Endothelial dysfunction in neurodegenerative disease: Is endothelial inflammation an overlooked druggable target?

Neurological diseases with a neurodegenerative component have been associated with alterations in the cerebrovasculature. At the anatomical level, these are centred around changes in cerebral blood flow and vessel organisation. At the molecular level, there is extensive expression of cellular adhesion molecules and increased release of pro-inflammatory mediators. Together, these has been found to negatively impact blood-brain barrier integrity. Systemic inflammation has been found to accelerate and exacerbate endothelial dysfunction, neuroinflammation and degeneration. Here, we review the role of cerebrovasculature dysfunction in neurodegenerative disease and discuss the potential contribution of intermittent pro-inflammatory systemic disease in causing endothelial pathology, highlighting a possible mechanism that may allow broad-spectrum therapeutic targeting in the future.

Developmental priming of early cerebrovascular ageing: Implications across a lifetime.

INTRODUCTION: Neurological conditions such as Alzheimer's disease and stroke represent a substantial health burden to the world's ageing population. Cerebrovascular dysfunction is a key contributor to these conditions, affecting an individual's risk profile, age of onset, and severity of neurological disease. Recent data shows that early-life events, such as maternal health during pregnancy, birth weight and exposure to environmental toxins can 'prime' the vascular system for later changes. With age, blood vessels can become less flexible and more prone to damage. This can lead to reduced blood flow to the brain, which is associated with cognitive decline and an increased risk of stroke and other cerebrovascular diseases. These in turn increase the risk of vascular dementia and Alzheimer's disease. OBJECTIVES: We aim to explore how early life factors influence cerebrovascular health, ageing and disease. METHODS: We have reviewed recently published literature from epidemiological studies, clinical cases and basic research which explore mechanisms that contribute to cerebrovascular and blood-brain barrier dysfunction, with a particularly focus on those that assess contribution of early-life events or vascular priming to subsequent injury. RESULTS: Perinatal events have been linked to acute cerebrovascular dysfunction and long-term structural reorganisation. Systemic disease throughout the lifetime that produce inflammatory or oxidative stress may further sensitise the cerebrovasculature to disease and contribute to neurodegeneration. CONCLUSIONS: By identifying these early-life determinants and understanding their mechanisms, scientists aim to develop strategies for preventing or mitigating cerebrovascular ageing-related issues.

Sex-specific behavioural deficits in adulthood following acute activation of the GABAA receptor in the neonatal mouse.

INTRODUCTION: Sex differences exist in the prevalence of neurodevelopmental disorders (NDDs). Part of the aetiology of NDDs has been proposed to be alterations in the balance between excitatory and inhibitory neurotransmission, leading to the question of whether males and females respond differently to altered neurotransmitter balance. We investigated whether pharmacological alteration of GABAA signalling in early development results in sex-dependent changes in adult behaviours associated with NDDs. METHODS: Male and female C57BL/6J mice received intraperitoneal injections of 0.5mg/kg muscimol or saline on postnatal days (P) 3-5 and were subjected to behavioural testing, specifically open field, light dark box, marble burying, sucralose preference, social interaction and olfactory habituation/dishabituation tests between P60-90. RESULTS: Early postnatal administration of muscimol resulted in reduced anxiety in the light dark box test in both male and female adult mice. Muscimol reduced sucralose preference in males, but not females, whereas female mice showed reduced social behaviours. Regional alterations in cortical thickness were observed in the weeks following GABAA receptor activation, pointing to an evolving structural difference in the brain underlying adult behaviour. CONCLUSIONS: We conclude that activation of the GABAA receptor in the first week of life resulted in long-lasting changes in a range of behaviours in adulthood following altered neurodevelopment. Sex of the individual affected the nature and severity of these abnormalities, explaining part of the varied pathophysiology and neurodevelopmental diagnosis that derive from excitatory/inhibitory imbalance.

Montelukast reduces grey matter abnormalities and functional deficits in a mouse model of inflammation-induced encephalopathy of prematurity.

