Biology subjects

Volk, L. J.

Publications and source records attributed to Volk, L. J..

8 recordsLinked to original sources

bioRxiv2026

Peripheral B cell populations tune spontaneous neuronal activity in the uninjured hippocampus after stroke

B cells infiltrate the contralesional hippocampus following stroke, but whether lymphocytes modulate post-stroke plasticity and neuronal network function remains unknown. To identify immune cell mechanism(s) supporting remote plasticity, we examined the impact of B cell depletion on synaptic and neuronal activity in the hippocampal circuit following stroke. Basal synaptic transmission in the contralesional dentate gyrus (DG) following a stroke in adult male mice was decreased with B cell depletion. Expanding our studies to encompass the CA1 and DG regions of the hippocampal circuit in male and female mice of different ages, we utilized synapsin-Cre/GCaMP6s mice to visualize spontaneous calcium activity during a 3-week B cell depletion with and without prior stroke. Systemic B cell depletion in the absence of injury altered neuronal activity in the DG, suggesting a novel neuromodulatory role for circulating immune cells. Stroke increased Ca2+ transient amplitudes in the contralesional DG and CA1, with B cell depletion again reducing DG amplitudes while increasing the frequency of Ca2+ transients. Robust linear regression revealed significant main effects and higher-order interactions (depletionxsexxagexinjury), including increased Ca2+ transient amplitudes in older post-stroke mice lowered by systemic B cell depletion, though overall the DG appears more sensitive to modulation versus CA1. These results suggest that circulating B cells can tune hippocampal network activity dependent on age, sex, and the presence of brain injury. The selective vulnerability of the DG to depletion-age-injury interactions opens an avenue for future studies on region-specific neuroimmune crosstalk during post-stroke cognitive recovery. Presubmission inquiry for NeuronWe uncover crucial insights on the capacity of circulating B cells to directly modulate hippocampal network activity, showing that B cells are not just passive players, but active neuromodulators whose effects are dependent on sex, age, and stroke injury status. In fact, B cells are central players to functional recovery whose evolving role shifts over time, from acutely beneficial and neurotrophic to chronically maladaptive, depending on timing, context, and responding B cell subset. Our study demonstrates a mechanistic link between systemic immune modulation and neuronal calcium activity. This integrative perspective aligns with Neurons mission to publish studies that link cellular processes to systems-level functions. These novel findings also add to a more unified model of neuro-immune interactions that highlights how immunotherapies could be harnessed to improve neuronal function during stroke and aging, with several FDA-approved immunotherapeutics available to modulate systemic adaptive immune responses.

neuroscience↗

bioRxiv2024

PICK1 links KIBRA and AMPA receptors in coiled-coil-driven supramolecular complexes

The human memory-associated protein KIBRA regulates synaptic plasticity and trafficking of AMPA-type glutamate receptors, and is implicated in multiple neuropsychiatric and cognitive disorders. How KIBRA forms complexes with and regulates AMPA receptors remains unclear. Here, we show that KIBRA does not interact directly with the AMPA receptor subunit GluA2, but that PICK1, a key regulator of AMPA receptor trafficking, can serve as a bridge between KIBRA and GluA2. We identified structural determinants of KIBRA-PICK1-AMPAR complexes by investigating interactions and cellular expression patterns of different combinations of KIBRA and PICK1 domain mutants. We find that the PICK1 BAR domain, a coiled-coil structure, is sufficient for interaction with KIBRA, whereas mutation of the BAR domain disrupts KIBRA-PICK1-GluA2 complex formation. In addition, KIBRA recruits PICK1 into large supramolecular complexes, a process which requires KIBRA coiled-coil domains. These findings reveal molecular mechanisms by which KIBRA can organize key synaptic signaling complexes.

neuroscience↗

bioRxiv2024

Modulation of GABAAreceptor trafficking by WWC2 reveals class-specific mechanisms of synapse regulation by WWC family proteins

WWC2 (WW and C2 domain-containing protein) is implicated in several neurological disorders, however its function in the brain has yet to be determined. Here, we demonstrate that WWC2 interacts with inhibitory but not excitatory postsynaptic scaffolds, consistent with prior proteomic identification of WWC2 as a putative component of the inhibitory postsynaptic density. Using mice lacking WWC2 expression in excitatory forebrain neurons, we show that WWC2 suppresses GABAAR incorporation into the plasma membrane and regulates HAP1 and GRIP1, which form a complex promoting GABAAR recycling to the membrane. Inhibitory synaptic transmission is dysregulated in CA1 pyramidal cells lacking WWC2. Furthermore, unlike the WWC2 homolog KIBRA (WWC1), a key regulator of AMPA receptor trafficking at excitatory synapses, deletion of WWC2 does not affect synaptic AMPAR expression. In contrast, loss of KIBRA does not affect GABAAR membrane expression. These data reveal unique, synapse class-selective functions for WWC proteins as regulators of ionotropic neurotransmitter receptors and provide insight into mechanisms regulating GABAAR membrane expression.

neuroscience↗

bioRxiv2023

A novel, lightweight drive implant for chronic tetrode recordings in juvenile mice

