Biology subjects

Maguire, J.

Publications and source records attributed to Maguire, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Network and behavioral signatures of postpartum behavioral deficits improve with a neurosteroid-based treatment

Postpartum depression (PPD) impacts nearly 20% of mothers and a much larger percentage (up to 75%) suffer from postpartum blues. Despite this high incidence, we still have an incomplete understanding of the underlying neurobiology of PPD. Deficits in neurosteroid signaling has been implicated in the vulnerability to postpartum behavioral deficits and mice with reduced expression of {delta} subunit-containing GABAA receptors (GABAARs) (Gabrd -/- or Gabrd +/-), the predominant site of action for 5-reduced neurosteroids, exhibit behavioral deficits restricted to the postpartum period. Allopregnanolone and allopregnanolone analogs (SGE-516) can improve postpartum behavioral outcomes and their ability to modulate oscillations in the basolateral amygdala (BLA) involved in emotional processing has been proposed to contribute to their antidepressant effects. Here we demonstrate that the behavioral differences in postpartum wild type, Gabrd+/-, and SGE-516-treated Gabrd+/- dams is largely driven by theta oscillations in the BLA. Previous studies have linked theta oscillations in the BLA to altered behavioral responding in response to stress or threat. Interestingly, here we demonstrate that Gabrd+/- dams exhibit a failure to properly respond to their own pup calls, with reduced theta oscillations that correlates with deficits in maternal approach behavior both of which are restored with SGE-516 treatment. Further, unbiased MoSeq analysis identified altered behavioral syllable expression in Gabrd+/- dams in response to their pup calls compared to wild type dams that are restored with SGE-516 treatment. These findings demonstrate network and behavioral signatures of postpartum behavioral deficits and characterize the effects associated with neurosteroid-based treatment response.

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bioRxiv2026

Repurposing drugs to treat Amoebic Gill Disease in Atlantic Salmon

Neoparameoba perurans causes Amoebic Gill Disease (AGD), a major parasitic disease of marine-phase Atlantic salmon and rainbow trout worldwide. Treatment options are limited to freshwater baths, which are costly at scale and exhibit only limited long-term efficacy. N. perurans contains an obligate eukaryotic symbiont, Perkinsela-like organism (PLO). PLO belongs to the class Kinetoplastida, which includes medically and veterinary important parasites such as Trypanosoma and Leishmania. As such, we hypothesised that trypanocidal drugs developed against other kinetoplastids might also affect N. perurans, potentially through disruption of its PLO symbiont, and used this hypothesis as a rationale for prioritising a focused panel of candidate compounds for screening. A holographic motility-based cytotoxicity assay was established to identify promising candidates in vitro, followed by controlled host tolerance testing and finally a field efficacy sea trial using naturally AGD-exposed site in the west of Ireland. Several compounds showed activity in vitro, especially miltefosine (EC50 1.84 uM, amoebicidal) and isometamidum (EC50 4.63 uM, amoebostatic). In vivo (two intramuscular injections, two weeks apart), miltefosine (Odds Ratio (OR) 0.62), isometamidum (OR 0.61) and benznidazole (OR 0.64) significantly improved gill score over four weeks, with miltefosine showing the largest effect size. Gill parasitaemia, measured via qPCR, was not reduced. Instead, two compounds increased apparent amoeba loads. This work support trypanocidal as potential AGD treatments in the field, although optimisation of dosing, delivery and mode of action requires further study.

microbiology↗

bioRxiv2026

Impact of impaired endogenous neurosteroidogenesis on outcomes following chronic alcohol exposure.

