Gerard W. O’Keeffe

Microbiota and neurodevelopmental windows: implications for brain disorders

Gut microbiota is essential to human health, playing a major role in the bidirectional communication between the gastrointestinal tract and the central nervous system. The microbiota undergoes a vigorous process of development throughout the lifespan and establishes its symbiotic rapport with the host early in life. Early life perturbations of the developing gut microbiota can impact neurodevelopment and potentially lead to adverse mental health outcomes later in life. This review compares the parallel early development of the intestinal microbiota and the nervous system. The concept of parallel and interacting microbial-neural critical windows opens new avenues for developing novel microbiota-modulating based therapeutic interventions in early life to combat neurodevelopmental deficits and brain disorders.

Prenatal stress-induced alterations in major physiological systems correlate with gut microbiota composition in adulthood

Early-life adverse experiences, including prenatal stress (PNS), are associated with a higher prevalence of neurodevelopmental, cardiovascular and metabolic disorders in affected offspring. Here, in a rat model of chronic PNS, we investigate the impact of late gestational stress on physiological outcomes in adulthood. Sprague-Dawley pregnant dams were subjected to repeated restraint stress from embryonic day 14 to day 20, and their male offspring were assessed at 4 months of age. PNS induced an exaggeration of the hypothalamic-pituitary-adrenal (HPA) axis response to stress, as well as an elevation of blood pressure and impairment of cognitive function. Altered respiratory control was also observed, as demonstrated by increased variability in basal respiratory frequency and abnormal frequency responses to both hypoxic and hypercapnic challenges. PNS also affected gastrointestinal neurodevelopment and function, as measured by a decrease in the innervation density of distal colon and an increase in the colonic secretory response to catecholaminergic stimulation. Finally, PNS induced long lasting alterations in the intestinal microbiota composition. 16S rRNA gene 454 pyrosequencing revealed a strong trend towards decreased numbers of bacteria in the Lactobacillus genus, accompanied by elevated abundance of the Oscillibacter, Anaerotruncus and Peptococcus genera in PNS animals. Strikingly, relative abundance of distinct bacteria genera significantly correlated with certain respiratory parameters and the responsiveness of the HPA axis to stress. Together, these findings provide novel evidence that PNS induces long-term maladaptive alterations in the gastrointestinal and respiratory systems, accompanied by hyper-responsiveness to stress and alterations in the gut microbiota.

BMP-Smad 1/5/8 signalling in the development of the nervous system

The transcription factors, Smad1, Smad5 and Smad8, are the pivotal intracellular effectors of the bone morphogenetic protein (BMP) family of proteins. BMPs and their receptors are expressed in the nervous system (NS) throughout its development. This review focuses on the actions of Smad 1/5/8 in the developing NS. The mechanisms by which these Smad proteins regulate the induction of the neuroectoderm, the central nervous system (CNS) primordium, and finally the neural crest, which gives rise to the peripheral nervous system (PNS), are reviewed herein. We describe how, following neural tube closure, the most dorsal aspect of the tube becomes a signalling centre for BMPs, which directs the pattern of the development of the dorsal spinal cord (SC), through the action of Smad1, Smad5 and Smad8. The direct effects of Smad 1/5/8 signalling on the development of neuronal and non-neuronal cells from various neural progenitor cell populations are then described. Finally, this review discusses the neurodevelopmental abnormalities associated with the knockdown of Smad 1/5/8.

Exposure of foetal neural progenitor cells to IL-1β impairs their proliferation and alters their differentiation – a role for maternal inflammation?

J. Neurochem. (2012) 120, 964–973.

Negative regulation of TLX by IL-1β correlates with an inhibition of adult hippocampal neural precursor cell proliferation

Adult hippocampal neurogenesis is modulated by a number of intrinsic and extrinsic factors including local signalling molecules, exercise, aging and inflammation. Inflammation is also a major contributor to several hippocampal-associated disorders. Interleukin-1beta (IL-1β) is the most predominant pro-inflammatory cytokine in the brain, and an increase in its concentration is known to decrease the proliferation of both embryonic and adult hippocampal neural precursor cells (NPCs). Recent research has focused on the role of nuclear receptors as intrinsic regulators of neurogenesis, and it is now established that the orphan nuclear receptor TLX is crucial in maintaining the NPC pool in neurogenic brain regions. To better understand the involvement of TLX in IL-1β-mediated effects on hippocampal NPC proliferation, we examined hippocampal NPC proliferation and TLX expression in response to IL-1β treatment in an adult rat hippocampal neurosphere culture system. We demonstrate that IL-1β reduced the proliferation of hippocampal NPCs and TLX expression in a dose and time-dependent manner and that co-treatment with IL-1β receptor antagonist or IL-1 receptor siRNA prevented these effects. We also report a dose-dependent effect of IL-1β on the composition of cell phenotypes in the culture and on expression of TLX in these cells. This study thus provides evidence of an involvement of TLX in IL-1β-induced changes in adult hippocampal neurogenesis, and offers mechanistic insight into disorders in which neuroinflammation and alterations in neurogenesis are characteristic features.