SHORT ABSTRACTWe describe a novel micro-drive design, surgical implantation procedure, and post-surgery recovery strategy that allows for chronic field and single-unit recordings from up to sixteen brain regions simultaneously in juvenile and adolescent mice across a critical developmental window from p20 to p60 and beyond. LONG ABSTRACTIn vivo electrophysiology provides unparalleled insight into sub-second-level circuit dynamics of the intact brain and represents a method of particular importance for studying mouse models of human neuro-psychiatric disorders. However, such methods often require large cranial implants which cannot be used in mice at early developmental timepoints. As such, virtually no studies of in vivo physiology have been performed in freely behaving infant or juvenile mice, despite the fact that a better understanding of neurological development in this critical window is likely to provide unique insights into age-dependent developmental disorders such as autism or schizophrenia. Here, we describe a novel micro-drive design, surgical implantation procedure, and post-surgery recovery strategy that allows for chronic field and single-unit recordings from up to sixteen brain regions simultaneously in mice as they age from postnatal day 20 (p20) to postnatal day 60 (p60) and beyond, a time window roughly corresponding to human ages 2-years-old through adult. The number of recording electrodes and final recording sites can be easily modified and expanded, allowing flexible experimental control of in vivo monitoring of behavior- or disease-relevant brain regions across development.

neuroscience↗

bioRxiv2022

Bidirectional synaptic changes in deep and superficial hippocampal neurons following in vivo activity

Neuronal activity during experience is thought to induce plastic changes within the hippocampal network which underlie memory formation, although the extent and details of such changes in vivo remain unclear. Here, we employed a temporally precise marker of neuronal activity, CaMPARI2, to label active CA1 hippocampal neurons in vivo, followed by immediate acute slice preparation and electrophysiological quantification of synaptic properties. Recently active neurons in the superficial sublayer of stratum pyramidale displayed larger post-synaptic responses at excitatory synapses from area CA3, with no change in pre-synaptic release probability. In contrast, in vivo activity weakened both pre- and post-synaptic excitatory weights onto pyramidal cells in the deep sublayer. In vivo activity of deep and superficial neurons within sharp-wave ripples was bidirectionally changed across experience, consistent with the observed changes in synaptic weights. These findings reveal novel, fundamental mechanisms through which the hippocampal network is modified by experience to store information.

neuroscience↗

bioRxiv2022

Experience alters hippocampal and cortical network communication via a KIBRA-dependent mechanism

Synaptic plasticity is hypothesized to underlie "replay" of salient experience during hippocampal sharp-wave/ripple (SWR)-based ensemble activity and to facilitate systems-level memory consolidation coordinated by SWRs and cortical sleep spindles. However, it remains unclear how molecular changes at synapses contribute to experience-induced modification of network function. The synaptic protein KIBRA regulates plasticity and memory, although its impact on circuit dynamics remains unknown. Here, we recorded in vivo neural activity from WT mice and littermates lacking KIBRA to examine circuit function before, during, and after novel experience. In WT mice, experience altered network dynamics in a manner consistent with incorporation of new information content in replay and enhanced hippocampal-cortical communication. However, while baseline SWR features were normal in KIBRA cKO mice, experience-dependent alterations in SWRs were absent. Furthermore, intra-hippocampal and hippocampal-cortical communication during SWRs was disrupted following KIBRA deletion. These results reveal molecular mechanisms that underlie network-level memory formation and consolidation.

neuroscience↗

bioRxiv2022

KIBRA Regulates AMPA Receptor Expression, Synaptic Plasticity, and Memory in an Age-Dependent Manner

The biological mechanisms supporting age-dependent changes in learning and memory remain elusive. While a growing body of human literature implicates KIBRA in memory and neurodevelopmental disorders, KIBRAs molecular function and contribution to maturation of synaptic function and cognition remain poorly understood. Despite being expressed throughout early postnatal development, germline deletion of KIBRA impairs synaptic plasticity selectively in adult rodents. However, it is unclear whether KIBRA facilitates proper brain maturation necessary for adult plasticity or whether it plays a distinct role in plasticity in the adult brain. Here, using an inducible KIBRA knockout mouse, we demonstrate that acutely deleting KIBRA in adult forebrain neurons impairs both spatial memory and long-term potentiation (LTP). The deficits in LTP correlate with an adult-selective decrease in extrasynaptic AMPA receptors under basal conditions. We also identify a novel role for KIBRA in LTP-induced AMPAR upregulation. In contrast, acute deletion of KIBRA in juvenile forebrain neurons did not affect LTP and had minimal effects on basal AMPAR expression. These data suggest that KIBRA serves a unique role in adult hippocampal function through regulation of basal and activity-dependent AMPAR proteostasis that supports synaptic plasticity. Significance StatementSynaptic plasticity supported by trafficking of postsynaptic AMPA receptors is a conserved mechanism underlying learning and memory. The nature and efficacy of learning and memory undergo substantial changes during childhood and adolescent development, but the mechanisms underlying this cognitive maturation remain poorly understood. Here, we demonstrate that the human memory- and neurodevelopmental disorder-associated gene KIBRA facilitates memory and hippocampal synaptic plasticity selectively in the adult hippocampus. Furthermore, we show that selective loss of KIBRA from adult but not juvenile neurons reduces expression of extrasynaptic AMPA receptors and prevents LTP-induced increases in AMPAR expression. Overall, our results suggest that KIBRA participates in cellular and molecular processes that become uniquely necessary for memory and synaptic plasticity in early adulthood.

neuroscience↗

bioRxiv2020

The immediate early gene Arc is not required for hippocampal long-term potentiation.

The immediate early gene Arc is critical for maintenance of long-term memory. How Arc mediates this process remains unclear, but it has been proposed to sustain Hebbian synaptic potentiation, which is a key component of memory encoding. This form of plasticity is modelled experimentally by induction of long-term potentiation (LTP), which increases Arc mRNA and protein expression. However, mechanistic data implicates Arc in the endocytosis of AMPA-type glutamate receptors and the weakening of synapses. Here, we took a comprehensive approach to determine if Arc is necessary for hippocampal LTP. We find that Arc is not required for LTP maintenance and must regulate memory storage through alternative mechanisms.

neuroscience↗