Encephalopathy of prematurity (EoP) affects approximately 30% of infants born < 32 weeks gestation and is highly associated with inflammation in the foetus. Here we evaluated the efficacy of montelukast, a cysteinyl leukotriene receptor antagonist widely used to treat asthma in children, to ameliorate peripheral and central inflammation, and subsequent grey matter neuropathology and behaviour deficits in a mouse model of EoP. Male CD-1 mice were treated with intraperitoneal (i.p.) saline or interleukin-1beta (IL-1ß, 40 µg/kg, 5 µL/g body weight) from postnatal day (P)1-5 ± concomitant montelukast (1-30 mg/kg). Saline or montelukast treatment was continued for a further 5 days post-injury. Assessment of systemic and central inflammation and short-term neuropathology was performed from 4 h following treatment through to P10. Behavioural testing, MRI and neuropathological assessments were made on a second cohort of animals from P36 to 54. Montelukast was found to attenuate both peripheral and central inflammation, reducing the expression of pro-inflammatory molecules (IL-1ß, IL-6, TNF) in the brain. Inflammation induced a reduction in parvalbumin-positive interneuron density in the cortex, which was normalised with high-dose montelukast. The lowest effective dose, 3 mg/kg, was able to improve anxiety and spatial learning deficits in this model of inflammatory injury, and alterations in cortical mean diffusivity were not present in animals that received this dose of montelukast. Repurposed montelukast administered early after preterm birth may, therefore, improve grey matter development and outcome in EoP.

Connecting the Neurobiology of Developmental Brain Injury: Neuronal Arborisation as a Regulator of Dysfunction and Potential Therapeutic Target.

Neurodevelopmental disorders can derive from a complex combination of genetic variation and environmental pressures on key developmental processes. Despite this complex aetiology, and the equally complex array of syndromes and conditions diagnosed under the heading of neurodevelopmental disorder, there are parallels in the neuropathology of these conditions that suggest overlapping mechanisms of cellular injury and dysfunction. Neuronal arborisation is a process of dendrite and axon extension that is essential for the connectivity between neurons that underlies normal brain function. Disrupted arborisation and synapse formation are commonly reported in neurodevelopmental disorders. Here, we summarise the evidence for disrupted neuronal arborisation in these conditions, focusing primarily on the cortex and hippocampus. In addition, we explore the developmentally specific mechanisms by which neuronal arborisation is regulated. Finally, we discuss key regulators of neuronal arborisation that could link to neurodevelopmental disease and the potential for pharmacological modification of arborisation and the formation of synaptic connections that may provide therapeutic benefit in the future.

Cortical Gray Matter Injury in Encephalopathy of Prematurity: Link to Neurodevelopmental Disorders.

Preterm-born infants frequently suffer from an array of neurological damage, collectively termed encephalopathy of prematurity (EoP). They also have an increased risk of presenting with a neurodevelopmental disorder (e.g., autism spectrum disorder; attention deficit hyperactivity disorder) later in life. It is hypothesized that it is the gray matter injury to the cortex, in addition to white matter injury, in EoP that is responsible for the altered behavior and cognition in these individuals. However, although it is established that gray matter injury occurs in infants following preterm birth, the exact nature of these changes is not fully elucidated. Here we will review the current state of knowledge in this field, amalgamating data from both clinical and preclinical studies. This will be placed in the context of normal processes of developmental biology and the known pathophysiology of neurodevelopmental disorders. Novel diagnostic and therapeutic tactics required integration of this information so that in the future we can combine mechanism-based approaches with patient stratification to ensure the most efficacious and cost-effective clinical practice.

The molecular anatomy and functions of the choroid plexus in healthy and diseased brain.

The choroid plexus (CP) is located in the ventricular system of the brain (one in each ventricle), and the CP epithelial cells form an important barrier between the blood and the cerebrospinal fluid (CSF). Their main function comprises CSF secretion, maintenance of brain homeostasis, signalling, and forming a neuroprotective barrier against harmful external and internal compounds. The CPs mature early and demonstrate expressional changes of barrier-specific genes and proteins related to location and developmental stage of the CP. Important proteins for the barrier function include tight junction proteins, numerous transporters and enzymes. Natural senescence leads to structural changes in the CP cells and reduced or loss of function, while further loss of CP function and changes in immune status may be relevant in neurodegenerative diseases such as Alzheimer's disease and Multiple Sclerosis. Neuroprotective genes expressed at CPs may be unexplored targets for new therapies for neurodegenerative diseases.

TNF deficiency causes alterations in the spatial organization of neurogenic zones and alters the number of microglia and neurons in the cerebral cortex.

