Biology subjects

Thomas, K. L.

Publications and source records attributed to Thomas, K. L..

8 recordsLinked to original sources

bioRxiv2026

PARP inhibition with 3-aminobenzimide attenuates behavioral, cardiovascular, and neuroinflammatory effects of chronic stress

BackgroundMajor depressive disorder (MDD) affects approximately 20% of the population, with over 30% of cases demonstrating treatment resistance. Postmortem analyses have revealed increased poly (ADP-ribose) polymerase 1 (PARP-1) expression in prefrontal cortical white matter of individuals with MDD, suggesting PARP-1 as a potential therapeutic target. Chronic stress, a major risk factor for depression, affects multiple physiological domains including behavior, cardiovascular function, neuroinflammation, and gut-brain axis signaling. MethodsWe conducted a comprehensive multi-system investigation of PARP inhibition effects on stress-induced pathophysiology using the social defeat stress/chronic unpredictable stress (SDS+CUS) rodent model. In the primary study, male Sprague-Dawley rats (N=32) underwent 10 days of SDS+CUS while receiving daily treatment with the PARP inhibitor 3-aminobenzamide (3-AB; 40mg/kg), selective serotonin reuptake inhibitor fluoxetine (FLX; 10mg/kg), or saline (0.9% NaCl), with non-stressed controls included. Behavioral outcomes were assessed via sucrose preference and social interaction tests. Neurobiological analyses examined PARP-1 expression, microglial morphology, and proinflammatory cytokine levels (IL-1{beta}, TNF-, IL-6) in relevant brain regions. In a parallel cardiovascular study, a separate cohort of stressed rats (N=8) received either saline or 3-AB treatment while hemodynamic parameters were monitored via telemetry before, during, and after stress exposure. ResultsSaline-treated stressed rats demonstrated significantly elevated anhedonia compared to the 3-AB/Stress rats and social avoidance compared to the 3-AB/Stress and Control/ No-Stress groups. Cardiovascular monitoring revealed that stressed saline-treated rats developed significant elevations in systolic and mean blood pressure with decreased heart rate compared to baseline, whereas 3-AB treatment prevented changes in systolic and mean blood pressure. Neurobiological analyses of PARP-1 expression in PFC did not reveal significant group differences. Microglial morphological analysis revealed a shift toward more prolate (activated) soma morphology in the saline-treated stressed rats compared to the non-stressed controls. Additionally, 3-AB-treated rats showed significantly more oblate (quiescent) microglia than saline-treated rats. Saline-treated stressed rats exhibited significantly increased hippocampal proinflammatory cytokines, with 3-AB treatment specifically attenuating TNF- and IL-1{beta} levels. Conclusion3-AB treatment provided multi-system protection against chronic stress effects, preventing behavioral deficits and cardiovascular dysfunction, and attenuating select markers of neuroinflammation. These findings suggest that 3-AB, and potentially PARP-1 inhibition, warrants further investigation as a therapeutic approach for stress-related disorders. Significant OutcomesO_LI3-aminobenzamide (3-AB) treatment was associated with reduced stress-induced behavioral anhedonia and social avoidance relative to saline-treated stressed rats in a validated rodent model combining social defeat and chronic unpredictable stress. C_LIO_LI3-AB treatment prevented stress-induced increases in arterial blood pressure. C_LIO_LI3-AB treatment prevented the stress-induced shift toward a more prolate microglial morphology and significantly attenuated the stress-induced increase in hippocampal TNF- and IL-1{beta}. C_LIO_LIThe multi-domain protective effects of 3-AB, spanning behavioral, cardiovascular, and neuroinflammatory measures, support further investigation of PARP inhibition as a potential therapeutic strategy for stress-related disorders. C_LI LimitationsO_LIThis study examined only male rats, limiting generalizability to female subjects despite the higher prevalence of MDD in women. C_LIO_LIBehavioral assessments were limited to anhedonia and social interaction; additional tests of other depression-relevant behaviors would provide a more comprehensive phenotypic profile. C_LIO_LILong-term effects of 3-AB treatment beyond the 10-day stress paradigm remain unexplored. C_LI

neuroscience↗

bioRxiv2025

Sex differences in latent inhibition and their implications for psychotic disorders

Latent inhibition (LI) has been extensively studied to investigate associative learning and memory processes as well as modelling aberrant attribution of salience to irrelevant stimuli in both humans and animals, a process which is thought to underpin hallucinations and delusions in psychosis. Despite sex differences observed in numerous aspects of psychosis, few studies have attempted to characterise sex differences in LI. This systematic review outlines the current evidence of sex differences in LI in both human and rodent studies, showing predominantly inconclusive and conflicting evidence for sex differences. We present data demonstrating sex differences in latent inhibition of contextual fear conditioning and associated gene expression in the hippocampus in rodents, supporting sex differences in latent inhibition at the behavioural and neurobiological levels. The systematic review suggests that although there have been relatively few studies of sex differences in LI, the data suggest that in hippocampally dependent forms of LI, sex differences may be more apparent, which may be of relevance in relation to sex differences in the presentation of psychosis.

