Multi-synaptic boutons are a feature of CA1 hippocampal connections in the stratum oriens

Rigby, Mark R.; Grillo, Federico W.; Compans, Benjamin; Neves, Guilherme; Gallinaro, Júlia V.; Nashashibi, Sophie; Horton, Sally; Machado, Pedro; Carbajal, Maria Alejandra; Vizcay‐Barrena, Gema; Sibarita, Jean‐Baptiste; Kirkland, Angus I.; Fleck, Roland A.; Clopath, Claudia; Burrone, Juan

doi:10.1016/j.celrep.2023.112397

Cited by 6 publications

(7 citation statements)

References 50 publications

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“…Although MSBs have been observed by EM across various brain regions 44,45,48 , their molecular composition is yet to be unraveled. The patterning of MSBs along axons, their postsynaptic targets, and the intricate nature of these interactions are likely controlled by unique sets of surface adhesion, scaffolding, and signaling molecules 58 .…”

Section: Discussionmentioning

confidence: 99%

“…While the bulk of en passant synapses of long-range glutamatergic axons have one-to-one spine-toterminal ratios, some terminals are connected to multiple spines, usually residing on different dendritic arbors [43][44][45] . Owing to their putative ability to synchronize outputs to several downstream targets, these atypical multi-synaptic boutons (MSBs) are thought to improve the fidelity of neurotransmitter signaling within circuits and coordinate the induction of Hebbian plasticity for sensory processing and learning [45][46][47][48] .…”

Section: Initial Engram Ensembles Expand Their Connectomes Through Msbsmentioning

confidence: 99%

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Synaptic architecture of a memory engram in the mouse hippocampus

Uytiepo,

Zhu,

Bushong

et al. 2024

Preprint

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Memory engrams are formed through experience-dependent remodeling of neural circuits, but their detailed architectures have remained unresolved. Using 3D electron microscopy, we performed nanoscale reconstructions of the hippocampal CA3-CA1 pathway following chemogenetic labeling of cellular ensembles with a remote history of correlated excitation during associative learning. Projection neurons involved in memory acquisition expanded their connectomes via multi-synaptic boutons without altering the numbers and spatial arrangements of individual axonal terminals and dendritic spines. This expansion was driven by presynaptic activity elicited by specific negative valence stimuli, regardless of the co-activation state of postsynaptic partners. The rewiring of initial ensembles representing an engram coincided with local, input-specific changes in the shapes and organelle composition of glutamatergic synapses, reflecting their weights and potential for further modifications. Our findings challenge the view that the connectivity among neuronal substrates of memory traces is governed by Hebbian mechanisms, and offer a structural basis for representational drifts.

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Section: Discussionmentioning

confidence: 99%

Section: Initial Engram Ensembles Expand Their Connectomes Through Msbsmentioning

confidence: 99%

Synaptic architecture of a memory engram in the mouse hippocampus

Uytiepo,

Zhu,

Bushong

et al. 2024

Preprint

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“…A noticeable feature in both Csf1r ΔFIRE/ΔFIRE and microglia-depleted WT mice is the impairment of multivesicular release (Basilico et al, 2022 ; Table 2 ), a hallmark of mature hippocampal synaptic transmission (Hsia et al, 1998 ; Rigby et al, 2023 ). This may be due to a preferential interaction of microglia with presynaptic structures, contributing to the formation of multi-synaptic boutons in the developing hippocampus (Zhan et al, 2014 ; Weinhard et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Lifelong absence of microglia alters hippocampal glutamatergic networks but not synapse and spine density

Surala,

Soso-Zdravkovic,

Munro

et al. 2024

EMBO Rep

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Microglia sculpt developing neural circuits by eliminating excess synapses in a process called synaptic pruning, by removing apoptotic neurons, and by promoting neuronal survival. To elucidate the role of microglia during embryonic and postnatal brain development, we used a mouse model deficient in microglia throughout life by deletion of the fms-intronic regulatory element (FIRE) in the Csf1r locus. Surprisingly, young adult Csf1rΔFIRE/ΔFIRE mice display no changes in excitatory and inhibitory synapse number and spine density of CA1 hippocampal neurons compared with Csf1r+/+ littermates. However, CA1 neurons are less excitable, receive less CA3 excitatory input and show altered synaptic properties, but this does not affect novel object recognition. Cytokine profiling indicates an anti-inflammatory state along with increases in ApoE levels and reactive astrocytes containing synaptic markers in Csf1rΔFIRE/ΔFIRE mice. Notably, these changes in Csf1rΔFIRE/ΔFIRE mice closely resemble the effects of acute microglial depletion in adult mice after normal development. Our findings suggest that microglia are not mandatory for synaptic pruning, and that in their absence pruning can be achieved by other mechanisms.