Alcohol use disorder is a major public health concern worldwide and there is a high comorbidity with psychiatric disorders. The basolateral amygdala (BLA) has been implicated in both mood and alcohol use disorders; however, the mechanisms contributing to the shared pathophysiology remain unknown. Extensive evidence indicates that ethanol modulates GABAergic signaling in the BLA, including actions on neurosteroid-sensitive, extrasynaptic {delta} subunit-containing GABAA receptors (GABAARs), which has been suggested to mediate many of the behavioral effects. In fact, several studies have suggested that 5-reduced neurosteroids, such as allopregnanolone, may mediate some of the behavioral effects of alcohol. Here we demonstrate that chronic intermittent ethanol (CIE) exposure impairs endogenous neurosteroidogenesis via downregulation of key neurosteroidogenic enzymes, 5-reductase type 1 and type 2. To examine the impact of impaired endogenous neurosteroidogenesis of the behavioral consequences of chronic alcohol exposure, including withdrawal-induced anxiety and increased alcohol consumption, we used CRISPR/Cas9 mediated knockdown of 5-reductase in the BLA. Reduced expression of 5-reductase in the BLA did not impact post-CIE alcohol intake or anxiety-like behaviors during withdrawal, perhaps because endogenous neurosteroidogenesis is already impaired following CIE. Therefore, we examined the impact of enhancing neurosteroid levels, treating mice post-CIE with SGE-516, a synthetic GABAAR positive allosteric modulator, which increased voluntary alcohol intake. These findings implicate endogenous neurosteroidogenesis in behavioral outcomes associated with withdrawal from chronic alcohol exposure. Further, this study suggests that targeting endogenous neurosteroidogenesis may be a novel and useful therapeutic target.

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bioRxiv2025

An Amygdalar Oscillatory Switch Governs Valence Assignment

Reward pursuit and punishment avoidance are among the most fundamental behaviors necessary for survival. The binary valuation of an experience as either positive or negative - "valence assignment" - is imperative for successful navigation of a regularly updating environment. Mounting evidence highlights the critical role of valence responsive basolateral amygdala (BLA) ensembles in coding valence information. However, how BLA ensembles are recruited to drive real-time valence assignment remains elusive. Here, we show locus coeruleus (LC)-derived norepinephrine coordinates this neural computational process via modulatory control over network-organizing BLA parvalbumin-expressing (PV) interneuron activity. Specifically, optogenetic activation of LC to BLA noradrenergic terminals (LC-BLANE) drives real-time negative valence assignment and suppression of BLA fast gamma oscillatory activity via BLA interneuronal 1a adrenergic receptor signaling. Conversely, positive valence assignment also requires BLA PV interneuron activity but is associated with an enhancement of local fast gamma power. Together, these converging data highlight a PV-driven amygdalar oscillatory switch that governs valence assignment.

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bioRxiv2025

Noradrenergic neuromodulation of cholecystokinin interneurons in the basolateral amygdala alters rhythmic activity and restrains fear memory

Norepinephrine (NE) release in the basolateral amygdala (BLA) during emotional arousal plays an essential role in the processing of fear. However, the cell type-specific NE neuromodulation of the fear circuit in the BLA has not been fully resolved. We reported previously a facilitation of fear memory by Gq-coupled receptor induction of repetitive bursting in parvalbumin-expressing interneurons and suppression of gamma oscillations in the BLA. Here, using patch clamp recordings, Cre-dependent DLX-driven intersectional targeting, and genetic manipulations, we demonstrate that NE also activates cholecystokinin (CCK)-expressing interneurons to generate synchronized trains of rhythmic CB1-sensitive IPSCs in BLA principal neurons via Gq-coupled 1A adrenoreceptor activation. The Gq-dependent mechanism in CCK interneurons is generalizable to chemogenetic Gq manipulation and Gq-coupled 5-HT2C serotoninergic receptor activation. We next tested the role of Gq neuromodulation of CCK interneurons in the regulation of BLA network activity associated with the behavioral expression of fear learning by rescued expression of 1A adrenoreceptors or chemogenetic Gq activation selectively in BLA CCK interneurons in a global 1A adrenoreceptor knockout mouse. Restoration of the rhythmic inhibitory synaptic activity via rescue of Gq-coupled receptor signaling in CCK interneurons enhanced LFP theta power in the BLA in vivo and decreased fear memory acquisition and recall. These data indicate an inhibitory role for CCK interneuron Gq signaling in fear learning via activation of patterned inhibitory synaptic input to principal neurons and enhanced theta oscillations in the BLA, and reveal a G protein-dependent, receptor-nonselective neuromodulatory mechanism in the BLA that regulates network and behavioral states.