BACKGROUND: Although tumor necrosis factor (TNF) inhibitors are used to treat chronic inflammatory diseases, there is little information about how long-term inhibition of TNF affects the homeostatic functions that TNF maintains in the intact CNS. MATERIALS AND METHODS: To assess whether developmental TNF deficiency causes alterations in the naïve CNS, we estimated the number of proliferating cells, microglia, and neurons in the developing neocortex of E13.5, P7 and adult TNF knock out (TNF-/-) mice and wildtype (WT) littermates. We also measured changes in gene and protein expression and monoamine levels in adult WT and TNF-/- mice. To evaluate long-term effects of TNF inhibitors, we treated healthy adult C57BL/6 mice with either saline, the selective soluble TNF inhibitor XPro1595, or the nonselective TNF inhibitor etanercept. We estimated changes in cell number and protein expression after two months of treatment. We assessed the effects of TNF deficiency on cognition by testing adult WT and TNF-/- mice and mice treated with saline, XPro1595, or etanercept with specific behavioral tasks. RESULTS: TNF deficiency decreased the number of proliferating cells and microglia and increased the number of neurons. At the same time, TNF deficiency decreased the expression of WNT signaling-related proteins, specifically Collagen Triple Helix Repeat Containing 1 (CTHRC1) and Frizzled receptor 6 (FZD6). In contrast to XPro1595, long-term inhibition of TNF with etanercept in adult C57BL/6 mice decreased the number of BrdU+ cells in the granule cell layer of the dentate gyrus. Etanercept, but not XPro1595, also impaired spatial learning and memory in the Barnes maze memory test. CONCLUSION: TNF deficiency impacts the organization of neurogenic zones and alters the cell composition in brain. Long-term inhibition of TNF with the nonselective TNF inhibitor etanercept, but not the soluble TNF inhibitor XPro1595, decreases neurogenesis in the adult mouse hippocampus and impairs learning and memory after two months of treatment.

Interneuron Development Is Disrupted in Preterm Brains With Diffuse White Matter Injury: Observations in Mouse and Human.

Preterm brain injury, occurring in approximately 30% of infants born <32 weeks gestational age, is associated with an increased risk of neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). The mechanism of gray matter injury in preterm born children is unclear and likely to be multifactorial; however, inflammation, a high predictor of poor outcome in preterm infants, has been associated with disrupted interneuron maturation in a number of animal models. Interneurons are important for regulating normal brain development, and disruption in interneuron development, and the downstream effects of this, has been implicated in the etiology of neurodevelopmental disorders. Here, we utilize postmortem tissue from human preterm cases with or without diffuse white matter injury (WMI; PMA range: 23+2 to 28+1 for non-WMI group, 26+6 to 30+0 for WMI group, p = 0.002) and a model of inflammation-induced preterm diffuse white matter injury (i.p. IL-1ß, b.d., 10 µg/kg/injection in male CD1 mice from P1-5). Data from human preterm infants show deficits in interneuron numbers in the cortex and delayed growth of neuronal arbors at this early stage of development. In the mouse, significant reduction in the number of parvalbumin-positive interneurons was observed from postnatal day (P) 10. This decrease in parvalbumin neuron number was largely rectified by P40, though there was a significantly smaller number of parvalbumin positive cells associated with perineuronal nets in the upper cortical layers. Together, these data suggest that inflammation in the preterm brain may be a contributor to injury of specific interneuron in the cortical gray matter. This may represent a potential target for postnatal therapy to reduce the incidence and/or severity of neurodevelopmental disorders in preterm infants.

Hepatic acute phase response protects the brain from focal inflammation during postnatal window of susceptibility.

