Synapse specificity of long-term potentiation breaks down with aging

Abstract

Memory shows age-related decline. According to the current prevailing theoretical model, encoding of memories relies on modifications in the strength of the synapses connecting the different cells within a neuronal network. The selective increases in synaptic weight are thought to be biologically implemented by long-term potentiation (LTP). Here, we report that tetanic stimulation of afferent fibers in slices from 12-mo-old mice triggers an LTP not restricted to the activated synapses. This phenomenon, which can be anticipated to hinder memory encoding, is suppressed by blocking either L-type Ca ++ channels or Ca ++ -induced Ca ++ release, both well known to become disregulated with aging.During the normal aging process, humans and animals experience age-related memory decline (Bach et al. 1999;Rosenzweig and Barnes 2003). Historically, it was thought that the primary contribution to the etiology of this decline was a massive loss of neurons in all the cortical layers and in the hippocampus (Brody 1955;Scheibel et al. 1976;Scheibel 1979). However, when it became possible to eliminate many of the confounding factors of the previous studies, this was proved to be a misconception (Burke and Barnes 2006). Nowadays, a great number of studies have identified multiple changes in Ca ++ -related electrophysiological processes as consistent biomarkers of aging (Landfield and Pitler 1984;Thibault and Landfield 1996;Norris et al. 1998;Thibault et al. 2001;Gant et al. 2006). One of the current prevailing hypotheses is that those Ca ++ dysregulations underlie many aspects of aging. However, the potential link between agerelated Ca ++ dysregulations and memory decline is still missing.For neurocomputing theorists, every memory is encoded in a neuronal network thanks to a change in the distribution of its synaptic weights (Zipser and Andersen 1988). Among the possible biological mechanisms, long-term potentiation (LTP) is the favored candidate to be at the basis of memory storage because this activity-induced increase in synaptic strength is (1) durable and (2) input-selective (restricted to the activated synapses). In the hippocampal synapses between Schaffer collaterals and CA1 pyramidal neurons, a single train of tetanic stimulation triggers a short-lasting LTP (S-LTP), which lasts 1-2 h, whereas multiple trains induce a long-lasting LTP (L-LTP) lasting >4 h (Huang and Kandel 1994;Abel et al. 1997). Potential age-related LTP defects have been sought out in the past. It has been reported that S-LTP in area CA1 from aged animals was normal when supra-threshold stimulation parameters were used (Moore et al. 1993;Burke and Barnes 2006) and showed deficits only when peri-threshold stimulation was applied (Barnes et al. 1992;Burke and Barnes 2006). The L-LTP triggered by multiple trains has been reported to be decreased in aged mice (18 mo) (Bach et al. 1999). In contrast, a brief 1-Hz paired-pulse stimulation has been found to induce an L-LTP in old mice but not in young animals (Huang and Kandel 2006). In our work, we focused on...

Diminished KCC2 confounds synapse specificity of LTP during senescence

“…L-655,708 (200nM), a negative allosteric modulator of α5 subunit-containing GABA A receptors, also partially antagonized LTP in old (Supplementary Fig.5a). Blocking NMDA receptors critical for LTP induction 3 (D-AP5 50μM) fully blocked LTP in young, but only partially in old (Supplementary Fig.5b), consistent with the idea of a Ca 2+ dysregulation contributing to LTP induction observed in 12 months-old mice 6,7 . Applying GBZ before (Supplementary Fig.6a) and 40 min after (Supplementary Fig.6b) LTP induction reduced fEPSPs only in old and only in the tetanized input.…”

“…LTP was induced by theta-burst stimulation 8 (TBS). As previously reported in 12 to 14-month-old mice 6,7 (∼40-45 years in humans), LTP showed no synapse specificity (Fig.1a; Supplementary Table1). These data are a subset of all LTP experiments (n=17 young and n=21 old mice) where the magnitude of LTP in old, 40 min after TBS, was larger than in young (fEPSP slope as ratio to pre-TBS values, old: 2.23±0.16, n=44 slices, young: 1.67±0.07, n=37 slices, p=0.0022, t=3.321, df=58.5, two-tailed unpaired t-test, unequal variances) mostly due to a larger proportion of rising LTP and some very large magnitude LTP in the old (Supplementary Fig.3).…”

“…Spread of plasticity to elements not part of the memory-related cluster interferes with the learning and memory process 5 . Synaptic specificity of LTP reportedly breaks down with age 1,2,6,7 . Here we address potential mechanisms underlying this memory interference at an advanced age in mice.…”

Diversity of presynaptic calcium channels displaying different synaptic properties

“…Thus, changes of Ca 2 + channel expression in the aging brain may cause changes of cerebral function. Synaptic long-term potentiation breaks down with aging and might be an explanation for age-related decline of memory (Ris and Godaux, 2007).…”

Late phase of L-LTP elicited in isolated CA1 dendrites cannot be transferred by synaptic capture

“…Actinomycin D, an inhibitor of transcription, has been repeatedly reported to block this form of L-LTP [3][4][5]. As the late phase of L-LTP, like its early phase, is input-selective, that is, it is restricted to the activated synapses, the products of gene transcription must be dispatched only to these activated synapses [6,7]. According to Frey and Morris' model, this is achieved thanks to the creation in each stimulated synapse of a 'tag' capable of capturing the products of the gene expression after their transport along dendrites [4,6,8].…”