Altered neurotransmitter release, vesicle recycling and presynaptic structure in the pilocarpine model of temporal lobe epilepsy

Abstract

In searching for persistent seizure-induced alterations in brain function that might be causally related to epilepsy, presynaptic transmitter release has relatively been neglected. To measure directly the long-term effects of pilocarpine-induced status epilepticus on vesicular release and recycling in hippocampal mossy fibre presynaptic boutons, we used (i) two-photon imaging of FM1-43 vesicular release in rat hippocampal slices; and (ii) transgenic mice expressing the genetically encoded pH-sensitive fluorescent reporter synaptopHluorin preferentially at glutamatergic synapses. In this study we found that, 1-2 months after pilocarpine-induced status epilepticus, there were significant increases in mossy fibre bouton size, faster rates of action potential-driven vesicular release and endocytosis. We also analysed the ultrastructure of rat mossy fibre boutons using transmission electron microscopy. Pilocarpine-induced status epilepticus led to a significant increase in the number of release sites, active zone length, postsynaptic density area and number of vesicles in the readily releasable and recycling pools, all correlated with increased release probability. Our data show that presynaptic release machinery is persistently altered in structure and function by status epilepticus, which could contribute to the development of the chronic epileptic state and may represent a potential new target for antiepileptic therapies.

Critical Role of Endoplasmic Reticulum Stress in Chronic Intermittent Hypoxia-Induced Deficits in Synaptic Plasticity and Long-Term Memory

“…These findings are consistent with studies reporting that activation of ER stress could promote synaptic degeneration and disrupt neurotransmission associated with changes in synaptic morphology and submicroscopic structures (41,44). Shortening of the active zone may reflect a condition of impaired synaptic transmission and plasticity (57,67) and is consistent with our finding that TUDCA could restore the length of the active zone and rescue LTP. In parallel, mushroom spines, or memory spines, are related to strong synaptic connections and neuronal plasticity (18).…”

Experience-dependent regulation of presynaptic NMDARs enhances neurotransmitter release at neocortical synapses

“…Interestingly, increased release probability has also been described in other preparations where overall levels of activity are increased, after chemically induced seizures or in cortical dysplasia (Scimemi et al 2006;Yang et al 2006;Chen et al 2007;Upreti et al 2012) but see Pitsch et al (2012). The changes that are reported here are anti-homeostatic; they do not act to dampen the excitability of neurons in the face of increased sensory-evoked activity.…”

Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond

“…It is tempting to speculate that the striking increase in the anti-seizure effect of levetiracetam on 6-Hz seizures in epileptic mice is mediated by epilepsy-associated changes of its target, SV2A [50, 51]. Indeed, profound changes in synaptic vesicle release machinery were reported in post-SE models of TLE; however, SV2A density in individual synaptic boutons has not been directly measured in these studies [52, 53]. …”

“…Further work is needed to fully interpret those findings since immunohistological and PET assessments of SV2A expression could be confounded by neuronal loss often observed in TLE. It is essential to study SV2A at the level of individual synapses in patients with TLE since recent reports indicate significant increases in synaptic vesicle density within limbic structures of animals with chronic TLE [52, 53]. …”