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“…In the CA1, the SLM receives entorhinal and thalamic afferents and contains interneurons important for rhythmic synchronization of pyramidal cells involved in mnemonic processes ( Chapman and Lacaille, 1999 ; Vu et al, 2020 ) and affect neuronal protection and survival ( Lana et al, 2021 ). The CA1 SO contains a variety of inhibitory interneurons ( Hardy et al, 2021 ), in addition to the axons ( Arszovszki et al, 2014 ) and basal dendrites ( Bannister and Larkman, 1995 ; Rigby et al, 2023 ) of principle cells and receives inputs from the entorhinal cortex ( Takács et al, 2012 ; Bell et al, 2021 ), local ( Takács et al, 2012 ; Huh et al, 2016 ; Bell et al, 2021 ) or commissural ( Supèr and Soriano, 1994 ) principle hippocampal neurons, and from the medial septal nucleus ( Yamada and Jinno, 2015 ), the site of cholinergic neurons ( Müller and Remy, 2018 ). The CA2/CA3a regions are innervated by the hypothalamic supramammillary nucleus believed to participate in theta rhythms influencing encoding of new memories ( Jones and McHugh, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Hippocampal glial inflammatory markers are differentially altered in a novel mouse model of perimenopausal cerebral amyloid angiopathy

Platholi,

Marongiu,

Park

et al. 2023

Front. Aging Neurosci.

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Dementia is often characterized by age-dependent cerebrovascular pathology, neuroinflammation, and cognitive deficits with notable sex differences in risk, disease onset, progression and severity. Women bear a disproportionate burden of dementia, and the onset of menopause (i.e., perimenopause) may be a critical period conferring increased susceptibility. However, the contribution of early ovarian decline to the neuroinflammatory processes associated with cerebrovascular dementia risks, particularly at the initial stages of pathology that may be more amenable to proactive intervention, is unknown. To better understand the influence of early ovarian failure on dementia-associated neuroinflammation we developed a model of perimenopausal cerebral amyloid angiopathy (CAA), an important contributor to dementia. For this, accelerated ovarian failure (AOF) was induced by 4-vinylcyclohexene diepoxide (VCD) treatment to isolate early-stage ovarian failure comparable to human perimenopause (termed “peri-AOF”) in transgenic SWDI mice expressing human vasculotropic mutant amyloid beta (Aβ) precursor protein, that were also tested at an early stage of amyloidosis. We found that peri-AOF SWDI mice showed increased astrocyte activation accompanied by elevated Aβ in select regions of the hippocampus, a brain system involved in learning and memory that is severely impacted during dementia. However, although SWDI mice showed signs of increased hippocampal microglial activation and impaired cognitive function, this was not further affected by peri-AOF. In sum, these results suggest that elevated dysfunction of key elements of the neurovascular unit in select hippocampal regions characterizes the brain pathology of mice at early stages of both CAA and AOF. However, neurovascular unit pathology may not yet have passed a threshold that leads to further behavioral compromise at these early periods of cerebral amyloidosis and ovarian failure. These results are consistent with the hypothesis that the hormonal dysregulation associated with perimenopause onset represents a stage of emerging vulnerability to dementia-associated neuropathology, thus providing a selective window of opportunity for therapeutic intervention prior to the development of advanced pathology that has proven difficult to repair or reverse.

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Multi-synaptic boutons are a feature of CA1 hippocampal connections in the stratum oriens

Cited by 6 publications

References 50 publications

Synaptic architecture of a memory engram in the mouse hippocampus

Synaptic architecture of a memory engram in the mouse hippocampus

Lifelong absence of microglia alters hippocampal glutamatergic networks but not synapse and spine density

Hippocampal glial inflammatory markers are differentially altered in a novel mouse model of perimenopausal cerebral amyloid angiopathy

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