Filopodia are a structural substrate for silent synapses in adult neocortex

Vardalaki, Dimitra; Chung, Kwanghun; Harnett, Mark T.

doi:10.1038/s41586-022-05483-6

Cited by 61 publications

(67 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The increase in mEPSC amplitude could reflect an increase in the number of postsynaptic receptors, altered vesicle size or an increase in the number of synapses if the mEPSCs are multiquantal [ 68 , 86 , 135 ]. It is also possible that synapses that were previously silent (exhibiting NMDA-receptor mediated synaptic transmission but lacking AMPA receptors) might be unsilenced (via insertion of AMPARs) to give more functional synapses [ 126 ]. Silent synapses, which are normally found at the tips of dendritic protrusions called filopodia, allow neurons to maintain more potential for plasticity and have recently been demonstrated to be more abundant in adult mice than once thought [ 126 ].…”

Section: Discussionmentioning

confidence: 99%

Tau in cerebrospinal fluid induces neuronal hyperexcitability and alters hippocampal theta oscillations

Brown

Camporesi

Lantero‐Rodriguez

et al. 2023

acta neuropathol commun

View full text Add to dashboard Cite

Alzheimer’s disease (AD) and other tauopathies are characterized by the aggregation of tau into soluble and insoluble forms (including tangles and neuropil threads). In humans, a fraction of both phosphorylated and non-phosphorylated N-terminal to mid-domain tau species, are secreted into cerebrospinal fluid (CSF). Some of these CSF tau species can be measured as diagnostic and prognostic biomarkers, starting from early stages of disease. While in animal models of AD pathology, soluble tau aggregates have been shown to disrupt neuronal function, it is unclear whether the tau species present in CSF will modulate neural activity. Here, we have developed and applied a novel approach to examine the electrophysiological effects of CSF from patients with a tau-positive biomarker profile. The method involves incubation of acutely-isolated wild-type mouse hippocampal brain slices with small volumes of diluted human CSF, followed by a suite of electrophysiological recording methods to evaluate their effects on neuronal function, from single cells through to the network level. Comparison of the toxicity profiles of the same CSF samples, with and without immuno-depletion for tau, has enabled a pioneering demonstration that CSF-tau potently modulates neuronal function. We demonstrate that CSF-tau mediates an increase in neuronal excitability in single cells. We then observed, at the network level, increased input–output responses and enhanced paired-pulse facilitation as well as an increase in long-term potentiation. Finally, we show that CSF-tau modifies the generation and maintenance of hippocampal theta oscillations, which have important roles in learning and memory and are known to be altered in AD patients. Together, we describe a novel method for screening human CSF-tau to understand functional effects on neuron and network activity, which could have far-reaching benefits in understanding tau pathology, thus allowing for the development of better targeted treatments for tauopathies in the future. Graphical Abstract

show abstract

Section: Discussionmentioning

confidence: 99%

Tau in cerebrospinal fluid induces neuronal hyperexcitability and alters hippocampal theta oscillations

Brown

Camporesi

Lantero‐Rodriguez

et al. 2023

acta neuropathol commun

View full text Add to dashboard Cite

show abstract

“…The increase in mEPSC amplitude could reflect an increase in the number of postsynaptic receptors, altered vesicle size or an increase in the number of synapses if the mEPSCs are multiquantal [63, 80, 127]. It is also possible that synapses that were previously silent (exhibiting NMDA-receptor mediated synaptic transmission but lacking AMPA receptors) might be unsilenced (via insertion of AMPARs) to give more functional synapses [118]. Silent synapses, which are normally found at the tips of dendritic protrusions called filopodia, allow neurons to maintain more potential for plasticity and have recently been demonstrated to be more abundant in adult mice than once thought [118].…”

Section: Discussionmentioning

confidence: 99%

“…It is also possible that synapses that were previously silent (exhibiting NMDA-receptor mediated synaptic transmission but lacking AMPA receptors) might be unsilenced (via insertion of AMPARs) to give more functional synapses [118]. Silent synapses, which are normally found at the tips of dendritic protrusions called filopodia, allow neurons to maintain more potential for plasticity and have recently been demonstrated to be more abundant in adult mice than once thought [118]. In the rTg4510 tauopathy mouse model, a loss of spine density in the cortex is reported over time and this results from a reduction in mushroom spines.…”

Section: Discussionmentioning

confidence: 99%

Tau in cerebrospinal fluid induces neuronal hyperexcitability and alters hippocampal theta oscillations

