Biology subjects

Wenner, P.

Publications and source records attributed to Wenner, P..

4 recordsLinked to original sources

bioRxiv2025

Localization of Fascin to Dendritic Protrusions Regulates Postsynaptic Plasticity

The Fascin family of actin-bundling proteins is best known for organizing actin filaments (F-actin) into tightly packed bundles that drive dynamic membrane protrusions such as filopodia. In neurons, fascin has been thought to primarily function in axons, as previous studies reported its absence from dendritic filopodia and spines. Here, we demonstrate that fascin is both present and functionally important in dendritic compartments. Using optimized immunocytochemistry and CRISPR-based endogenous tagging of fascin1 in cultured hippocampal neurons, we show that fascin is concentrated in developing dendritic filopodia and enriched in mature dendritic spines. Super- resolution imaging further reveals that fascin is organized into discrete nanoscale foci within spine heads, but not the spine neck. Finally, we show that CRISPR-mediated knockout of fascin1 in mature hippocampal neurons impairs synaptic potentiation, without affecting baseline excitatory synaptic transmission. Together, our findings uncover a previously overlooked aspect of actin organization in dendritic spines and establish fascin as a critical regulator of postsynaptic plasticity. Summary StatementThe actin bundling protein fascin localizes to dendritic filopodia and spines, where it regulates activity-dependent synaptic plasticity.

neuroscience↗

bioRxiv2024

Whisker deprivation triggers a distinct form of cortical homeostatic plasticity that is impaired in the Fmr1 KO

Mouse models of Fragile X Syndrome (FXS) have demonstrated impairments in excitatory and inhibitory sensory-evoked neuronal firing. Homeostatic plasticity, which encompasses a set of mechanisms to stabilize baseline activity levels, does not compensate for these changes in activity. Previous work has shown that impairments in homeostatic plasticity are observed in FXS, including deficits in synaptic scaling and intrinsic excitability. Here, we aimed to examine how homeostatic plasticity is altered in vivo in an Fmr1 KO mouse model following unilateral whisker deprivation (WD). We show that WD in the wild type leads to an increase in the proportion of L5/6 somatosensory neurons that are recruited, but this does not occur in the KO. In addition, we observed a change in the threshold of excitatory neurons at a later developmental stage in the KO. Compromised homeostatic plasticity in development could influence sensory processing and long-term cortical organization.

neuroscience↗

bioRxiv2023

GABAergic synaptic scaling is triggered by changes in spiking activity rather than transmitter receptor activation.

Homeostatic plasticity represents a set of mechanisms that are thought to recover some aspect of neural function. One such mechanism called AMPAergic scaling was thought to be a likely candidate to homeostatically control spiking activity. However, recent findings have forced us to reconsider this idea as several studies suggest AMPAergic scaling is not directly triggered by changes in spiking. Moreover, studies examining homeostatic perturbations in vivo have suggested that GABAergic synapses may be more critical in terms of spiking homeostasis. Here we show results that GABAergic scaling can act to homeostatically control spiking levels. We found that perturbations which increased or decreased spiking in cortical cultures triggered multiplicative GABAergic upscaling and downscaling, respectively. In contrast, we found that changes in AMPAR or GABAR transmission only influence GABAergic scaling through their indirect effect on spiking. We propose that GABAergic scaling represents a stronger candidate for spike rate homeostat than AMPAergic scaling. Significance StatementThe nervous system maintains excitability in order to perform network behaviors when called upon to do so. Networks are thought to maintain spiking levels through homeostatic synaptic scaling, where compensatory multiplicative changes in synaptic strength are observed following alterations in cellular spike rate. Although we demonstrated that AMPAergic synaptic scaling does not appear meet these criteria as a spike rate homeostat, we now show that GABAergic scaling could play this role. Here we present evidence that the characteristics of GABAergic scaling place it in an excellent position to be a spiking homeostat. This work highlights the importance of inhibitory circuitry in the homeostatic control of excitability. Further, it provides a point of focus into neurodevelopmental disorders where excitability is impaired.

neuroscience↗

bioRxiv2021

The type 2 diabetes factor methylglyoxal mediates axon initial segment shortening and neuronal network activity changes

Recent evidence suggests that alteration of axon initial segment (AIS) geometry (i.e., length or position along the axon) contributes to CNS dysfunction in neurological diseases. For example, AIS length is shorter in the prefrontal cortex of type 2 diabetic mice with cognitive impairment. The key type 2 diabetes-related factor that alters AIS geometry is unknown. Here, we tested whether modifying the levels of insulin, glucose, or methylglyoxal, a reactive carbonyl species that is a metabolite of glucose, changes AIS geometry in mature cultures of dissociated postnatal mouse cortex using immunofluorescent imaging of the AIS proteins AnkyrinG and {beta}IV spectrin. Neither insulin nor glucose modification appreciably altered AIS length. Elevation of methylglyoxal produced reversible AIS shortening without cell death. Multi-electrode array recordings revealed a biphasic effect of methylglyoxal on neuronal network activity: an immediate, transient [~]300% increase in spiking and bursting rates was followed by a [~]20% reduction from baseline at 3 h. AIS length was unchanged at 0.5 h or 3 h after adding methylglyoxal, whereas development of AIS shortening at 24 h was associated with restoration of spiking to baseline levels. Immunostaining for the excitatory neuron marker Ca2+/calmodulin-dependent protein kinase II alpha revealed AIS shortening in both excitatory and inhibitory neuron populations. This suggests that complex mechanisms maintain neuronal network operation after acute exposure to the disease metabolite methylglyoxal. Importantly, our results indicate that methylglyoxal could be a key mediator of AIS shortening during type 2 diabetes. Significance StatementSmall changes in the structure of the axon initial segment affect neuronal function and may be a key mediator of neurological complications in various disease states. However, the specific disease factors that mediate structural changes at the axon initial segment are relatively unknown. This is the first study to show that increase of methylglyoxal is sufficient to reduce axon initial segment length and modulate neuronal network function. Methylglyoxal is a disease factor implicated in a wide variety of conditions including type 2 diabetes, Alzheimers disease, and aging. Thus, these findings could significantly impact the understanding of neurological complications in several disease states and are of broad pathophysiological relevance.

neuroscience↗