Bidirectional synaptic plasticity rapidly modifies hippocampal representations.
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ABSTRACT:
SUBMITTER: Milstein AD
PROVIDER: S-EPMC8776257 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Experience-dependent synaptic plasticity is a fundamental feature of neural networks involved in the encoding of information, and the capability of synapses to express plasticity is itself activity-dependent. Here, we introduce a "low-frequency burst stimulation" protocol, which can readily induce both long-term potentiation (LTP) and long-term depression (LTD) at in vivo medial perforant path-dentate gyrus synapses. By varying stimulation parameters, we were able to build a stimulus-response map of synaptic plasticity as a LTP-LTD continuum. The response curve displayed a bidirectional shift toward LTP and LTD, depending on the degree and timing of neural activity of the basolateral amygdala. The range of this plastic modulation was also modified by past activity of the basolateral amygdala, suggesting that the amygdala can arrange its ability to regulate the dentate plastic responses. The effects of the BLA activation were replicated by stimulation of the lateral perforant path and, hence, BLA stimulation may recruit the lateral entorhinal cortex. These results represent a high-order dimension of heterosynaptic modulations of hippocampal synaptic plasticity.
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Project description:Synapses in the brain are bidirectionally modifiable, but the routes of induction are diverse. In various experimental paradigms, N-methyl-d-aspartate receptor-dependent long-term depression and long-term potentiation have been induced selectively by varying the membrane potential of the postsynaptic neurons during presynaptic stimulation of a constant frequency, the rate of presynaptic stimulation, and the timing of pre- and postsynaptic action potentials. In this paper, we present a mathematical embodiment of bidirectional synaptic plasticity that is able to explain diverse induction protocols with a fixed set of parameters. The key assumptions and consequences of the model can be tested experimentally; further, the model provides the foundation for a unified theory of N-methyl-d-aspartate receptor-dependent synaptic plasticity.
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Project description:How signaling molecules achieve signal diversity and specificity is a long-standing cell biology question. Here we report the development of a targeted delivery method that permits specific expression of homologous Ras-family small GTPases (i.e., Ras, Rap2, and Rap1) in different subcellular microdomains, including the endoplasmic reticulum, lipid rafts, bulk membrane, lysosomes, and Golgi complex, in rodent hippocampal CA1 neurons. The microdomain-targeted delivery, combined with multicolor fluorescence protein tagging and high-resolution dual-quintuple simultaneous patch-clamp recordings, allows systematic analysis of microdomain-specific signaling. The analysis shows that Ras signals long-term potentiation via endoplasmic reticulum PI3K and lipid raft ERK, whereas Rap2 and Rap1 signal depotentiation and long-term depression via bulk membrane JNK and lysosome p38MAPK, respectively. These results establish an effective subcellular microdomain-specific targeted delivery method and unveil subcellular microdomain-specific signaling as the mechanism for homologous Ras and Rap to achieve signal diversity and specificity to control multiple forms of synaptic plasticity.
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Project description:BackgroundThe hippocampus is particularly vulnerable to the teratogenic effects of prenatal ethanol exposure (PNEE), and hippocampal structural and functional deficits are thought to contribute to the learning and memory deficits that are a hallmark feature of fetal alcohol spectrum disorders.MethodsSprague Dawley dams were exposed to a liquid diet that contained EtOH (35.5% EtOH-derived calories) throughout gestation, and then, PNEE juvenile (P21-28) male and female offspring were used for in vitro electrophysiological recordings. We examined long-term potentiation (LTP), long-term depression (LTD), and depotentiation in the medial perforant path input to the dentate gyrus (DG) to determine the impact of PNEE on the dynamic range of bidirectional synaptic plasticity in both sexes.ResultsPNEE reduced the responsiveness of the DGs of male but not in female offspring, and this effect was no longer apparent when GABAergic signaling was inhibited. There was also a sex-specific LTD impairment in males, but increasing the duration of the conditioning stimulus could overcome this deficit. The magnitude of LTP was also reduced, but in both sexes following PNEE. This appears to be an increase in the threshold for induction, not in capacity, as the level of LTP induced in PNEE animals was increased to control levels when additional conditioning stimuli were administered.ConclusionsThese data are the first to describe, in a single study, the impact of PNEE on the dynamic range of bidirectional synaptic plasticity in the juvenile DG in both males and in females. The data suggest that PNEE increases the threshold for LTP in the DG in both sexes, but produces a sex-specific increase in the threshold for LTD in males These alterations reduce the dynamic range for synaptic plasticity in both sexes.
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Project description:Stargazin is a transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor regulatory protein that controls the surface and synaptic expression of AMPA-type glutamate receptors (AMPARs). Synaptic anchoring of AMPARs is influenced by the interaction between stargazin's C-terminal post-synaptic density-95 (PSD-95)/discs large/zona occludens-1 (PDZ) ligand and the synaptic scaffolding protein PSD-95. Phosphorylation of the stargazin PDZ ligand by protein kinase A (PKA) disrupts stargazin's interaction with PSD-95, but whether this phosphorylation plays a role in activity-dependent regulation of stargazin/AMPAR synaptic trafficking is unknown. Here, we show that stargazin is phosphorylated within the PDZ ligand at threonine residue 321 (T321) by mitogen-activated protein kinases (MAPKs) as well as PKA. By expressing constructs that selectively block T321 phosphorylation by either PKA or MAPKs, we show that stargazin T321 phosphorylation is required for activity-dependent changes in stargazin synaptic clustering in dissociated rat hippocampal neuron cultures. Specifically, we find that mutations that block stargazin T321 phosphorylation by PKA prevent activity-dependent increases in stargazin synaptic clustering, whereas a point mutant that blocks MAPK phosphorylation of T321 prevents activity-dependent decreases in stargazin synaptic clustering. Taken together, our studies implicate phosphorylation of stargazin T321 by PKA and MAPKs in bidirectional control of stargazin/AMPAR synaptic clustering during synaptic plasticity.
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