Mossy Fiber-CA3 Synapses Mediate Homeostatic Plasticity in Mature Hippocampal Neurons

Abstract

SUMMARY Network activity homeostatically alters synaptic efficacy to constrain neuronal output. However, it is unclear how such compensatory adaptations coexist with synaptic information storage, especially in established networks. Here, we report that in mature hippocampal neurons in vitro, network activity preferentially regulated excitatory synapses within the proximal dendrites of CA3 neurons. These homeostatic synapses exhibited morphological, functional, and molecular signatures of the specialized contacts between mossy fibers of dentate granule cells and thorny excrescences (TEs) of CA3 pyramidal neurons. In vivo TEs were also selectively and bidirectionally altered by chronic activity changes. TE formation required presynaptic synaptoporin and was suppressed by the activity-inducible kinase, Plk2. These results implicate the mossy fiber-TE synapse as an independently tunable gain control locus that permits efficacious homeostatic adjustment of mossy fiber-CA3 synapses, while preserving synaptic weights that may encode information elsewhere within the mature hippocampal circuit.

Miro1‐dependent mitochondrial positioning drives the rescaling of presynaptic Ca 2+ signals during homeostatic plasticity

“…The resulting fraction of terminals with mitochondria (34.3% ± 3.6) is similar to previous findings 8. To decrease network activity, we treated neurons with the sodium channel blocker tetrodotoxin (TTX) (1 μM, 48 h), whereas an increase in activity was achieved by applying the GABA A receptor antagonist picrotoxin (PTX) (100 μM, 48 h) 30. Silencing neurons with TTX led to a significant decrease in the fraction of SYN‐GFP clusters containing a mitochondrion (16.6% ± 3.1, P < 0.01), whereas conversely increasing neuronal activity, driven by PTX treatment, increased the fraction of SYN‐GFP synapses containing mitochondria compared to control (DMSO vehicle control 28.7% ± 3.9, PTX 50.0% ± 7.2, ** P < 0.01; Fig 4A and D) indicating that long‐term activity serves to alter mitochondrial occupancy at the synapse.…”

GABA B receptor deficiency causes failure of neuronal homeostasis in hippocampal networks

“…Homeostatic regulation of synaptic strength represents a basic mechanism of neuronal adaptation to constant changes in ongoing activity levels. Strong evidence exists on homeostatic augmentation of Pr and readily releasable pool size in response to prolong inactivity in hippocampal neurons (19,22,(34)(35)(36)(37)(38)(39)(40)(41)(42). These homeostatic adaptations are associated with modulation of presynaptic Ca 2+ flux (29) and remodeling of a large number of proteins in presynaptic cytomatrix (7).…”

Histone Methylation by the Kleefstra Syndrome Protein EHMT1 Mediates Homeostatic Synaptic Scaling

“…In contrast, blocking NMDAdependent calcium influx with APV for 48 hr did not increase H3K9me2 nor was there a cumulative effect when combined with TTX (Figures 1E and S1B) . Furthermore, the TTX-induced increase in H3K9me2 was prevented (Figures 1E and S1B) when endoplasmic reticulum calcium reuptake was blocked by thapsigargin (Lee et al, 2013).…”

“…These include blocking L-type calcium channels or AMPA receptor function, respectively, with nimodipine or CNQX for 48 hr (Lee et al, 2013;Wierenga et al, 2005;Thiagarajan et al, 2005, Ibata et al, 2008. Either nimodipine or CNQX alone increased H3K9me2 fluorescence, but they occluded the TTX-induced increase in H3K9me2 ( Figures 1E and S1B).…”