Presynaptic Ultrastructural Plasticity Along CA3→CA1 Axons During Long‐Term Potentiation in Mature Hippocampus

Abstract

In area CA1 of the mature hippocampus, synaptogenesis occurs within 30 min after the induction of LTP; however, by 2 hr many small dendritic spines are lost, and those remaining have larger synapses. Little is known, however, about associated changes in presynaptic vesicles and axonal boutons. Axons in CA1 stratum radiatum were evaluated with three-dimensional reconstructions from serial section electron microscopy at 30 min and 2 hr after induction of LTP by theta-burst stimulation (TBS). The frequency of axonal boutons with a single postsynaptic partner was decreased by 33% at 2 hr, corresponding perfectly to the 33% loss specifically of small dendritic spines (head diameters <0.45 μm). Docked vesicles were reduced at 30 min and then returned to control levels by 2 hr following induction of LTP. By 2 hr there were fewer small synaptic vesicles overall in the presynaptic vesicle pool. Clathrin-mediated endocytosis was used as a marker of local activity, and axonal boutons containing clathrin-coated pits showed a more pronounced decrease in presynaptic vesicles at both 30 min and 2 hr after induction of LTP relative to control values. Putative transport packets, identified as a cluster of less than 10 axonal vesicles occurring between synaptic boutons, were stable at 30 min but markedly reduced by 2 hr after the induction of LTP. APV blocked these effects, suggesting that the loss of axonal boutons and presynaptic vesicles was dependent on NMDA receptor activation during LTP. These findings show that specific presynaptic ultrastructural changes complement postsynaptic ultrastructural plasticity during LTP.

Combined Treatment With Environmental Enrichment and (-)-Epigallocatechin-3-Gallate Ameliorates Learning Deficits and Hippocampal Alterations in a Mouse Model of Down Syndrome

“…In CA1, Ts65Dn mice showed the same phenotype, VGLUT1 puncta being more abundant and smaller; however, in this region, VGAT puncta were enlarged, leading to an increased VGLUT1/VGAT ratio but a reduction of VGLUT1/VGAT percentage of area occupied. That in both DG and CA1 VGLUT1 puncta were more abundant and smaller in Ts65Dn could affect the probability or efficiency in neurotransmitter release (Harris and Sultan, 1995; Bozdagi et al, 2000; Antonova et al, 2001; Bamji et al, 2006; Bourne et al, 2013) and could also be related to the previously reported enhanced GABA A and GABA B evoked inhibitory postsynaptic currents in DG of 3- to 4-month-old male mice (Kleschevnikov et al, 2012) and increased GABA release in the hippocampus of male and female adult mice (Begenisic et al, 2011). Consistent with our results, previous work showed no changes in density of VGAT puncta nor density of inhibitory synapses using electron microscopy in the DG of 3-month-old male mice, although apposition length of symmetric (inhibitory) synapses was larger (Belichenko et al, 2009).…”

Mitochondrial support of persistent presynaptic vesicle mobilization with age-dependent synaptic growth after LTP

“…In adults, control stimulation produced spine recovery to perfusion-fixed levels, whereas TBS prevented spine formation and resulted in larger synapses by 120 min after the induction of LTP (Bourne and Harris, 2011; Bell et al, 2014). In adults, control stimulation resulted in more single synaptic boutons, whereas TBS induction of LTP prevented new single synaptic bouton formation and had no effect on multisynaptic boutons or nonsynaptic boutons (Bourne et al, 2013). …”

Alpha-synuclein modulates NR2B-containing NMDA receptors and decreases their levels after rotenone exposure

“…It has been recently reported that in a transgenic mouse model of Lewy body disease the onset of axonopathy is associated with extensive accumulation of C-terminally cleaved α-syn, thus suggesting that this form of the protein may play a relevant role in the onset of axon damage (Games et al, 2013). Interestingly, presynaptic NMDAR are emerging as crucial mediators of synaptic plasticity along axons during LTP in mature neurons (Bourne et al, 2013;Park et al, 2014). Thus, all these findings suggest that the axonal accumulation of C-terminal cleaved α-syn species may damage neurons by reducing NR2B-containing NMDAR content and the related activation of synaptic plasticity mechanisms along the axon.…”