Brown

Camporesi

Lantero‐Rodriguez

et al. 2023

Preprint

View full text Add to dashboard Cite

Alzheimer's disease (AD) is the leading cause of dementia worldwide. In AD animal models, soluble tau aggregates have been shown to disrupt neuronal function, alter synaptic plasticity and impair cognitive function. In humans, small fractions of these toxic tau species are secreted into cerebrospinal fluid (CSF), some of which can be measured as diagnostic and prognostic biomarkers, starting from early stages of disease. However, the mechanisms of how these tau forms alter neuronal and network function are not fully understood. Here, we have developed and applied a novel approach to examine the electrophysiological effects of CSF from patients with a tau-positive biomarker profile. The method involves incubation of acutely-isolated wild-type mouse hippocampal brain slices with small volumes of diluted human CSF, followed by a suite of electrophysiological recording methods to evaluate their effects on neuronal function from single cells through to the network level. Comparison of the toxicity profiles of the same CSF samples, with and without immuno-depletion for tau, has enabled a pioneering demonstration that CSF-tau potently modulates neuronal function. We demonstrate that CSF-tau mediates an increase in neuronal excitability in single cells. We then observed, at the network level, increased input-output responses and enhanced paired-pulse facilitation as well as an increase in long-term potentiation. Finally, we show that CSF-tau modifies the generation and maintenance of hippocampal theta oscillations, which have important roles in learning and memory and are known to be altered in AD patients. Together, we describe a novel method for screening human CSF-tau to understand functional effects on neuron and network activity, which could have far-reaching benefits in understanding tau pathology, thus allowing for the development of better targeted treatments for tauopathies in the future.

show abstract

“…Optogenetic stimulation of projecting nerve terminals from RSC neurons con rmed the direct functional connection. While we still need direct evidence for silent synapses in the ACC 37 , our previous electrophysiology data consistently indicates the existence of some silent 'responses', or pure NMDA receptor mediated responses in the ACC 39,40 , and the recruitment of such silent synapses by LTP or chemicals 41,42 . Our current study provides new evidence for pure AMPA receptor containing excitatory synapses from RSC.…”

Section: Synaptic Responses In Cortico-cortical Connectionsmentioning

confidence: 91%

“…Previous anatomic studies reveal different projections to the ACC from other cortical and subcortical areas 9,25,26 . Few studies have provided direct evidence to demonstrate whether such projections are functional or silent 37 , or shown the characteristics of postsynaptic responses. In the present study, we effectively combine slice electrophysiology and optogenetic stimulation to investigate the projection from RSC to the ACC using in vitro brain slices.…”

Section: Synaptic Responses In Cortico-cortical Connectionsmentioning

confidence: 99%

Supraspinal facilitation of nociception by glutamatergic innervation from the retrosplenial cortex to anterior cingulate cortex

Xue¹,

Hao²,

Chen

et al. 2023

Preprint

View full text Add to dashboard Cite

Anterior cingulate cortex (ACC) is critical for pain perception; while the retrosplenial cortex (RSC) plays an important role in navigation and memory. It is known that RSC projects to ACC, less is known about the function of this projection. Here we used integrative approaches to show that there is direct excitatory glutamatergic projections from the RSC to the ACC, and postsynaptic excitatory responses are mediated by AMPA receptors. Activation of RSC-ACC by optogenetics significantly facilitated behavioral responses to nociceptive stimuli (mechanical and thermal) in freely moving mice. By contrast, spinal nociceptive tail-flick and anxiety-like activities were not affected. Our results suggest that RSC to ACC projection preferentially affects nociceptive process in supraspinal cortical region. Our results have identified a new facilitatory cortico-cortical circuit for sensory nociceptive process, and this pathway serves to link memory ‘engram’ to pain perception in humans and animals.

show abstract

Filopodia are a structural substrate for silent synapses in adult neocortex

Cited by 61 publications

References 45 publications

Tau in cerebrospinal fluid induces neuronal hyperexcitability and alters hippocampal theta oscillations

Tau in cerebrospinal fluid induces neuronal hyperexcitability and alters hippocampal theta oscillations

Tau in cerebrospinal fluid induces neuronal hyperexcitability and alters hippocampal theta oscillations

Supraspinal facilitation of nociception by glutamatergic innervation from the retrosplenial cortex to anterior cingulate cortex

Contact Info

Product

Resources

About