Fluorescent tracer in pilocarpine‐treated rats shows widespread aberrant hippocampal neuronal connectivity

To ensure operation of synaptic transmission within an appropriate dynamic range, neurons have evolved mechanisms of activitydependent plasticity, including changes in presynaptic efficacy. The multidomain protein RIM1␣ is an integral component of the cytomatrix at the presynaptic active zone and has emerged as key mediator of presynaptically expressed forms of synaptic plasticity. We have therefore addressed the role of RIM1␣ in aberrant cellular plasticity and structural reorganization after an episode of synchronous neuronal activity pharmacologically induced in vivo [status epilepticus (SE)]. Post-SE, all animals developed spontaneous seizure events, but their frequency was dramatically increased in RIM1␣-deficient mice (RIM1␣ Ϫ/Ϫ ). We found that in wild-type mice (RIM1␣ ϩ/ϩ ) SE caused an increase in paired-pulse facilitation in the CA1 region of the hippocampus to the level observed in RIM1␣ Ϫ/Ϫ mice before SE. In contrast, this form of short-term plasticity was not further enhanced in RIM1␣-deficient mice after SE. Intriguingly, RIM1␣ Ϫ/Ϫ mice showed a unique pattern of selective hilar cell loss (i.e., endfolium sclerosis), which so far has not been observed in a genetic epilepsy animal model, as well as less severe astrogliosis and attenuated mossy fiber sprouting. These findings indicate that the decrease in release probability and altered short-and long-term plasticity as present in RIM1␣ Ϫ/Ϫ mice result in the formation of a hyperexcitable network but act in part neuroprotectively with regard to neuropathological alterations associated with epileptogenesis. In summary, our results suggest that presynaptic plasticity and proper function of RIM1␣ play an important part in a neuron's adaptive response to aberrant electrical activity.

Section: Discussionmentioning

confidence: 99%

The Presynaptic Active Zone Protein RIM1α Controls Epileptogenesis following Status Epilepticus

Pitsch¹,

Opitz²,

Borm³

et al. 2012

“…The CA3 region of the hippocampus also exhibits cell dispersion, but we have not yet explored the functional consequences of that structural abnormality with respect to, for example, enhanced recurrent excitation (certainly a characteristic feature of CA3 circuitry) (Swann et al, 1990(Swann et al, , 1992. Although several different laboratories have demonstrated the development of abnormal synaptic reorganization, including recurrent excitation, in other areas of the hippocampus in human MTLE patients (Lehmann et al, 2000) and animal models of epilepsy (Perez et al, 1996;Lehmann et al, 2000Lehmann et al, , 2001Shao and Dudek, 2004), similar widespread abnormalities (e.g., in the CA1 subfield) have not yet been investigated in the p35Ϫ/Ϫ mouse.…”

Section: Structural and Functional Evidence Of Recurrent Excitationmentioning

confidence: 99%

Physiological and Morphological Characterization of Dentate Granule Cells in the p35 Knock-Out Mouse Hippocampus: Evidence for an Epileptic Circuit

Patel¹,

Wenzel²,

Schwartzkroin³

2004

There is a high correlation between pediatric epilepsies and neuronal migration disorders. What remains unclear is whether there are intrinsic features of the individual dysplastic cells that give rise to heightened seizure susceptibility, or whether these dysplastic cells contribute to seizure activity by establishing abnormal circuits that alter the balance of inhibition and excitation. Mice lacking a functional p35 gene provide an ideal model in which to address these questions, because these knock-out animals not only exhibit aberrant neuronal migration but also demonstrate spontaneous seizures.Extracellular field recordings from hippocampal slices, characterizing the input-output relationship in the dentate, revealed little difference between wild-type and knock-out mice under both normal and elevated extracellular potassium conditions. However, in the presence of the GABA A antagonist bicuculline, p35 knock-out slices, but not wild-type slices, exhibited prolonged depolarizations in response to stimulation of the perforant path. There were no significant differences in the intrinsic properties of dentate granule cells (i.e., input resistance, time constant, action potential generation) from wild-type versus knock-out mice. However, antidromic activation (mossy fiber stimulation) evoked an excitatory synaptic response in over 65% of granule cells from p35 knock-out slices that was never observed in wild-type slices. Ultrastructural analyses identified morphological substrates for this aberrant excitation: recurrent axon collaterals, abnormal basal dendrites, and mossy fiber terminals forming synapses onto the spines of neighboring granule cells. These studies suggest that granule cells in p35 knock-out mice contribute to seizure activity by forming an abnormal excitatory feedback circuit.

“…Dextran-amine-coupled fluorescence and cresyl violet. To visualize dendritic and axonal processes of granule cells by anterograde and retrograde transport of dye, slices (two to four per specimen) were labeled with fluorescein or tetramethylrhodamine conjugated with dextran-amines (fluoro-emerald and fluoro-ruby; Molecular Probes, Leyden, The Netherlands), as described previously (Lehmann et al, 2001). In brief, small crystals of dye were inserted into a hilar lesion obtained after perpendicular penetration of the slice with a 27 gauge injection needle.…”

Section: Methodsmentioning

confidence: 99%

Stimulus and Potassium-Induced Epileptiform Activity in the Human Dentate Gyrus from Patients with and without Hippocampal Sclerosis

Gabriel¹,

Njunting²,

Pomper³

et al. 2004

Self Cite

154

102

Hippocampal specimens resected to cure medically intractable temporal lobe epilepsy (TLE) provide a unique possibility to study functional consequences of morphological alterations. One intriguing alteration predominantly observed in cases of hippocampal sclerosis is an uncommon network of granule cells monosynaptically interconnected via aberrant supragranular mossy fibers. We investigated whether granule cell populations in slices from sclerotic and nonsclerotic hippocampi would develop ictaform activity when challenged by low-frequency hilar stimulation in the presence of elevated extracellular potassium concentration (10 and 12 mM) and whether the experimental activity differs according to the presence of aberrant mossy fibers.We found that ictaform activity could be evoked in slices from sclerotic and nonsclerotic hippocampi (27 of 40 slices, 14 of 20 patients; and 11 of 22 slices, 6 of 12 patients, respectively). However, the two patient groups differed with respect to the pattern of ictaform discharges and the potassium concentration mandatory for its induction. Seizure-like events were already induced with 10 mM K ϩ . They exclusively occurred in slices from sclerotic hippocampi, of which 80% displayed stimulus-induced oscillatory population responses (250 -300 Hz). In slices from nonsclerotic hippocampi, atypical negative field potential shifts were predominantly evoked with 12 mM K ϩ . In both groups, the ictaform activity was sensitive to ionotropic glutamate receptor antagonists and lowering of [Ca 2ϩ ] o . Our results show that, in granule cell populations of hippocampal slices from TLE patients, high K ϩ -induced seizure-like activity and ictal spiking coincide with basic electrophysiological abnormalities, hippocampal sclerosis, and mossy fiber sprouting, suggesting that network reorganization could play a crucial role in determining type and threshold of such activity.