Perinatal inflammation is known to contribute to neurodevelopmental diseases. Animal models of perinatal inflammation have revealed that the inflammatory response within the brain is age dependent, but the regulators of this variation remain unclear. In the adult, the peripheral acute phase response (APR) is known to be pivotal in the downstream recruitment of leukocytes to the injured brain. The relationship between perinatal brain injury and the APR has not been established. Here, we generated focal inflammation in the brain using interleukin (IL)-1ß at postnatal day (P)7, P14, P21 and P56 and studied both the central nervous system (CNS) and hepatic inflammatory responses at 4 h. We found that there is a significant window of susceptibility in mice at P14, when compared to mice at P7, P21 and P56. This was reflected in increased neutrophil recruitment to the CNS, as well as an increase in blood-brain barrier permeability. To investigate phenomena underlying this window of susceptibility, we performed a dose response of IL-1ß. Whilst induction of endogenous IL-1ß or intercellular adhesion molecule (ICAM)-1 in the brain and induction of a hepatic APR were dose dependent, the recruitment of neutrophils and associated blood-brain barrier breakdown was inversely proportional. Furthermore, in contrast to adult animals, an additional peripheral challenge (intravenous IL-1ß) reduced the degree of CNS inflammation, rather than exacerbating it. Together these results suggest a unique window of susceptibility to CNS injury, meaning that suppressing systemic inflammation after brain injury may exacerbate the damage caused, in an age-dependent manner.

Mitochondrial Optic Atrophy (OPA) 1 Processing Is Altered in Response to Neonatal Hypoxic-Ischemic Brain Injury.

Perturbation of mitochondrial function and subsequent induction of cell death pathways are key hallmarks in neonatal hypoxic-ischemic (HI) injury, both in animal models and in term infants. Mitoprotective therapies therefore offer a new avenue for intervention for the babies who suffer life-long disabilities as a result of birth asphyxia. Here we show that after oxygen-glucose deprivation in primary neurons or in a mouse model of HI, mitochondrial protein homeostasis is altered, manifesting as a change in mitochondrial morphology and functional impairment. Furthermore we find that the mitochondrial fusion and cristae regulatory protein, OPA1, is aberrantly cleaved to shorter forms. OPA1 cleavage is normally regulated by a balanced action of the proteases Yme1L and Oma1. However, in primary neurons or after HI in vivo, protein expression of YmelL is also reduced, whereas no change is observed in Oma1 expression. Our data strongly suggest that alterations in mitochondria-shaping proteins are an early event in the pathogenesis of neonatal HI injury.

Neurogenic niches in the brain: help and hindrance of the barrier systems.

In the developing central nervous system, most neurogenesis occurs in the ventricular and subventricular proliferative zones. In the adult telencephalon, neurogenesis contracts to the subependyma zone and the dentate gyrus (subgranular zone) of the hippocampus. These restricted niches containing progenitor cells which divide to produce neurons or glia, depending on the intrinsic and environmental cues. Neurogenic niches are characterized by a comparatively high vascular density and, in many cases, interaction with the cerebrospinal fluid (CSF). Both the vasculature and the CSF represent a source of signaling molecules, which can be relatively rapidly modulated by external factors and circulated through the central nervous system. As the brain develops, there is vascular remodeling and a compartmentalization and dynamic modification of the ventricular surface which may be responsible for the change in the proliferative properties. This review will explore the relationship between progenitor cells and the developing vascular and ventricular space. In particular the signaling systems employed to control proliferation, and the consequence of abnormal vascular or ventricular development on growth of the telencephalon. It will also discuss the potential significance of the barriers at the vascular and ventricular junctions in the influence of the proliferative niches.

STAT1-induced ASPP2 transcription identifies a link between neuroinflammation, cell polarity, and tumor suppression.

Inflammation and loss of cell polarity play pivotal roles in neurodegeneration and cancer. A central question in both diseases is how the loss of cell polarity is sensed by cell death machinery. Here, we identify apoptosis-stimulating protein of p53 with signature sequences of ankyrin repeat-, SH3 domain-, and proline-rich region-containing protein 2 (ASPP2), a haploinsufficient tumor suppressor, activator of p53, and regulator of cell polarity, as a transcriptional target of signal transducer and activator of transcription 1 (STAT1). LPS induces ASPP2 expression in murine macrophage and microglial cell lines, a human monocyte cell line, and primary human astrocytes in vitro. LPS and IFNs induce ASPP2 transcription through an NF-κB RELA/p65-independent but STAT1-dependent pathway. In an LPS-induced maternal inflammation mouse model, LPS induces nuclear ASPP2 in vivo at the blood-cerebral spinal fluid barrier (the brain's barrier to inflammation), and ASPP2 mediates LPS-induced apoptosis. Consistent with the role of ASPP2 as a gatekeeper to inflammation, ASPP2-deficient brains possess enhanced neuroinflammation. Elevated ASPP2 expression is also observed in mouse models and human neuroinflammatory disease tissue, where ASPP2 was detected in GFAP-expressing reactive astrocytes that coexpress STAT1. Because the ability of ASPP2 to maintain cellular polarity is vital to CNS development, our findings suggest that the identified STAT1/ASPP2 pathway may connect tumor suppression and cell polarity to neuroinflammation.

