  
Jesse I. Gilmer ◽  
Abigail L. Person
Keyword(s):  
Granule Cell ◽  
Granule Cells ◽  
Cell Layer ◽  
Mossy Fiber ◽  
Mossy Fibers ◽  
Cerebellar Granule Cell ◽  
Granule Cell Layer ◽  
Information Encoding ◽  
Cerebellar Granule ◽  
Local Sampling

AbstractCombinatorial expansion by the cerebellar granule cell layer (GCL) is fundamental to theories of cerebellar contributions to motor control and learning. Granule cells sample approximately four mossy fiber inputs and are thought to form a combinatorial code useful for pattern separation and learning. We constructed a spatially realistic model of the cerebellar granule cell layer and examined how GCL architecture contributes to granule cell (GrC) combinatorial diversity. We found that GrC combinatorial diversity saturates quickly as mossy fiber input diversity increases, and that this saturation is in part a consequence of short dendrites, which limit access to diverse inputs and favor dense sampling of local inputs. This local sampling also produced GrCs that were combinatorially redundant, even when input diversity was extremely high. In addition, we found that mossy fibers clustering, which is a common anatomical pattern, also led to increased redundancy of GrC input combinations. We related this redundancy to hypothesized roles of temporal expansion of GrC information encoding in service of learned timing, and show that GCL architecture produces GrC populations that support both temporal and combinatorial expansion. Finally, we used novel anatomical measurements from mice of either sex to inform modeling of sparse and filopodia-bearing mossy fibers, finding that these circuit features uniquely contribute to enhancing GrC diversification and redundancy. Our results complement information theoretic studies of granule layer structure and provide insight into the contributions of granule layer anatomical features to afferent mixing.Significance StatementCerebellar granule cells are among the simplest neurons, with tiny somata and on average just four dendrites. These characteristics, along with their dense organization, inspired influential theoretical work on the granule cell layer (GCL) as a combinatorial expander, where each granule cell represents a unique combination of inputs. Despite the centrality of these theories to cerebellar physiology, the degree of expansion supported by anatomically realistic patterns of inputs is unknown. Using modeling and anatomy, we show that realistic input patterns constrain combinatorial diversity by producing redundant combinations, which nevertheless could support temporal diversification of like-combinations, suitable for learned timing. Our study suggests a neural substrate for producing high levels of both combinatorial and temporal diversity in the GCL.

scholarly journals Serotonin regulates dynamics of cerebellar granule cell activity by modulating tonic inhibition

2019 ◽  
Vol 121 (1) ◽  
pp. 105-114 ◽  
Author(s):  
Elizabeth Fleming ◽  
Court Hull
Keyword(s):  
Granule Cell ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Cell Activity ◽  
Spike Timing ◽  
Tonic Inhibition ◽  
Granule Cell Layer ◽  
Golgi Cells ◽  
Cell Depolarization ◽  
Feed Forward Inhibition

Understanding how afferent information is integrated by cortical structures requires identifying the factors shaping excitation and inhibition within their input layers. The input layer of the cerebellar cortex integrates diverse sensorimotor information to enable learned associations that refine the dynamics of movement. Specifically, mossy fiber afferents relay sensorimotor input into the cerebellum to excite granule cells, whose activity is regulated by inhibitory Golgi cells. To test how this integration can be modulated, we have used an acute brain slice preparation from young adult rats and found that encoding of mossy fiber input in the cerebellar granule cell layer can be regulated by serotonin (5-hydroxytryptamine, 5-HT) via a specific action on Golgi cells. We find that 5-HT depolarizes Golgi cells, likely by activating 5-HT2A receptors, but does not directly act on either granule cells or mossy fibers. As a result of Golgi cell depolarization, 5-HT significantly increases tonic inhibition onto both granule cells and Golgi cells. 5-HT-mediated Golgi cell depolarization is not sufficient, however, to alter the probability or timing of mossy fiber-evoked feed-forward inhibition onto granule cells. Together, increased granule cell tonic inhibition paired with normal feed-forward inhibition acts to reduce granule cell spike probability without altering spike timing. Hence, these data provide a circuit mechanism by which 5-HT can reduce granule cell activity without altering temporal representations of mossy fiber input. Such changes in network integration could enable flexible, state-specific suppression of cerebellar sensorimotor input that should not be learned or enable reversal learning for unwanted associations. NEW & NOTEWORTHY Serotonin (5-hydroxytryptamine, 5-HT) regulates synaptic integration at the input stage of cerebellar processing by increasing tonic inhibition of granule cells. This circuit mechanism reduces the probability of granule cell spiking without altering spike timing, thus suppressing cerebellar input without altering its temporal representation in the granule cell layer.

Excitatory Synaptic Input to Granule Cells Increases With Time After Kainate Treatment

2001 ◽  
Vol 85 (3) ◽  
pp. 1067-1077 ◽  
Author(s):  
Jean-Pierre Wuarin ◽  
F. Edward Dudek
Keyword(s):  
Dentate Gyrus ◽  
Granule Cell ◽  
Synaptic Input ◽  
Granule Cells ◽  
Flash Photolysis ◽  
Cell Layer ◽  
Mossy Fiber ◽  
Hippocampal Slices ◽  
Granule Cell Layer ◽  
Excitatory Synaptic Input

Temporal lobe epilepsy is usually associated with a latent period and an increased seizure frequency following a precipitating insult. After kainate treatment, the mossy fibers of the dentate gyrus are hypothesized to form recurrent excitatory circuits between granule cells, thus leading to a progressive increase in the excitatory input to granule cells. Three groups of animals were studied as a function of time after kainate treatment: 1–2 wk, 2–4 wk, and 10–51 wk. All the animals studied 10–51 wk after kainate treatment were observed to have repetitive spontaneous seizures. Whole cell patch-clamp recordings in hippocampal slices showed that the amplitude and frequency of spontaneous excitatory postsynaptic currents (EPSCs) in granule cells increased with time after kainate treatment. This increased excitatory synaptic input was correlated with the intensity of the Timm stain in the inner molecular layer (IML). Flash photolysis of caged glutamate applied in the granule cell layer evoked repetitive EPSCs in 10, 32, and 66% of the granule cells at the different times after kainate treatment. When inhibition was reduced with bicuculline, photostimulation of the granule cell layer evoked epileptiform bursts of action potentials only in granule cells from rats 10–51 wk after kainate treatment. These data support the hypothesis that kainate-induced mossy fiber sprouting in the IML results in the progressive formation of aberrant excitatory connections between granule cells. They also suggest that the probability of occurrence of electrographic seizures in the dentate gyrus increases with time after kainate treatment.

Sign in / Sign up

Export Citation Format

Share Document