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bioRxiv2025

Motion sequencing reveals hidden patterns of repetitive behavior in a mouse model of epilepsy

Epilepsy is the 4th most prevalent neurological condition with 50 million cases worldwide. Patients with epilepsy bare a disproportionate burden of cognitive decline and psychiatric disorders which remain poorly understood and go unaddressed by current anti-epileptic treatments. Furthermore, pre-clinical work on behavioral comorbidities can be hampered by current testing frameworks which rely on well-defined, discreet tests with limited repeatability. Recent work has demonstrated a role for machine learning modalities such as Motion Sequencing (MoSeq) in assessing behavioral differences between naive and epileptic. In this study we combined MoSeq with a novel analysis pipeline to uncover repetitive behaviors in chronically epileptic mice. These repetitive behaviors emerge alongside epilepsy specific racing behaviors which persist in epileptic mice as disease progresses. We show that epileptic mice have more fragile and dispersed behavioral networks. Finally, we test this pipeline using the FDA approved anti-seizure medication carbamazepine, showing a rescue of racing syllable and a partial rescue of behavioral network dispersion. Together, these results lay a groundwork for extracting clinically relevant phenotypes from MoSeq data throughout disease progression.

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bioRxiv2025

Candida albicans Colonization Modulates Murine Ethanol Consumption and Behavioral Responses Through Elevation of Serum Prostaglandin E2 and Impact on the Striatal Dopamine System

Candida albicans is a commensal yeast that is a common component of the gastrointestinal (GI) microbiome of humans. C. albicans has been shown to bloom in the GI tract of individuals with alcohol use disorder (AUD) and can promote and increase the severity of alcoholic liver disease (ALD). However, the effects of C. albicans blooms on the host in the context of AUD or AUD-related phenotypes, such as ethanol preference, have been unstudied. In this work, we report a reduction in ethanol consumption and preference in mice colonized with C. albicans. C. albicans-colonized mice exhibited elevated levels of serum PGE2 and reduced ethanol preference was reversed by injection with antagonists of PGE2 receptors. Further, injection of mice with a PGE2 derivative decreased their ethanol preference. These results show that PGE2 acting on its receptors EP1 and EP2 drives reduced ethanol preference in C. albicans-colonized mice. We also showed altered transcription of dopamine receptors in the dorsal striatum of C. albicans-colonized mice and more rapid acquisition of ethanol conditioned taste aversion, suggesting alterations to reinforcement or aversion learning. Finally, C. albicans-colonized mice were more susceptible to ethanol-induced motor coordination impairment showing significant alterations to the behavioral effects of ethanol. This study identifies a member of the fungal microbiome that alters ethanol preference and demonstrates a role for PGE2 signaling in these phenotypes. ImportanceCandida albicans is a commensal yeast that is found in the gut of most individuals. C. albicans has been shown to contribute to alcoholic liver disease. Outside of this, the impact of intestinal fungi on alcohol-use disorder (AUD) had been unstudied. As AUD is a complex disorder characterized by high relapse rates, and there are only 3 FDA-approved therapies for the maintenance of abstinence, it is important to study novel AUD contributors to find new therapeutic targets. Here we show that an intestinal fungus, C. albicans, can alter mammalian ethanol consumption through an immune modulator, prostaglandin E2. The results highlight novel contributors to AUD-related phenotypes and further implicate the gut-brain axis in AUD. Future studies could lead to new therapeutic avenues for the treatment of AUD.

microbiology↗

bioRxiv2024

Pharmacological inhibition of Fms-like kinase 3 (FLT3) promotes neuronal maturation and suppresses seizure in a mouse model

Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase predominantly expressed in blood and brain cells. While the FLT3 signaling pathway has been extensively studied in blood cell development and leukemia, its role in the brain remains largely unexplored. Through our groups previous high-throughput drug screening work unexpectedly found that several small molecule FLT3 inhibitors (FLT3i), including KW-2449 and Sunitinib, enhance expression of the gene encoding chloride transporter KCC2 in neurons. KCC2 is crucial for brain development and function, and its dysregulation is linked to many brain diseases. These findings suggest previously unrecognized roles of FLT3 signaling in brain health and disease that have yet to be systematically studied. In this study, we utilized a functional genomics approach to investigate the transcriptomic changes induced by pharmacological inhibition of the FLT3 pathway in brain cells, including cultured primary mouse neurons, a human stem cell-derived neuronal model of Rett syndrome (RTT), and human stem cell-derived microglia cultures. Our results show that treating human or mouse neurons with FLT3i drugs significantly upregulates genes crucial for brain development while downregulating genes linked to neuroinflammation. In contrast, FLT3i treatment of human microglia, which do not express FLT3, has no effect on their gene expression, highlighting the cell type-specific roles of FLT3 signaling in the brain. To further understand how FLT3 signaling regulates the expression of neuronal maturation genes such as KCC2, we conducted a curated CRISPR screen that identified a number of transcription factors involved in FLT3i-mediated KCC2 activation in neurons. The mRNA and protein levels of several neurodevelopmental disorder (NDD) risk genes are significantly upregulated in FLT3i-treated neurons, indicating potential therapeutic applications of FLT3i in rescuing underexpression and/or haploinsufficiency of disease-associated genes. In our in vivo studies, we evaluated the efficacy of the FLT3i drug KW-2449 in mice, demonstrating that it can effectively cross the blood-brain barrier, induce KCC2 protein expression for up to 24 hours after a single injection, and reduces seizure activity in a chemoconvulsant-induced mouse model of temporal lobe epilepsy. Collectively, our findings uncover previously unrecognized roles of neuron-specific FLT3 signaling in promoting neuronal maturation and reducing neuroinflammation. These results suggest that FLT3 kinase signaling regulates a transcriptional program vital for brain development and function, position it as a promising therapeutic target for NDD treatment.

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bioRxiv2024

Early life stress influences epilepsy outcomes in mice

Stress is a common seizure trigger that has been implicated in worsening epilepsy outcomes. The neuroendocrine response to stress is mediated by the hypothalamic-pituitary-adrenal (HPA) axis and HPA axis dysfunction worsens epilepsy outcomes, increasing seizure burden, behavioral comorbidities, and risk for sudden unexpected death in epilepsy (SUDEP) in mice. Early life stress (ELS) reprograms the HPA axis into adulthood, impacting both the basal and stress-induced activity. Thus, we propose that ELS may influence epilepsy outcomes by influencing the function of the HPA axis. To test this hypothesis, we utilized the maternal separation paradigm and examined the impact on seizure susceptibility. We show that ELS exerts a sex dependent effect on seizure susceptibility in response to acute administration of the chemoconvulsant, kainic acid, which is associated with an altered relationship between seizure activity and HPA axis function. To further examine the impact of ELS on epilepsy outcomes, we utilized the intrahippocampal kainic acid model of chronic epilepsy in mice previously exposed to maternal separation. We find that the relationship between corticosterone levels and the extent of epileptiform activity is altered in mice subjected to ELS. We demonstrate that ELS impacts behavioral outcomes associated with chronic epilepsy in a sex-dependent manner, with females being more affected. We also observe reduced mortality (presumed SUDEP) in female mice subjected to ELS, consistent with previous findings suggesting a role for HPA axis dysfunction in SUDEP risk. These data demonstrate for the first time that ELS influences epilepsy outcomes and suggest that previous life experiences may impact the trajectory of epilepsy.

neuroscience↗

bioRxiv2024

Sex-dependent effects of early life stress on network and behavioral states.