neuroscience↗

bioRxiv2024

Reduced gene dosage of the psychiatric risk gene Cacna1c is associated with impairments in hypothalamic-pituitary-adrenal axis activity in rats

Common and rare variation in CACNA1C gene expression has been consistently associated with neuropsychiatric disorders such as schizophrenia, bipolar disorder, and major depression, however the underlying biological pathways that cause this association have yet to be fully determined. In this study, we present evidence that rats with a reduced gene dosage of Cacna1c have increased basal corticosterone levels in the periphery and reduced Nr3c1 gene expression in the hippocampus and hypothalamus. These results are consistent with an effect of Cacna1c dosage on hypothalamus-pituitary-adrenal (HPA) axis function. We also show that the reduction of Nr3c1 in the hippocampus may be caused by epigenetic modification of exon 17 of Nr3c1, including the reduced interaction with the histone modifying markers H3K4me3 and H3K27ac. Heterozygous Cacna1c rats additionally show increased anxiety behaviours. These results support an association of Cacna1c heterozygosity with the altered activity of the HPA axis and function in the resting state and this may be a predisposing mechanism that contributes to the increased risk of psychiatric disorders with stress.

neuroscience↗

bioRxiv2021

Behavioural and molecular characterisation of the Dlg2 haploinsufficiency rat model of genetic risk for psychiatric disorder

Genetic studies implicate disruption to the DLG2 gene in copy number variants as increasing risk for schizophrenia, autism spectrum disorders and intellectual disability. To investigate psychiatric endophenotypes associated with DLG2 haploinsufficiency (and concomitant PSD-93 protein reduction) a novel clinically relevant Dlg2+/- rat was assessed for abnormalities in anxiety, sensorimotor gating, hedonic reactions, social behaviour, and locomotor response to the N-Methyl-D-aspartic acid receptor antagonist phencyclidine. Dlg gene and protein expression were also investigated to assess model validity. Reductions in PSD-93 messenger RNA and protein were observed in the absence of compensation by other related genes or proteins. Behaviourally Dlg2+/- rats show potentiated locomotor response to phencyclidine, as is typical of psychotic disorder models, in the absence of deficits in the other behavioural phenotypes assessed here. This shows that the behavioural effects of Dlg2 haploinsufficiency may specifically relate to psychosis vulnerability but are subtle, providing a contrast to the gross deficits in Dlg2 homozygous models (Winkler, et al., 2018; Yoo et al., 2020a) which do not so specifically model the single chromosome DLG2 deletion in carriers of risk-associated copy number variants.

genetics↗

bioRxiv2021

Selective behavioural impairments in mice heterozygous for the cross disorder psychiatric risk gene DLG2

Mutations affecting DLG2 are emerging as a genetic risk factor associated with neurodevelopmental psychiatric disorders including schizophrenia, autism spectrum disorder and bipolar disorder. Discs large homolog 2 (DLG2) is a member of the membrane-associated guanylate kinase protein superfamily of scaffold proteins, a component of the post-synaptic density in excitatory neurons and regulator of synaptic function and plasticity. It remains an important question whether and how haploinsuffiency of DLG2 contributes to impairments in basic behavioural and cognitive functions that may underlie symptomatic domains in patients that cross diagnostic boundaries. Using a heterozygous Dlg2 mouse model we examined the impact of reduced Dlg2 expression on functions commonly impaired in neurodevelopmental psychiatric disorders including motor co-ordination and learning, pre-pulse inhibition and habituation to novel stimuli. The heterozygous Dlg2 mice exhibited behavioural impairments in long-term motor learning and long-term habituation to a novel context, but not motor co-ordination, initial responses to a novel context, PPI of acoustic startle or anxiety. We additionally showed evidence for the reduced regulation of the synaptic plasticity-associated protein cFos in the motor cortex during motor learning. The sensitivity of selective behavioural and cognitive functions, particularly those dependent on synaptic plasticity, to reduced expression of DLG2 give further credence for DLG2 playing a critical role in specific brain functions but also a mechanistic understanding of symptom expression shared across psychiatric disorders.

neuroscience↗

bioRxiv2021

Reduced expression of the psychiatric risk gene DLG2 (PSD93) impairs hippocampal synaptic integration and plasticity