CNS-targeted glucocorticoid reduces pathology in mouse model of amyotrophic lateral sclerosis.

BACKGROUND: Hallmarks of CNS inflammation, including microglial and astrocyte activation, are prominent features in post-mortem tissue from amyotrophic lateral sclerosis (ALS) patients and in mice overexpressing mutant superoxide dismutase-1 (SOD1G93A). Administration of non-targeted glucocorticoids does not significantly alter disease progression, but this may reflect poor CNS delivery. Here, we sought to discover whether CNS-targeted, liposomal encapsulated glucocorticoid would inhibit the CNS inflammatory response and reduce motor neuron loss. SOD1G93A mice were treated with saline, free methylprednisolone (MP, 10 mg/kg/week) or glutathione PEGylated liposomal MP (2B3-201, 10 mg/kg/week) and compared to saline treated wild-type animals. Animals were treated weekly with intravenous injections for 9 weeks from 60 days of age. Weights and motor performance were monitored during this period. At the end of the experimental period (116 days) mice were imaged using T2-weighted MRI for brainstem pathology; brain and spinal cord tissue were then collected for histological analysis. RESULTS: All SOD1G93A groups showed a significant decrease in motor performance, compared to baseline, from ~100 days. SOD1G93A animals showed a significant increase in signal intensity on T2 weighted MR images, which may reflect the combination of neuronal vacuolation and glial activation in these motor nuclei. Treatment with 2B3-201, but not free MP, significantly reduced T2 hyperintensity observed in SOD1G93A mice. Compared to saline-treated and free-MP-treated SOD1G93A mice, those animals given 2B3-201 displayed significantly improved histopathological outcomes in brainstem motor nuclei, which included reduced gliosis and neuronal loss. CONCLUSIONS: In contrast to previous reports that employed free steroid preparations, CNS-targeted anti-inflammatory agent 2B3-201 (liposomal methylprednisolone) has therapeutic potential, reducing brainstem pathology in the SOD1G93A mouse model of ALS. 2B3-201 reduced neuronal loss and vacuolation in brainstem nuclei, and reduced activation preferentially in astrocytes compared with microglia. These data also suggest that other previously ineffective therapies could be of therapeutic value if delivered specifically to the CNS.

T2-weighted MRI detects presymptomatic pathology in the SOD1 mouse model of ALS.

Neuroinflammation has been identified as a potential therapeutic target in amyotrophic lateral sclerosis (ALS), but relevant biomarkers are needed. The superoxide dismutase (SOD1)(G93A) transgenic mouse model of ALS offers a unique opportunity to study and potentially manipulate presymptomatic pathology. While T2-weighted magnetic resonance imaging (MRI) has been shown to be sensitive to pathologic changes at symptom onset, no earlier biomarkers were previously identified and the underlying histopathologic correlates remain uncertain. To address these issues, we used a multimodal MRI approach targeting structural (T2, T1, apparent diffusion coefficient (ADC), magnetization transfer ratio (MTR)), vascular (gadolinium diethylene triamine pentaacetic acid), and endothelial (vascular cell adhesion molecule-microparticles of iron oxide) changes, together with histopathologic analysis from presymptomatic to symptomatic stages of disease. Presymptomatic changes in brainstem nuclei were evident on T2-weighted images from as early as 60 days (P<0.05). Histologic indices of vacuolation, astro- and microglial activation all correlated with T2-weighted changes. Significant reductions in ADC (P<0.01) and MTR (P<0.05) were found at 120 days in the same brainstem nuclei. No changes in T1 relaxation, vascular permeability, or endothelial activation were found at any stage of disease. These findings suggest that T2-weighted MRI offers the strongest biomarker potential in this model, and that MRI has unique potential for noninvasive and longitudinal assessment of presymptomatically applied therapeutic and neuroprotective agents.

Immune responses at brain barriers and implications for brain development and neurological function in later life.