BackgroundAdverse childhood experiences (ACEs) are associated with numerous detriments in health, including increased vulnerability to psychiatric illnesses. Early life stress (ELS) in rodents has been shown to effectively model several of the behavioral and endocrine impacts of ACEs and has been utilized to investigate the underlying mechanisms contributing to disease. However, the precise neural mechanisms responsible for mediating the impact of ELS on vulnerability to psychiatric illnesses remain largely unknown. MethodsWe use behavior, immunoassay, in vivo LFP recording, histology, and patch clamp to describe the effects of ELS on stress behaviors, endocrinology, network states, protein expression, and cellular physiology in male and female mice. ResultsWe demonstrate that a murine maternal separation (MS) ELS model causes sex-dependent alterations in behavioral and hormonal responses following an acute stressor. Local field potential (LFP) recordings in the basolateral amygdala (BLA) and frontal cortex (FC) reveal similar sex-dependent alterations at baseline, in response to acute ethological stress, and during fear memory extinction, supporting a large body of literature demonstrating that these network states contribute to stress reactivity and vulnerability to psychiatric illnesses. Sex differences were accompanied by altered physiology of BLA principal neurons in males and BLA PV interneurons in females. ConclusionsCollectively, these results implicate novel, sex-dependent mechanisms through which ACEs may impact psychiatric health, involving altered cellular physiology and network states involved in emotional processing.

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bioRxiv2023

Loss of PV interneurons in the BLA contributes to altered network and behavioral states in chronically epileptic mice

Psychiatric disorders, including anxiety and depression, are highly comorbid in people with epilepsy. However, the mechanisms mediating the shared pathophysiology are currently unknown. There is considerable evidence implicating the basolateral amygdala (BLA) in the network communication of anxiety and fear, a process demonstrated to involve parvalbumin-positive (PV) interneurons. The loss of PV interneurons has been well described in the hippocampus of chronically epileptic mice and in postmortem human tissue of patients with temporal lobe epilepsy (TLE). We hypothesize that a loss of PV interneurons in the BLA may contribute to comorbid mood disorders in epilepsy. To test this hypothesis, we employed a ventral intrahippocampal kainic acid (vIHKA) model of chronic epilepsy in mice, which exhibits profound behavioral deficits associated with chronic epilepsy. We demonstrate a loss of PV interneurons and dysfunction of remaining PV interneurons in the BLA of chronically epileptic mice. Further, we demonstrate altered principal neuron function and impaired coordination of BLA network and behavioral states in chronically epileptic mice. To determine whether these altered network and behavioral states were due to the loss of PV interneurons, we ablated a similar percentage of PV interneurons observed in chronically epileptic mice by stereotaxically injecting AAV-Flex-DTA into the BLA of PV-Cre mice. Loss of PV interneurons in the BLA is sufficient to alter behavioral states, inducing deficits in fear learning and recall of fear memories. These data suggest that compromised inhibition in the BLA in chronically epileptic mice contributes to behavioral deficits, suggesting a novel mechanism contributing to comorbid anxiety and epilepsy. Significance StatementPsychiatric illnesses and epilepsy are highly comorbid and negatively impact the quality of life of people with epilepsy. The pathophysiological mechanisms mediating the bidirectional relationship between mood disorders and epilepsy remain unknown and, therefore, treatment options remain inadequate. Here we demonstrate a novel mechanism, involving the loss of PV interneurons in the BLA, leading to a corruption of network and behavioral states in mice. These findings pinpoint a critical node and demonstrate a novel cellular and circuit mechanism involved in the comorbidity of psychiatric illnesses and epilepsy.

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bioRxiv2023

Semi-automated seizure detection using interpretable machine learning models

Numerous methods have been proposed for seizure detection automation, yet the tools to harness these methods and apply them in practice are limited. Here we compare four interpretable and widely-used machine learning models (decision tree, gaussian naive bayes, passive aggressive classifier, stochastic gradient descent classifier) on an extensive electrographic seizure dataset collected from chronically epileptic mice. We find that the gaussian naive bayes model achieved the highest precision and f1 score, while also detecting all seizures in our dataset and only requires a small amount of data to train the model and achieve good performance. We use this model to create an open-source python application SeizyML that couples model performance with manual curation allowing for efficient and accurate detection of electrographic seizures. Author SummarySeizure detection based on electrographic recordings is critical for epilepsy diagnosis and research. However, the current gold standard for seizure detection is manual curation, which is biased, costly, incredibly laborious, and requires extensive training and expertise, prohibiting advances in epilepsy diagnosis and research. Here we demonstrate that fast, simple, and interpretable machine learning (ML) models are sufficient to detect all seizures in an extensive dataset collected from a well-established mouse model of epilepsy. Importantly, we created an open-source python application, SeizyML, that integrates the most precise model tested here with human curation of the detected events. This semi-automated approach greatly enhances efficiency and precision of seizure detection while also being transparent. We believe that the adoption of semi-automated and transparent technologies is indispensable for understanding ML model predictions, improving their reliability, and fostering trust between ML models and neurodiagnostic professionals.

