Biology subjects

Vissel, B.

Publications and source records attributed to Vissel, B..

6 recordsLinked to original sources

bioRxiv2026

Novel PSD95 reporter mice reveal medium spiny neuron subtype-specific synapse loss in PD and L-dopa induced dyskinesia and identify microglia mediated synapse removal as a therapeutic target for dyskinesia

BackgroundL-Dopa remains the primary treatment for Parkinsons disease (PD), but chronic administration frequently leads to L-Dopa-induced dyskinesia (LID). While D1 and D2 medium spiny neuron (MSN) specific structural changes on the spine level have been observed in the striatum of PD and LID, studying microglia mediated synapse loss has not been done to date. MethodsHere we generated novel reporter mice by crossing floxed PSD95c(mCherry/eGFP) mice with D1-Cre and D2-Cre lines, producing D1-PSD95-EGFP and D2-PSD95-EGFP strains for MSN-specific synapse visualization. Using the 6-OHDA mouse model of PD and LID we assessed microglia mediated MSN subtype specific synapse loss in these mice while PLX3397 was used to investigate effects of microglia depletion and repopulation on LID development and synapse loss. ResultsBoth D1- and D2-MSNs exhibited significant PSD95 synapse loss in PD, with D1-MSN loss further exacerbated in LID. Microglia displayed increased phagocytic activity and accumulated PSD95 material within lysosomes, particularly in LID. PLX3397-mediated microglial depletion reduced LID severity and preserved D1-MSN synapses. A depletion and repopulation paradigm attenuated LID severity, preserved D1-MSN synapses, and reduced synaptic material within microglia. ConclusionsMicroglia-mediated synapse loss in MSN subtypes contributes to PD and LID pathogenesis. Pharmacological microglial depletion and repopulation mitigate synapse loss and dyskinesia, highlighting microglial turnover as a promising therapeutic strategy for LID.

neuroscience↗

bioRxiv2025

Wnt-3a exacerbates production of TNF-α in LPS stimulated microglia independent of the β-catenin canonical pathway

BackgroundNeuroinflammatory pathways are emerging therapeutic targets for neurological conditions such as Parkinsons disease (PD). Studies have indicated Wnt-3a, a member of the wingless type MMTV integration (Wnt) signalling cascade, may exert anti-inflammatory effects via canonical pathway activation and {beta}-catenin stabilisation. Furthermore, dysregulation of the Wnt/{beta}-catenin pathway has been implicated in the degeneration of dopamine neurons in PD, however, stimulation of the canonical pathway via application of Wnt-3a to protect against inflammation and dopaminergic degeneration has not been explored. MethodsPrimary microglial cultures were stimulated with lipopolysaccharide (LPS) for 24 hours with or without Wnt-3a. TNF- levels were measured via ELISA while changes in NFkB inflammatory pathway proteins and phosphorylated and non-phosphorylated {beta}-catenin were analysed via capillary western blot. To assess Wnt pathway involvement, cultures were treated with DKK1 ({beta}-catenin canonical pathway inhibitor), SP600125 (Wnt/Pcp pathway inhibitor) or U73122 (Wnt/Ca2+ pathway inhibitor). Finally, C57BL/6 mice received continuous intracerebroventricular infusion of Wnt-3a via osmotic pumps to investigate the effects of Wnt-3a on dopaminergic neuron survival and on microglial numbers in the MPTP model of PD. ResultsWnt-3a alone had no effect on TNF- release from microglia. However, when co-administered with LPS, there was a significant increase in cytokine release beyond that seen with LPS alone. Protein analysis revealed that this exacerbation in TNF- levels was not due to alterations in the NFkB pathway or differences in activation of {beta}-catenin. Furthermore, DKK1 treated cells showed no changes in TNF- levels, however both SP600125 and U723122 were able to block Wnt-3a + LPS induced TNF- release, implicating the non-canonical pathways. Meanwhile Wnt-3a in vivo did not alter dopaminergic or microglial populations in the substantia nigra in MPTP lesioned animals. ConclusionTogether, these results suggest a pro-inflammatory response to Wnt-3a in an inflammatory context with little or no effect on resting microglia. Importantly, this outcome was independent of the {beta}-catenin canonical pathway, revealing that Wnt-3a can increase pro-inflammatory TNF- release via non-canonical signaling in an inflammatory environment. This demonstrates the importance of cellular context when identifying potential therapies for neurodegenerative diseases where neuroinflammation is a critical mediator of pathology.

neuroscience↗

bioRxiv2022

GluK2 Q/R editing regulates kainate receptor signalling and synaptic AMPA receptor expression and function.

Q/R editing of the kainate receptor (KAR) subunit GluK2 radically alters properties of recombinant KARs, but the effects in vivo remain largely unexplored. We compared GluK2 editing-deficient mice that express [~]95% unedited GluK2(Q) to wild-type counterparts that express [~]85% edited GluK2(R). At mossy fibre-CA3 (MF-CA3) synapses GluK2(Q) mice displayed enhanced postsynaptic KAR function and increased KAR-mediated presynaptic facilitation, demonstrating heightened ionotropic function. Conversely, there was reduced metabotropic KAR function, assessed by KAR-mediated afterhyperpolarization currents, in GluK2(Q) mice. GluK2(Q) mice had fewer GluA1- and GluA3-containing AMPA receptors (AMPARs) and reduced postsynaptic AMPAR currents at both MF-CA3 and CA1-Schaffer collateral synapses. Moreover, long-term potentiation of AMPAR-mediated transmission at CA1-Schaffer collateral synapses was reduced in GluK2(Q) mice. These findings suggest that GluK2 Q/R editing influences ionotropic/metabotropic balance of KAR signalling to regulate synaptic expression of AMPARs and plasticity.

