Targeted deletion of AKAP7 in dentate granule cells impairs spatial discrimination

Jones, Brian W.; Deem, Jennifer D.; Younts, Thomas J.; Weisenhaus, Michael; Sanford, Christina A.; Slack, Margaret C; Chin, Jenesa; Nachmanson, Daniela; McKennon, Alex; Castillo, Pablo E.; McKnight, G. Stanley

doi:10.7554/elife.20695

Cited by 33 publications

(27 citation statements)

References 68 publications

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“…Our findings suggest that changes in the docked vesicle pool in mossy fiber terminals may contribute to formation of engrams. Although our results demonstrate that the PKA pathway regulates vesicle pool size, previous work indicated a link between the PKA pathway in GCs and contextual memory formation ( Jones et al., 2016 ). Taken together, these results may suggest an intriguing connection between synaptic vesicle pools and hippocampal memory.…”

Section: Discussioncontrasting

confidence: 95%

Short-Term Plasticity at Hippocampal Mossy Fiber Synapses Is Induced by Natural Activity Patterns and Associated with Vesicle Pool Engram Formation

Vandael

Borges-Merjane

Zhang

et al. 2020

Neuron

122

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Summary Post-tetanic potentiation (PTP) is an attractive candidate mechanism for hippocampus-dependent short-term memory. Although PTP has a uniquely large magnitude at hippocampal mossy fiber-CA3 pyramidal neuron synapses, it is unclear whether it can be induced by natural activity and whether its lifetime is sufficient to support short-term memory. We combined in vivo recordings from granule cells (GCs), in vitro paired recordings from mossy fiber terminals and postsynaptic CA3 neurons, and “flash and freeze” electron microscopy. PTP was induced at single synapses and showed a low induction threshold adapted to sparse GC activity in vivo . PTP was mainly generated by enlargement of the readily releasable pool of synaptic vesicles, allowing multiplicative interaction with other plasticity forms. PTP was associated with an increase in the docked vesicle pool, suggesting formation of structural “pool engrams.” Absence of presynaptic activity extended the lifetime of the potentiation, enabling prolonged information storage in the hippocampal network.

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Section: Discussioncontrasting

confidence: 95%

Short-Term Plasticity at Hippocampal Mossy Fiber Synapses Is Induced by Natural Activity Patterns and Associated with Vesicle Pool Engram Formation

Vandael

Borges-Merjane

Zhang

et al. 2020

Neuron

122

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“…Cerebellum and heart are notable exceptions to this rule. The approximately twofold higher expression of RI than RII in cerebellum may be related to the different (presynaptic) role that PKA plays in synaptic plasticity in cerebellar granule cells (31,32). The elevated expression of the β isoform of RII in brain extracts is consistent with previous reports (33).…”

Section: Resultssupporting

confidence: 89%

Mechanisms for restraining cAMP-dependent protein kinase revealed by subunit quantitation and cross-linking approaches

Walker-Gray

Stengel

Gold

2017

Proc. Natl. Acad. Sci. U.S.A.

103

110

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Protein phosphorylation by cyclic AMP-dependent protein kinase (PKA) underlies key cellular processes, including sympathetic stimulation of heart cells, and potentiation of synaptic strength in neurons. Unrestrained PKA activity is pathological, and an enduring challenge is to understand how the activity of PKA catalytic subunits is directed in cells. We developed a light-activated cross-linking approach to monitor PKA subunit interactions with temporal precision in living cells. This enabled us to refute the recently proposed theory that PKA catalytic subunits remain tethered to regulatory subunits during cAMP elevation. Instead, we have identified other features of PKA signaling for reducing catalytic subunit diffusion and increasing recapture rate. Comprehensive quantitative immunoblotting of protein extracts from human embryonic kidney cells and rat organs reveals that regulatory subunits are always in large molar excess of catalytic subunits (average ∼17-fold). In the majority of organs tested, type II regulatory (RII) subunits were found to be the predominant PKA subunit. We also examined the architecture of PKA complexes containing RII subunits using cross-linking coupled to mass spectrometry. Quantitative comparison of cross-linking within a complex of RIIβ and Cβ, with or without the prototypical anchoring protein AKAP18α, revealed that the dimerization and docking domain of RIIβ is between its second cAMP binding domains. This architecture is compatible with anchored RII subunits directing the myristylated N terminus of catalytic subunits toward the membrane for release and recapture within the plane of the membrane.