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bioRxiv2023

Early life stress impairs VTA coordination of BLA network and behavioral states

Motivated behaviors, such as social interactions, are governed by the interplay between mesocorticolimbic structures, such as the ventral tegmental area (VTA), basolateral amygdala (BLA), and medial prefrontal cortex (mPFC). Adverse childhood experiences and early life stress (ELS) can impact these networks and behaviors, which is associated with increased risk for psychiatric illnesses. While it is known that the VTA projects to both the BLA and mPFC, the influence of these inputs on local network activity which govern behavioral states - and whether ELS impacts VTA-mediated network communication - remains unknown. Our study demonstrates that VTA inputs influence BLA oscillations and mPFC activity, and that ELS weakens the ability of the VTA to coordinate BLA network states, likely due to ELS-induced impairments in dopamine signaling between the VTA and BLA. Consequently, ELS mice exhibit increased social avoidance, which can be recapitulated in control mice by inhibiting VTA-BLA communication. These data suggest that ELS impacts social reward via the VTA-BLA dopamine network.

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bioRxiv2023

Basolateral amygdala parvalbumin interneurons coordinate oscillations to drive reward behaviors

The basolateral amygdala (BLA) has been implicated in mediating both fear and reward learning. Parvalbumin interneurons (PVs) in the BLA have previously been shown to contribute to BLA oscillatory states integral to fear expression, but whether BLA oscillatory states and PV interneurons also contribute to reward learning is unknown and critical to our understanding of reward processing. Local field potentials in the BLA were collected as animals consumed a sucrose reward, where prominent changes in the beta band (15-30 Hz) emerged with reward experience. Rhythmic optogenetic stimulation of PV interneurons to entrain the BLA network to 20Hz during consumption of one bottle during a two-bottle choice test produced a robust bottle preference. Finally, to demonstrate that PV activity is necessary for reward value use, PVs were chemogenetically targeted and inhibited following outcome devaluation, rendering those animals incapable of using updated reward value information to guide their behavior. Taken together, these experiments provide novel information regarding the physiological signatures of reward learning while highlighting the importance of PV interneurons in reward learning. This work builds upon the fields established knowledge of PV involvement in fear expression and provides evidence that PV orchestration of unique BLA network states is involved in both learning types.

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bioRxiv2023

Tofacitinib effects profound seizure suppression through mimicking EZH2 antagonism of a pro-inflammatory gene network in epilepsy.

All current drug treatments for epilepsy, a neurological disorder affecting over 50 million people(1, 2) merely treat symptoms, and a third of patients do not respond to medication. There are no disease modifying treatments that may be administered briefly to patients to enduringly eliminate spontaneous seizures and reverse cognitive deficits(3, 4). Applying network approaches to rodent models and human temporal lobectomy samples at both whole tissue and single-nuclei resolutions, we observe the well-characterized pattern of rapid induction and subsequent quenching exhibited of the JAK/STAT pathway within days of epileptogenic insult. This is followed by a resurgent activation weeks to months later with the onset of spontaneous seizures. Targeting the first wave of activation after epileptic insult does not prevent disease. However, brief inhibition of the second wave with CP690550 (Tofacitinib) (5, 6) enduringly suppresses seizures, rescues deficits in spatial memory, and alleviates epilepsy-associated histopathological alterations. Seizure suppression lasts for at least 2 months after the final dose. Using discovery-based transcriptomic analysis across models of epilepsy and validation of putative mechanisms with human data, we demonstrate a powerful approach to identifying disease modifying targets; this may be useful for other neurological disorders. With this approach, we find that reignition of inflammatory JAK/STAT3 signaling in chronic epilepsy opens a window for disease modification with the FDA-approved, orally available drug CP690550.