neuroscience↗

bioRxiv2022

Goal-directed action is transiently impaired in an hAPP-J20 mouse model of Alzheimer's disease, and in aging male mice regardless of genotype

Cognitive-behavioural testing in preclinical models of Alzheimers disease has typically been limited to visuo-spatial memory tests and has failed to capture the broad scope of deficits patients also display in goal-directed action control. The current study addresses this gap by providing the first comprehensive investigation of how goal-directed actions are affected in a transgenic mouse model of Alzheimers disease. Specifically, we tested outcome devaluation performance - a popular test of goal-directed action - in male and female human amyloid precursor protein (hAPP)-J20 mice. Mice were first trained to press a left and right lever for unique pellet and sucrose outcomes respectively (counterbalanced) over four days. On test, mice were fed one of the two outcomes to reduce its value via sensory specific satiety and subsequently given a choice between levers. Goal-directed action was intact for 36-week-old wildtype mice of both sexes, because they responded more on the lever associated with the still-valued outcome than that associated with the devalued outcome (i.e. Valued > Devalued). Goal-directed action was impaired (Valued = Devalued) for J20 mice of both sexes, and for 52-week-old male mice regardless of genotype. Following an additional 4 days of lever press training (i.e., 8 days lever pressing in total), outcome devaluation was intact for all mice regardless of age or genotype. Immunohistochemical analysis revealed that increased microglial expression in the dorsal CA1 region of the hippocampus was associated with poorer outcome devaluation performance on initial tests, but not with tests performed after 8 days of lever pressing. Together, these data demonstrate that goal-directed action is transiently impaired in J20 mice of both sexes and in aging male mice regardless of genotype, and that this impairment is related to neuroinflammation in the dorsal CA1 region of the hippocampus.

animal behavior and cognition↗

bioRxiv2021

Outcome-selective reinstatement is partially context-dependent, and associated with c-Fos activation in the posterior dorsomedial striatum

Research from human and animal studies has found that responding that has been successfully reduced following treatment can return upon exposure to certain contexts. An individual in recovery from alcohol use disorder, for example, might relapse to drinking upon visiting their favourite bar. However, most of these data have been derived from experiments involving a single (active) response, and the context-dependence of returned responding in situations involving choice between multiple actions and outcomes is less well-understood. We thus investigated how outcome-selective reinstatement - a procedure involving choice between multiple actions - was affected by altering the physical context in rats. In Experiment 1, rats were trained over 6 days to press a left lever for one food outcome (pellets or sucrose) and a right lever for the other outcome. Then, rats received an extinction session in either the same context (A) as lever press training, or in a different context (B). Rats were tested immediately (5 minutes) after extinction in Context A or B such that there were four groups in total: AAA, ABB, ABA, and AAB. Reinstatement testing consisted of one food outcome being delivered freely (i.e. unearned by lever pressing and unsignalled by cues) to the food magazine every 4 minutes in the following order: Sucrose, Pellet, Pellet, Sucrose. Selective reinstatement was considered intact if pellet delivery increased pressing selectively on the pellet lever, and sucrose delivery selectively increased pressing on the sucrose lever. This result (Reinstated > Nonreinstated) was observed for rats in group AAA and ABB, but not rats in groups ABA and AAB. Experiment 2 was conducted identically, except that rats received two extinction sessions over two days and tested one day later. This time, all groups demonstrated intact outcome-selective reinstatement regardless of context. Analysis of c-Fos expression in several brain regions revealed that only c-Fos expression in the posterior dorsomedial striatum (pDMS) was related to intact reinstatement performance. Overall, these results suggest that outcome-selective reinstatement is predominantly context-independent, and that intact reinstatement is related to neuronal activity in the pDMS. HighlightsO_LIOutcome-selective reinstatement is predominantly context-independent C_LIO_LIOutcome-selective reinstatement is entirely context-independent after multiple extinction sessions C_LIO_LIOutcome-selective reinstatement increases c-Fos expression in dorsomedial striatum C_LIO_LIc-Fos expression in orbitofrontal cortex and dorsal hippocampus is unaffected by selective reinstatement. C_LI

animal behavior and cognition↗

bioRxiv2020

Medial Orbitofrontal Cortex Regulates Instrumental Conditioned Punishment, but not Pavlovian Conditioned Fear

Bidirectionally aberrant medial orbitofrontal cortical (mOFC) activity has been consistently linked with compulsion and compulsive disorders. Although rodent studies have established a causal link between mOFC excitation and compulsive-like actions, no such link has been made with mOFC inhibition. Here we use excitotoxic lesions of mOFC to investigate its role in sensitivity to punishment; a core characteristic of many compulsive disorders. In our first experiment, we demonstrated that mOFC lesions prevented instrumental conditioned punishment learning in a manner that could not be attributed to differences in Pavlovian conditioned fear. We then showed that increasing the frequency of punishing outcomes allowed mOFC-lesioned animals to overcome their initial deficit. Our second experiment demonstrated that the retrieval of instrumental punishment is also mOFC-dependent, as mOFC lesions prevented the extended retrieval of punishment contingencies relative to shams. In contrast, mOFC lesions did not prevent the re-acquisition of conditioned punishment that was learned prior to lesions being administered. Together, these results reveal that the mOFC does indeed regulate punishment learning and retrieval in a manner that is disassociated from any role in Pavlovian fear learning. These results imply that aberrant mOFC activity may contribute to the punishment insensitivity that is observed across multiple compulsive disorders.

neuroscience↗