Gap Junctions and Epileptic Seizures – Two Sides of the Same Coin?

Electrical synapses (gap junctions) play a pivotal role in the synchronization of neuronal ensembles which also makes them likely agonists of pathological brain activity. Although large body of experimental data and theoretical considerations indicate that coupling neurons by electrical synapses promotes synchronous activity (and thus is potentially epileptogenic), some recent evidence questions the hypothesis of gap junctions being among purely epileptogenic factors. In particular, an expression of inter-neuronal gap junctions is often found to be higher after the experimentally induced seizures than before. Here we used a computational modeling approach to address the role of neuronal gap junctions in shaping the stability of a network to perturbations that are often associated with the onset of epileptic seizures. We show that under some circumstances, the addition of gap junctions can increase the dynamical stability of a network and thus suppress the collective electrical activity associated with seizures. This implies that the experimentally observed post-seizure additions of gap junctions could serve to prevent further escalations, suggesting furthermore that they are a consequence of an adaptive response of the neuronal network to the pathological activity. However, if the seizures are strong and persistent, our model predicts the existence of a critical tipping point after which additional gap junctions no longer suppress but strongly facilitate the escalation of epileptic seizures. Our results thus reveal a complex role of electrical coupling in relation to epileptiform events. Which dynamic scenario (seizure suppression or seizure escalation) is ultimately adopted by the network depends critically on the strength and duration of seizures, in turn emphasizing the importance of temporal and causal aspects when linking gap junctions with epilepsy

Metabotropic glutamate receptor 1 (mGluR1) and 5 (mGluR5) regulate late phases of LTP and LTD in the hippocampal CA1 region in vitro

The group I metabotropic glutamate receptors, mGluR1 and mGluR5, exhibit differences in their regulation of synaptic plasticity, suggesting that these receptors may subserve separate functional roles in information storage. In addition, although effects in vivo are consistently described, conflicting reports of the involvement of mGluRs in hippocampal synaptic plasticity in vitro exist. We therefore addressed the involvement of mGluR1 and mGluR5 in long-term potentiation (LTP) and long-term depression (LTD) in the hippocampal CA1 region of adult male rats in vitro. The mGluR1 antagonist (S)-(+)-α-amino-4-carboxy-2-methylbenzene-acetic acid (LY367385) impaired both induction and late phases of both LTP and LTD, when applied before high-frequency tetanization (HFT; 100 Hz) or low-frequency stimulation (LFS; 1 Hz), respectively. Application after either HFT or LFS had no effect. The mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP), when given before HFT, inhibited both the induction and late phases of LTP. When given after HFT, late LTP was inhibited. MPEP, given prior to LFS, impaired LTD induction, although stable LTD was still expressed. Application after LFS significantly impaired late phases of LTD. Activation of protein synthesis may comprise a key mechanism underlying the group I mGluR contribution to synaptic plasticity. The mGluR5 agonist (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG) converted short-term depression into LTD. Effects were prevented by application of the protein synthesis inhibitor anisomycin, suggesting that protein synthesis is triggered by group I mGluR activation to enable persistency of synaptic plasticity. Taken together, these data support the notion that both mGluR1 and mGluR5 are critically involved in bidirectional synaptic plasticity in the CA1 region and may enable functional differences in information encoding through LTP and LTD

Human Umbilical Cord Blood Cells Restore Brain Damage Induced Changes in Rat Somatosensory Cortex

Intraperitoneal transplantation of human umbilical cord blood (hUCB) cells has been shown to reduce sensorimotor deficits after hypoxic ischemic brain injury in neonatal rats. However, the neuronal correlate of the functional recovery and how such a treatment enforces plastic remodelling at the level of neural processing remains elusive. Here we show by in-vivo recordings that hUCB cells have the capability of ameliorating the injury-related impairment of neural processing in primary somatosensory cortex. Intact cortical processing depends on a delicate balance of inhibitory and excitatory transmission, which is disturbed after injury. We found that the dimensions of cortical maps and receptive fields, which are significantly altered after injury, were largely restored. Additionally, the lesion induced hyperexcitability was no longer observed in hUCB treated animals as indicated by a paired-pulse behaviour resembling that observed in control animals. The beneficial effects on cortical processing were reflected in an almost complete recovery of sensorimotor behaviour. Our results demonstrate that hUCB cells reinstall the way central neurons process information by normalizing inhibitory and excitatory processes. We propose that the intermediate level of cortical processing will become relevant as a new stage to investigate efficacy and mechanisms of cell therapy in the treatment of brain injury

Calcium dynamics in dendrites of hippocampal CA1 interneurons in awake mice

Hippocampal inhibitory interneurons exhibit a large diversity of dendritic Ca2+ mechanisms that are involved in the induction of Hebbian and anti-Hebbian synaptic plasticity. High resolution imaging techniques allowed examining somatic Ca2+ signals and, accordingly, the recruitment of hippocampal interneurons in awake behaving animals. However, little is still known about dendritic Ca2+ activity in interneurons during different behavioral states. Here, we used two-photon Ca2+ imaging in mouse hippocampal CA1 interneurons to reveal Ca2+ signal patterns in interneuron dendrites during animal locomotion and immobility. Despite overall variability in dendritic Ca2+ transients (CaTs) across different cells and dendritic branches, we report consistent behavior state-dependent organization of Ca2+ signaling in interneurons. As such, spreading regenerative CaTs dominated in dendrites during locomotion, whereas both spreading and localized Ca2+ signals were seen during immobility. Thus, these data indicate that while animal locomotion is associated with widespread Ca2+ elevations in interneuron dendrites that may reflect regenerative activity, local CaTs that may be related to synaptic activity become apparent during animal quiet state

Calcium dynamics in dendrites of hippocampal CA1 interneurons in awake mice

Hippocampal inhibitory interneurons exhibit a large diversity of dendritic Ca2+ mechanisms that are involved in the induction of Hebbian and anti-Hebbian synaptic plasticity. High resolution imaging techniques allowed examining somatic Ca2+ signals and, accordingly, the recruitment of hippocampal interneurons in awake behaving animals. However, little is still known about dendritic Ca2+ activity in interneurons during different behavioral states. Here, we used two-photon Ca2+ imaging in mouse hippocampal CA1 interneurons to reveal Ca2+ signal patterns in interneuron dendrites during animal locomotion and immobility. Despite overall variability in dendritic Ca2+ transients (CaTs) across different cells and dendritic branches, we report consistent behavior state-dependent organization of Ca2+ signaling in interneurons. As such, spreading regenerative CaTs dominated in dendrites during locomotion, whereas both spreading and localized Ca2+ signals were seen during immobility. Thus, these data indicate that while animal locomotion is associated with widespread Ca2+ elevations in interneuron dendrites that may reflect regenerative activity, local CaTs that may be related to synaptic activity become apparent during animal quiet state