Andrew W Cassidy

University College Dublin, Dublin, Leinster, Ireland

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Publications (6)21.57 Total impact

  • Andrew G Foley · Andrew W Cassidy · Ciaran M Regan ·
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    ABSTRACT: In utero exposure of rodents to valproic acid (VPA) has been proposed to induce an adult phenotype with behavioural characteristics reminiscent of those observed in autism spectrum disorder (ASD). Our previous studies have demonstrated the social cognition deficits observed in this model, a major core symptom of ASD, to be ameliorated following chronic administration of histone deacetylase (HDAC) inhibitors. Using this model, we now demonstrate pentyl-4-yn-VPA, an analogue of valproate and HDAC inhibitor, to significantly ameliorate deficits in social cognition as measured using the social approach avoidance paradigm as an indicator of social reciprocity and spatial learning to interrogate dorsal stream cognitive processing. The effects obtained with pentyl-4-yn-VPA were found to be similar to those obtained with SAHA, a pan-specific HDAC inhibitor. Histones isolated from the cerebellar cortex and immunoblotted with antibodies recognising lysine-specific modification revealed SAHA and pentyl-4-yn-VPA to enhance the acetylation status of H4K8. Additionally, the action of pentyl-4-yn-VPA, could be differentiated from that of SAHA by its ability to decrease H3K9 acetylation and enhance H3K14 acetylation. The histone modifications mediated by pentyl-4-yn-VPA are suggested to act cooperatively through differential acetylation of the promoter and transcription regions of active genes.
    European journal of pharmacology 01/2014; 727(1). DOI:10.1016/j.ejphar.2014.01.050 · 2.53 Impact Factor
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    ABSTRACT: In utero exposure of rodents to valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, has been proposed to induce an adult phenotype with behavioural characteristics reminiscent of those observed in autism spectrum disorder (ASD). We have evaluated the face validity of this model in terms of social cognition deficits which are a major core symptom of ASD. We employed the social approach avoidance paradigm as a measure of social reciprocity, detection of biological motion that is crucial to social interactions, and spatial learning as an indicator of dorsal stream processing of social cognition and found each parameter to be significantly impaired in Wistar rats with prior in utero exposure to VPA. We found no significant change in the expression of neural cell adhesion molecule polysialylation state (NCAM PSA), a measure of construct validity, but a complete inability to increase its glycosylation state which is necessary to mount the neuroplastic response associated with effective spatial learning. Finally, in all cases, we found chronic HDAC inhibition, with either pan-specific or HDAC1-3 isoform-specific inhibitors, to significantly ameliorate deficits in both social cognition and its associated neuroplastic response. We conclude that in utero exposure to VPA provides a robust animal model for the social cognitive deficits of ASD and a potential screen for the development of novel therapeutics for this condition.
    Neuropharmacology 06/2012; 63(4):750-60. DOI:10.1016/j.neuropharm.2012.05.042 · 5.11 Impact Factor
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    ABSTRACT: Given that suppressed reelin protein synthesis is associated with cognitive dysfunction in both rodents and humans, we examined the ontogeny of these deficits in rats reared in isolation as a basis for understanding developmental emergence of neuropsychiatric illness. Isolation rearing exerted minimal effects on spatial learning other than to inhibit the transient learning improvement observed in social reared rats at postnatal day 60. By contrast, at postnatal day 80, animals reared in isolation were significantly impaired in an avoidance conditioning paradigm, a deficit that correlated with suppressed reelin synthesis restricted to the ventral aspect of the dentate gyrus. These findings suggest that environmental factors alone can impair forms of cognitive development with relevant region-specific dysfunctional plasticity.
    Behavioural brain research 11/2010; 213(1):130-4. DOI:10.1016/j.bbr.2010.04.040 · 3.03 Impact Factor
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    ABSTRACT: J. Neurochem. (2010) 113, 601–614. The critical sequence of molecular, neurotransmission and synaptic disruptions that underpin the emergence of psychiatric disorders like schizophrenia remain to be established with progress only likely using animal models that capture key features of such disorders. We have related the emergence of behavioural, neurochemical and synapse ultrastructure deficits to transcriptional dysregulation in the medial prefrontal cortex of Wistar rats reared in isolation. Isolation reared animals developed sensorimotor deficits at postnatal day 60 which persisted into adulthood. Analysis of gene expression prior to the emergence of the sensorimotor deficits revealed a significant disruption in transcriptional control, notably of immediate early and interferon-associated genes. At postnatal day 60 many gene transcripts relating particularly to GABA transmission and synapse structure, for example Gabra4, Nsf, Syn2 and Dlgh1, transiently increased expression. A subsequent decrease in genes such as Gria2 and Dlgh2 at postnatal day 80 suggested deficits in glutamatergic transmission and synapse integrity, respectively. Microdialysis studies revealed decreased extracellular glutamate suggesting a state of hypofrontality while ultrastructural analysis showed total and perforated synapse complement in layer III to be significantly reduced in the prefrontal cortex of postnatal day 80 isolated animals. These studies provide a molecular framework to understand the developmental emergence of the structural and behavioural characteristics that may in part define psychiatric illness.
    Journal of Neurochemistry 04/2010; 113(3):601 - 614. DOI:10.1111/j.1471-4159.2010.06617.x · 4.28 Impact Factor
  • A.W. Cassidy · S.K. Mulvany · M.N. Pangalos · K.J. Murphy · C.M. Regan ·
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    ABSTRACT: As the pathophysiological mechanism(s) of many neuropsychiatric disorders relate to GABAergic interneuron structure and function, we employed isolation rearing of Wistar rats as a model to correlate developmental emergence of cognitive deficits with the expression of reelin-producing interneurons in the medial prefrontal cortex (PFC). Prepulse inhibition deficits emerged at postnatal day 60 and persisted into adulthood. Paralleling the emergence of these neurobehavioural deficits was an increase in reelin production and reelin-immunopositive cells in layer I of the PFC and this later became significantly reduced at postnatal day 80. Cells expressing reelin immunoreactivity in a horizontal orientation were mainly located to the upper regions of layer I whereas those with a vertical orientation, whose arbors extend into cortical layers II and III, were more numerous in the lower regions of layer I and became significantly dysregulated during postnatal development. No behavioural deficits or altered reelin expression was observed at postnatal days 30 or 40. Developmental emergence of neurobehavioural and reelin deficits in isolation reared animals is proposed to reflect maladaptive wiring within the medial prefrontal cortex during a critical maturation period of this circuitry.
    Neuroscience 03/2010; 166(2):377-85. DOI:10.1016/j.neuroscience.2009.12.045 · 3.36 Impact Factor
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    Frontiers in Behavioral Neuroscience 01/1970; DOI:10.3389/conf.neuro.08.2009.09.173 · 3.27 Impact Factor