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“…1a,b). Accordingly, we also observed a strong impairment in spatial pattern separation, a cognitive process associated with proper DG function and MF LTP (13,14,15,16,17), that is responsible for the disambiguation and independent storage of similar memories (Fig 1c-e). No changes were found in novel object location and recognition paradigms that are sensitive to interruption of hippocampal CA1 synaptic function ( Fig.…”

mentioning

confidence: 59%

SIPA1L2 controls trafficking and signaling of TrkB-containing amphisomes at presynaptic terminals

Andres-Alonso

Ammar

Butnaru

et al. 2019

Preprint

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2 SummaryAmphisomes are transient organelles that derive from fusion of autophagosomes with late endosomes. They rapidly transform into degradative autolysosomes, whereas non-degradative roles of the autophagic pathway have been barely described. Here we show that in neurons BDNF/TrkB receptor bearing Rab7 / Light chain 3 (LC3) -positive amphisomes signal at presynaptic boutons during retrograde trafficking to the soma. Local signaling and inward transport essentially require the Rap GTPase-activating (RapGAP) protein SIPA1L2, which directly binds to TrkB and Snapin to connect TrkB-containing amphisomes to dynein.Association with LC3 regulates the RapGAP activity of SIPA1L2 and thereby retrograde trafficking. Following induction of presynaptic plasticity amphisomes dissociate from dynein at boutons, and this enables local signaling and promotes transmitter release. Accordingly, sipa1l2 knockout mice show impaired BDNF-dependent presynaptic plasticity. Collectively, the data suggest that TrkB-signaling endosomes are in fact amphisomes that during retrograde transport have local signaling capacity in the context of presynaptic plasticity.3 TrkB signaling endosomes that carry axonal neurotrophic signals are generated at axon terminals and constitute an important long-range retrograde signaling mechanism conveying information of synaptic activity (1). Upon binding to BDNF, BDNF/TrkB have been shown to be internalized either via pinocytosis (2,3) or in a clathrin-dependent manner (4) to specialized vesicular compartments and sorted to diverse pathways by yet unknown mechanisms. TrkB signaling is required for different aspects of neuronal function including the expression of presynaptic LTP at mossy fiber (MF) synapses (5). By binding to different adaptor proteins, TrkB activates three major molecular cascades: the Ras-MAPK pathway, the phosphatidyl inositol-3 (PI3)-kinase cascade and the phospholipase C-γ1 pathway (6).Rap-1 based signaling ensures sustained ERK activation since prenylated Rap1 is associated to TrkB containing endosomes. These are long-lived and persist during transport from nerve terminals to the cell soma (7, 8 9,10). SIPA1L2 (also known as SPAR2) is a member of the SIPA1L family of neuronal RapGAPs ( Fig. S1) (11). The protein is most abundant in granule cells of the dentate gyrus (DG) and cerebellum and shows RapGAP activity for the small GTPases Rap1 and 2 (12). Here, we report that SIPA1L2 binds directly to TrkB, and links the receptor tyrosine kinase to a Dynein motor for retrograde trafficking via a direct interaction with the adaptor protein Snapin.Interestingly, SIPA1L2 concurrently associates via LC3b to Rab7-positive amphisomes and binding of LC3b promotes RapGAP activity. The amphisome trafficks retrogradely along axons, it stops at presynaptic boutons and both motility and signaling are controlled by SIPA1L2 whose RapGAP activity reduces the velocity of amphisome transport. Presynaptic long-term potentiation (LTP) induces a Protein kinase A (PKA)-dependent dissociation of the SIPA1L2/Snap...

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Targeted deletion of AKAP7 in dentate granule cells impairs spatial discrimination

Cited by 33 publications

References 68 publications

Short-Term Plasticity at Hippocampal Mossy Fiber Synapses Is Induced by Natural Activity Patterns and Associated with Vesicle Pool Engram Formation

Short-Term Plasticity at Hippocampal Mossy Fiber Synapses Is Induced by Natural Activity Patterns and Associated with Vesicle Pool Engram Formation

Mechanisms for restraining cAMP-dependent protein kinase revealed by subunit quantitation and cross-linking approaches

SIPA1L2 controls trafficking and signaling of TrkB-containing amphisomes at presynaptic terminals

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