For a long time the brain has been considered an immune-privileged site due to a muted inflammatory response and the presence of protective brain barriers. It is now recognized that neuroinflammation may play an important role in almost all neurological disorders and that the brain barriers may be contributing through either normal immune signaling or disruption of their basic physiological mechanisms. The distinction between normal function and dysfunction at the barriers is difficult to dissect, partly due to a lack of understanding of normal barrier function and partly because of physiological changes that occur as part of normal development and ageing. Brain barriers consist of a number of interacting structural and physiological elements including tight junctions between adjacent barrier cells and an array of influx and efflux transporters. Despite these protective mechanisms, the capacity for immune-surveillance of the brain is maintained, and there is evidence of inflammatory signaling at the brain barriers that may be an important part of the body's response to damage or infection. This signaling system appears to change both with normal ageing, and during disease. Changes may affect diapedesis of immune cells and active molecular transfer, or cause rearrangement of the tight junctions and an increase in passive permeability across barrier interfaces. Here we review the many elements that contribute to brain barrier functions and how they respond to inflammation, particularly during development and aging. The implications of inflammation-induced barrier dysfunction for brain development and subsequent neurological function are also discussed.

The Long and the Short of it: Gene and Environment Interactions During Early Cortical Development and Consequences for Long-Term Neurological Disease.

Cortical development is a complex amalgamation of proliferation, migration, differentiation, and circuit formation. These processes follow defined timescales and are controlled by a combination of intrinsic and extrinsic factors. It is currently unclear how robust and flexible these processes are and whether the developing brain has the capacity to recover from disruptions. What is clear is that there are a number of cognitive disorders or conditions that are elicited as a result of disrupted cortical development, although it may take a long time for the full pathophysiology of the conditions to be realized clinically. The critical window for the manifestation of a neurodevelopmental disorder is prolonged, and there is the potential for a complex interplay between genes and environment. While there have been extended investigations into the genetic basis of a number of neurological and mental disorders, limited definitive associations have been discovered. Many environmental factors, including inflammation and stress, have been linked to neurodevelopmental disorders, and it may be that a better understanding of the interplay between genes and environment will speed progress in this field. In particular, the development of the brain needs to be considered in the context of the whole materno-fetal unit as the degree of the metabolic, endocrine, or inflammatory responses, for example, will greatly influence the environment in which the brain develops. This review will emphasize the importance of extending neurodevelopmental studies to the contribution of the placenta, vasculature, cerebrospinal fluid, and to maternal and fetal immune response. These combined investigations are more likely to reveal genetic and environmental factors that influence the different stages of neuronal development and potentially lead to the better understanding of the etiology of neurological and mental disorders such as autism, epilepsy, cerebral palsy, and schizophrenia.

Reduced ventricular proliferation in the foetal cortex following maternal inflammation in the mouse.

It has been well established that maternal inflammation during pregnancy alters neurological function in the offspring, but its impact on cortical development and long-term consequences on the cytoarchitecture is largely unstudied. Here we report that lipopolysaccharide-induced systemic maternal inflammation in C57Bl/6 mice at embryonic Day 13.5 of pregnancy, as early as 8 h after challenge, caused a significant reduction in cell proliferation in the ventricular zone of the developing cerebral cortex, as revealed by quantification of anti-phospho-Histone H3 immunoreactivity and bromodeoxyuridine pulse labelling. The angle of mitotic cleavage, determined from analysis of haematoxylin and eosin staining, cyclin E1 gene expression and the pattern of ß-catenin immunoreactivity were also altered by the challenge, which suggests a change from symmetric to asymmetric division in the radial progenitor cells. Modifications of cortical lamination and gene expression patterns were detected at post-natal Day 8 suggesting prolonged consequences of these alterations during embryonic development. Cellular uptake of proteins from the cerebrospinal fluid was observed in brains from lipopolysaccharide-treated animals in radial progenitor cells. However, the foetal blood-brain barrier to plasma proteins remained intact. Together, these results indicate that maternal inflammation can disrupt the ventricular surface and lead to decreased cellular proliferation. Changes in cell density in Layers IV and V at post-natal Day 8 show that these initial changes have prolonged effects on cortical organization. The possible shift in the fate of progeny and the resulting alterations in the relative cell numbers in the cerebral cortex following a maternal inflammatory response shown here will require further investigation to determine the long-term consequences of inflammation on the development of neuronal circuitry and behaviour.