NMDAR-dependent presynaptic homeostasis in adult hippocampus: Synapse growth and cross-modal inhibitory plasticity

Chipman, Peter H.; Fetter, Richard D.; Panzera, Lauren C.; Bergerson, Samuel J; Karmelic, Daniel; Yokoyama, Sae; Hoppa, Michael B.; Davis, Graeme W.

doi:10.1016/j.neuron.2022.08.014

Cited by 15 publications

(8 citation statements)

References 76 publications

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Section: Discussionmentioning

confidence: 99%

“…RRP size can vary dramatically across boutons from several types of neurons in the CNS ( Ariel et al, 2013 ; Jung et al, 2021 ; Chipman et al, 2022 ). In hippocampal neurons taken from brain slices, the size of the AZ can vary by more than an order of magnitude up to 0.2 mm 2 , with the number of docked vesicles varying between 0 and 20 with an average of 6 ( Chipman et al, 2022 ). While the differences in spontaneous release that we observe are not stochastic at the level of individual boutons assuming identical rates of spontaneous fusion, they could still be a stochastic property of all docked vesicles, accounting for observed variations in spontaneous release frequency.…”

Section: Discussionmentioning

confidence: 99%

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Frequency of spontaneous neurotransmission at individual boutons corresponds to the size of the readily releasable pool of vesicles.

Ralowicz,

Hokeness,

Hoppa

2024

J. Neurosci.

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Synapses maintain two forms of neurotransmitter release to support communication in the brain. First, evoked neurotransmitter release is triggered by the invasion of an action potential across en passant boutons that form along axons. The probability of evoked release (Pr) varies substantially across boutons, even within a single axon. Such heterogeneity is the result of differences in the probability of a single synaptic vesicle fusing (Pv) and in the number of vesicles available for immediate release, known as the readily-releasable pool (RRP). Spontaneous release (also known as a mini) is an important form of neurotransmission that occurs in the absence of action potentials. Because it cannot be triggered with electrical stimulation, much less is known about potential heterogeneity in the frequency of spontaneous release between boutons. We utilized a photostable and bright fluorescent indicator of glutamate release (iGluSnFR3) to quantify both spontaneous and evoked release at individual glutamatergic boutons. We found that the rate of spontaneous release is quite heterogenous at the level of individual boutons. Interestingly, when measuring both evoked and spontaneous release at single synapses, we found that boutons with the highest rates of spontaneous release also displayed the largest evoked responses.Using a new optical method to measure RRP at individual boutons, we found that this heterogeneity in spontaneous release was strongly correlated with the size of the RRP, but not related to Pv. We conclude that the RRP is a critical and dynamic aspect of synaptic strength that contributes to both evoked and spontaneous vesicle release.Significance StatementNeurotransmitter is released through two mechanisms: action potential-evoked and spontaneous vesicle fusion. It is unknown if some synapses specialize in either evoked or spontaneous release with an antagonistic relationship, or if the two forms of release coexist and have a cooperative relationship. We used a robust optical glutamate indicator to measure both forms of release at individual synapses. We found that the frequency of spontaneous release displays significant heterogeneity and is directly related to the size of the readily releasable pool of vesicles. This finding links both mechanisms of neurotransmitter release and suggests an important signaling mechanism to the postsynaptic neuron at individual synapses.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Frequency of spontaneous neurotransmission at individual boutons corresponds to the size of the readily releasable pool of vesicles.

Ralowicz,

Hokeness,

Hoppa

2024

J. Neurosci.

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“…Homeostatic plasticity is a collective term for compensatory physiological processes that counterbalance neuronal perturbations, ensuring brain stability. Recently, it was shown that also in the adult rodent hippocampus, homeostatic potentiation of presynaptic neurotransmitter release compensates acute, partial blockade of postsynaptic GluRs 54 . This finding is consistent with the expression of PHP documented at peripheral synapses, prominently at the Drosophila larval NMJ synapse.…”

Section: An Equilibrium Between Spn and Syd-1 Regulation Controls The...mentioning

confidence: 99%

An antagonism between Spinophilin and Syd-1 operates upstream of memory-promoting presynaptic long-term plasticity

