Learning induces neurotrophin signaling at hippocampal synapses

Abstract

Learning-induced trophic activity is thought to be critical for maintaining health of the aging brain. We report here that learning, acting through an unexpected pathway, activates synaptic receptors for one of the brain's primary trophic factors. Unsupervised learning, but not exploratory activity alone, robustly increased the number of postsynaptic densities associated with activated (phosphorylated) forms of BDNF's TrkB receptor in adult rat hippocampus; these increases were blocked by an NMDA receptor antagonist. Similarly, stimulation of hippocampal slices at the learning-related theta frequency increased synaptic TrkB phosphorylation in an NMDA receptor-dependent fashion. Theta burst stimulation, which was more effective in this regard than other stimulation patterns, preferentially engaged NMDA receptors that, in turn, activated Src kinases. Blocking the latter, or scavenging extracellular TrkB ligands, prevented theta-induced TrkB phosphorylation. Thus, synaptic TrkB activation was dependent upon both ligand presentation and postsynaptic signaling cascades. These results show that afferent activity patterns and cellular events involved in memory encoding initiate BDNF signaling through synaptic TrkB, thereby ensuring that learning will trigger neurotrophic support.BDNF | NMDA receptor | Src kinase | theta burst stimulation | TrkB E nvironmental enrichment and learning modify brain anatomy (1) and chemistry (2, 3) in older animals and slow cognitive decline and the onset of dementia in aged humans (4). Although multiple factors likely contribute to these effects, it is generally agreed that trophic factors play a central role. These releasable peptides stimulate growth and help maintain neuronal viability (5, 6) and are logical candidates for the agency whereby experience slows age-related deterioration of brain networks (7). However, there is little evidence that learning or learning-related patterns of electrical activity actually stimulate neurotrophic signaling at brain synapses. The absence of tests of the learning/ trophic signaling hypothesis is likely due to difficulties in sampling the activation state of proteins in the very small percentage of synapses affected by physiologically relevant patterns of activity or by learning itself (8, 9). Recent advances in restorative deconvolution microscopy have partly obviated these problems (8, 10). We used these techniques in the present studies to test the hypothesis that learning and learning-related brain rhythms cause the rapid activation of BDNF's TrkB receptor within synapses of the adult hippocampus.BDNF is of particular interest with regard to experience and aging because its expression by cortical neurons is both regulated by activity (11) and related to age-associated changes in brain anatomy and functioning (12). Accordingly, we focused on BDNF and asked if a 30 min period of a ubiquitous form of mammalian learning (i.e., unsupervised learning of a novel environment) increases the number of synapses containing the activated form of TrkB (13). W...

The cellular and synaptic location of activated TrkB in mouse hippocampus during limbic epileptogenesis

“…These results are consistent with ultrastructural evidence localizing pY816 immunoreactivity to dendritic shafts of CA1 pyramids and a minority (5%) of spines within stratum radiatum of CA1 under basal conditions (Spencer-Segal et al, 2011); notably, activated TrkB was clustered next to the postsynaptic density. Light microscopic studies have also colocalized pTrkB immunoreactivity with a subset of PSD-95 (5%) in stratum radiatum of CA1, and the fraction of pTrkB colocalizing with PSD-95 increased approximately 2-fold following an unsupervised learning paradigm (Chen et al, 2010a;Chen et al, 2010b). These values are similar to those detected under basal conditions in the present study.…”

“…Like the mossy fiber-CA3 synapse, mutation of Y816, but not Y515, inhibited induction of LTP of the Schaffer collateral-CA1 synapse (He et al, 2010;Korte et al, 2000;Minichiello et al, 2002), the same residue implicated in promoting epileptogenesis. Furthermore, in immunohistochemical studies examining pTrkB using brain slices treated with LTPinducing stimuli at the Schaffer collateral-CA1 synapse, increases in numbers of pTrkBimmunoreactive puncta were observed in CA1 stratum radiatum (Lu et al, 2011), and enhanced colocalization of pTrkB puncta with PSD-95 was found in brain slices after such a stimuli (Chen et al, 2010b). The location of activated TrkB within spines of CA1 pyramidal neurons is optimally positioned to promote a postsynaptic LTP of this synapse.…”

Integrin Dynamics Produce a Delayed Stage of Long-Term Potentiation and Memory Consolidation

“…Past studies showed that TBS causes rapid (Ͻ2 min), integrin-dependent formation of subsynaptic actin filaments (Kramár et al, 2006) that are stabilized by processes reflecting a second signaling cascade over the following 5-10 min (Rex et al, 2009). It is possible that the integrin recovery is needed to anchor the newly formed actin networks to the extracellular matrix, and thereby to maintain the structural modifications of synapses that accompany and stabilize LTP (Chen et al, 2007(Chen et al, , 2010bYang et al, 2008;Bourne and Harris, 2012).…”

“…How theta bursts produce these effects remains to be determined although it is known that the stimulation pattern engages kinases and small GTPases (Chen et al, 2007(Chen et al, , 2010b) that regulate integrin status in various types of adhesion junctions (Munshi and Stack, 2006;Jin et al, 2011;Sil et al, 2011). Moreover, recent studies showed that LTP induction leads to focal activation of matrix metalloproteinase-9 (MMP-9; Nagy et al, 2006; Bozdagi et al, 2007), an extracellular proteinase that cleaves matrix proteins and thereby generates integrin ligands .…”

Protein synthesis and consolidation of memory-related synaptic changes

“…The second data set is cause for concern because it not only challenges the central argument, it questions the relevance of the well-documented findings that both behavior and LTP-inducing stimulation induce changes in gene expression (Alberini, 2009;Bramham and Messaoudi, 2005;Chen et al, 2010;Guzowski et al, 2001;Taubenfeld et al, 2001 The present paper addresses the above issues. We report evidence that reinforces the conclusion that the consolidation of LTP is not blocked by protein synthesis inhibition, then describe circumstances in which the inhibitors are effective, and finally demonstrate that multiple LTP events obviate the negative actions of the inhibitors when such are present.…”