Background: Genetic variations indicating loss of function in the DLG2 gene have been associated with markedly increased risk for schizophrenia, autism spectrum disorder, and intellectual disability. DLG2 encodes the postsynaptic scaffolding protein DLG2 (PSD93) that interacts with NMDA receptors, potassium channels, and cytoskeletal regulators but the net impact of these interactions on synaptic plasticity, likely underpinning cognitive impairments associated with these conditions, remains unclear. Methods: Hippocampal CA1 neuronal excitability and synaptic function were investigated in a novel clinically relevant heterozygous Dlg2+/- rat model using ex vivo patch-clamp electrophysiology, pharmacology, and computational modelling. Results: Dlg2+/- rats had increased NMDA receptor-mediated synaptic currents and, conversely, impaired associative long-term potentiation. This impairment resulted from an increase in potassium channel function leading to a decrease in input resistance and reduced supra-linear dendritic integration during induction of associative long-term potentiation. Enhancement of dendritic excitability by blockade of potassium channels or activation of muscarinic M1 receptors with selective allosteric agonist 77-LH-28-1 reduced the threshold for dendritic integration and 77-LH-28-1 rescued the associative long-term potentiation impairment in the Dlg2+/- rats. Conclusions: Despite increasing synaptic NMDA receptor currents, the combined impact of reduced DLG2 impairs synaptic integration in dendrites resulting in disrupted associative synaptic plasticity. This biological phenotype can be reversed by compound classes used clinically such as muscarinic M1 receptor agonists and is therefore a potential target for therapeutic intervention.

neuroscience↗

bioRxiv2020

Neurotrophin receptor activation rescues cognitive and synaptic abnormalities caused by mutation of the psychiatric risk gene Cacna1c

Genetic variation in CACNA1C, which encodes the alpha-1 subunit of CaV1.2 L-type voltage-gated calcium channels, is strongly linked to risk for psychiatric disorders including schizophrenia and bipolar disorder. To translate genetics to neurobiological mechanisms and rational therapeutic targets, we investigated the impact of altered Cacna1c dosage on rat cognitive, synaptic and circuit phenotypes implicated by patient studies. We show that rats hemizygous for Cacna1c harbor marked impairments in learning to disregard non-salient stimuli, a behavioral change previously associated with psychosis. This behavioral deficit is accompanied by dys-coordinated network oscillations during learning, pathway-selective disruption of hippocampal synaptic plasticity, attenuated Ca2+ signaling in dendritic spines and decreased signaling through the Extracellular-signal Regulated Kinase (ERK) pathway. Activation of the ERK pathway by a small molecule agonist of TrkB/TrkC neurotrophin receptors rescued both behavioral and synaptic plasticity deficits in Cacna1c+/- rats. These results map a route through which genetic variation in CACNA1C can disrupt experience-dependent synaptic signaling and circuit activity, culminating in cognitive alterations associated with psychiatric disorders. Our findings highlight targeted activation of neurotrophin signaling pathways with BDNF mimetic drugs as a novel, genetically informed therapeutic approach for rescuing behavioral abnormalities in psychiatric disorder. One Sentence SummaryNeurotrophin receptor activation reveals that BDNF mimetic drugs have therapeutic potential to ameliorate genetic risk for psychiatric disorders.

neuroscience↗

bioRxiv2018

Dynamic expression of risk genes for schizophrenia and bipolar disorder across development

AO_SCPCAPBSTRACTC_SCPCAPCommon genetic variation contributes a substantial proportion of risk for both schizophrenia and bipolar disorder. Furthermore, there is evidence of significant, but not complete, overlap in genetic risk between schizophrenia and bipolar disorder. It has been hypothesised that genetic variants conferring risk for these disorders do so by influencing brain development, leading to the later emergence of symptoms. The comparative profile of risk gene expression for schizophrenia and bipolar disorder across development over different brain regions however remains unclear. Using genotypes derived from genome wide associations studies of the largest available cohorts of patients and control subjects, we investigated whether genes enriched for schizophrenia and bipolar disorder association show a bias for expression across any of 13 developmental stages in prefrontal cortical and subcortical brain regions. We show that genes associated with schizophrenia have a strong bias towards increased expression in the prefrontal cortex during early midfetal development and early infancy, and decreased expression during late childhood which normalises in adolescence. Risk-associated genes for bipolar disorder shared this postnatal expression profile but did not exhibit a bias towards expression at any prenatal stage. These results emphasise the dynamic expression of genes harbouring risk for schizophrenia and bipolar disorder across prefrontal cortex development and support the view that prenatal neurodevelopmental events are more strongly associated with schizophrenia than bipolar disorder.

neuroscience↗