Ramesh

Escher

Turrel

et al. 2023

Preprint

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We still face fundamental gaps in understanding how molecular plastic changes of synapses intersect with circuit operation to define behavioral states. Here we show that an antagonism between two conserved regulatory proteins, Spinophilin (Spn) and Syd-1, controls presynaptic long-term plasticity and the maintenance of olfactory memories in Drosophila. While Spn mutants could not trigger nanoscopic active zone remodeling under homeostatic challenge and failed to stably potentiate neurotransmitter release, concomitant reduction of Syd-1 rescued all these deficits. The Spn/Syd-1 antagonism converged on active zone close F-actin, and genetic or acute pharmacological depolymerization of F-actin rescued the Spn deficits by allowing access to synaptic vesicle release sites. Within the intrinsic mushroom body neurons, the Spn/Syd-1 antagonism specifically controlled olfactory memory stabilization but not initial learning. Thus, this evolutionarily conserved protein complex controls behaviorally relevant presynaptic long-term plasticity, also observed in the mammalian brain but still enigmatic concerning its molecular mechanisms and behavioral relevance.

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“…Notably, PHP operates across central and peripheral nervous systems, underscoring its significance in maintaining synaptic stability (Chipman et al, 2022;Delvendahl et al, 2019;Wang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…PHP ensures stability in postsynaptic excitation by counteracting perturbations in glutamate receptors through compensatory upregulation in presynaptic neurotransmitter release (Dickman & Davis, 2009; Frank et al, 2006). Notably, PHP operates across central and peripheral nervous systems, underscoring its significance in maintaining synaptic stability (Chipman et al, 2022; Delvendahl et al, 2019; Wang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Dysregulated glial genes in Alzheimer's disease are essential for homeostatic plasticity: Evidence from integrative epigenetic and single cell analyses

Cai,

Cui,

Yin

et al. 2023

Aging Cell

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Synaptic homeostatic plasticity is a foundational regulatory mechanism that maintains the stability of synaptic and neural functions within the nervous system. Impairment of homeostatic regulation has been linked to synapse destabilization during the progression of Alzheimer's disease (AD). Recent epigenetic and transcriptomic characterizations of the nervous system have revealed intricate molecular details about the aging brain and the pathogenesis of neurodegenerative diseases. Yet, how abnormal epigenetic and transcriptomic alterations in different cell types in AD affect synaptic homeostatic plasticity remains to be elucidated. Various glial cell types play critical roles in modulating synaptic functions both during the aging process and in the context of AD. Here, we investigated the impact of glial dysregulation of histone acetylation and transcriptome in AD on synaptic homeostatic plasticity, using computational analysis combined with electrophysiological methods in Drosophila. By integrating snRNA‐seq and H3K9ac ChIP‐seq data from the same AD patient cohort, we pinpointed cell type‐specific signature genes that were transcriptionally altered by histone acetylation. We subsequently investigated the role of these glial genes in regulating presynaptic homeostatic potentiation in Drosophila. Remarkably, nine glial‐specific genes, which were identified through our computational method as targets of H3K9ac and transcriptional dysregulation, were found to be crucial for the regulation of synaptic homeostatic plasticity in Drosophila. Our genetic evidence connects abnormal glial transcriptomic changes in AD with the impairment of homeostatic plasticity in the nervous system. In summary, our integrative computational and genetic studies highlight specific glial genes as potential key players in the homeostatic imbalance observed in AD.

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NMDAR-dependent presynaptic homeostasis in adult hippocampus: Synapse growth and cross-modal inhibitory plasticity

Cited by 15 publications

References 76 publications

Frequency of spontaneous neurotransmission at individual boutons corresponds to the size of the readily releasable pool of vesicles.

Frequency of spontaneous neurotransmission at individual boutons corresponds to the size of the readily releasable pool of vesicles.

An antagonism between Spinophilin and Syd-1 operates upstream of memory-promoting presynaptic long-term plasticity

Dysregulated glial genes in Alzheimer's disease are essential for homeostatic plasticity: Evidence from integrative epigenetic and single cell analyses

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