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bioRxiv2023

Experience-dependent information routing through the basolateral amygdala

The basolateral amygdala (BLA) is an emotional processing hub and is well-established to influence both positive and negative valence processing. Selective engagement of a heterogeneous cell population in the BLA is thought to contribute to this flexibility in valence processing. However, how this process is impacted by previous experiences which influence valence processing is unknown. Here we demonstrate that previous positive (EE) or negative (chronic unpredictable stress) experiences differentially influence the activity of specific populations of BLA principal neurons projecting to either the nucleus accumbens core or bed nucleus of the stria terminalis. Using chemogenetic manipulation of these projection-specific neurons we can mimic or occlude the effects of chronic unpredictable stress or enriched environment on valence processing to bidirectionally control avoidance behaviors and stress-induced helplessness. These data demonstrate that previous experiences influence the responsiveness of projection-specific BLA principal neurons, biasing information routing through the BLA, to govern valence processing.

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bioRxiv2023

Witnessed trauma exposure induces fear in mice through a reduction in endogenous neurosteroid synthesis

Neurosteroids have been implicated in the pathophysiology of post-traumatic stress disorder (PTSD). Allopregnanolone is reduced in subsets of individuals with PTSD and has been explored as a novel treatment strategy. Both direct trauma exposure and witnessed trauma are risk factors for PTSD; however, the role of neurosteroids in the behavioral outcomes of these unique experiences has not been explored. Here we investigate whether observational fear is associated with a reduced capacity for endogenous neurosteroidogenesis and the relationship with behavioral outcomes. We demonstrate that both mice directly subjected to the threat (foot shocks) and those witnessing the threat have decreased plasma levels of allopregnanolone. The expression of a key enzyme involved in endogenous neurosteroid synthesis, 5-reductase type 2, is decreased in the basolateral amygdala (BLA), which is a major emotional processing hub implicated in PTSD. We demonstrate that knockdown of 5-reductase type 2 exaggerates the behavioral expression of fear in response to witnessed trauma, whereas treatment with an exogenous, synthetic neuroactive steroid GABAA receptor PAM with molecular pharmacology similar to allopregnanolone (SGE-516 [tool compound]) decreases the behavioral response to observational fear. These data implicate impaired endogenous neurosteroidogenesis in the pathophysiology of threat exposure, both direct and witnessed. Further, these data suggest that treatment with exogenous 5-reduced neurosteroids or targeting endogenous neurosteroidogenesis may be beneficial for the treatment of individuals with PTSD, whether resulting from direct or witnessed trauma.

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bioRxiv2023

ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons

Mutations in the AAA+ ATPase p97 (also known as valosin containing protein, VCP) cause multisystem proteinopathy 1 (MSP-1) which includes amyotrophic-lateral sclerosis (ALS); however, the pathogenic mechanisms that contribute to motor neuron loss in familial ALS caused by p97 mutations remain obscure. Here, we use two distinct induced pluripotent stem cell models differentiated into spinal motor neurons to investigate how p97 mutations perturb the motor neuron proteome. Using multiplexed quantitative proteomics in these cells, we find that motor neurons harboring the p97 R155H mutation have deficits in lysosome quality control and the selective autophagy of lysosomes (lysophagy). p97 R155H motor neurons are unable to efficiently clear damaged lysosomes and have reduced viability. Additionally, lysosomes in mutant motor neurons have increased pH compared to their wildtype counterparts. The endo-lysosomal damage repair (ELDR) complex is required for clearance of damaged lysosomes and involves UBXD1-p97 interaction which is disrupted in mutant motor neurons. Finally, we report that inhibition of the ATPase activity of p97 R155H using the ATP competitive inhibitor CB-5083 rescues lysophagy defects in mutant motor neurons. These results add to the increasing evidence that endo-lysosomal dysfunction is a key aspect of disease pathogenesis in p97-related disorders.

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