Canonical BMP-Smad signalling promotes neurite growth in rat midbrain dopaminergic neurons.

Ventral midbrain (VM) dopaminergic (DA) neurons project to the dorsal striatum via the nigrostriatal pathway to regulate voluntary movements, and their loss leads to the motor dysfunction seen in Parkinson’s disease (PD). Despite recent progress in the understanding of VM DA neurogenesis, the factors regulating nigrostriatal pathway development remain largely unknown. The bone morphogenetic protein (BMP) family regulates neurite growth in the developing nervous system and may contribute to nigrostriatal pathway development. Two related members of this family, BMP2 and growth differentiation factor (GDF)5, have neurotrophic effects, including promotion of neurite growth, on cultured VM DA neurons. However, the molecular mechanisms regulating their effects on DA neurons are unknown. By characterising the temporal expression profiles of endogenous BMP receptors (BMPRs) in the developing and adult rat VM and striatum, this study identified BMP2 and GDF5 as potential regulators of nigrostriatal pathway development. Furthermore, through the use of noggin, dorsomorphin and BMPR/Smad plasmids, this study demonstrated that GDF5- and BMP2-induced neurite outgrowth from cultured VM DA neurons is dependent on BMP type I receptor activation of the Smad 1/5/8 signalling pathway.

NF-κB: Emerging roles in hippocampal development and function

The nuclear factor kappa-B family of transcription factors have been extensively studied in the immune system where they function to orchestrate the molecular response to immune challenge. However in recent years, members of this family have also been shown to play physiological roles in the development and function of the nervous system. The two best studied members of the nuclear factor kappa-B family are the p65 and the p50 proteins. In this review, we outline recent developments regarding the functions of these proteins in regulating hippocampal neurogenesis, neuronal growth and learning and memory and discuss the implications of their dysregulation during the development of the nervous system.

Activin signalling and pre-eclampsia: From genetic risk to pre-symptomatic biomarker

Pre-eclampsia is a multi-system condition in pregnancy that is characterised by the onset of hypertension and proteinuria in women after the 20th week and it remains a leading cause of maternal and fetal mortality. Despite this the causative molecular basis of pre-eclampsia remains poorly understood. As a result, an intensive research effort has focused on understanding the molecular mechanisms involved in pre-eclampsia and using this information to identify new pre-symptomatic bio-markers of the condition. Activin A and its receptor, ACVR2A, have been extensively studied in this regard. Activin A is a member of the transforming growth factor (TGF)-β superfamily that has a wide range of biological functions depending on the cellular context. Recent work has shown that polymorphisms in ACVR2A may be a genetic risk factor for pre-eclampsia. Furthermore, both placenta and serum levels of Activin A are significantly increased in pre-eclampsia suggesting that Activin A may be a possible biomarker for the condition. Here we review the latest advances in this field and link these with new molecular data that suggest that the oxidative stress and pro-inflammatory cytokine production seen in pre-eclampsia may result in increased placental Activin A secretion in an attempt to maintain placental function.

Donor age affects differentiation of rat ventral mesencephalic stem cells.

This study examined the effect of gestational age of rat ventral mesencephalon (VM) on the characteristics of neurospheres generated from this region and on the yield of each cell type after differentiation of these neurospheres. Neurospheres generated from embryonic day (E) 12 and E13 VM had significantly larger diameters and volumes than those from E14 VM. Subsequent differentiation of these neurospheres resulted in decreasing yield of neurones (E12>E13>E14) and increasing yields of both astroglia and oligodendroglia (E12<E13<E14) with increasing donor age. Dopaminergic neurones were generated in low numbers from E12 and E13 cultures, and were virtually absent in E14 cultures. This study suggests that gestational age is a critical factor in the selection of tissue to generate particular cell types from neural stem cells. This has important implications for the use of neural stem cells in transplantation approaches to neurodegenerative diseases.

Class-IIa Histone Deacetylase Inhibition Promotes the Growth of Neural Processes and Protects Them Against Neurotoxic Insult

Small molecule histone deacetylase inhibitors (HDIs) hold much promise as pharmacological modifiers of the epigenetic status of the central nervous system (CNS), given their ability to cross the blood-brain barrier. This is particularly relevant given the lack of disease-modifying therapies for many neurodegenerative diseases and that epigenetic perturbations are increasingly recognised as playing a key role in their pathophysiology. In particular, emerging evidence in recent years has shown that epigenetic dysregulation may contribute to dopaminergic neuronal death in Parkinson’s disease. As a result, a number of pan-HDIs have been explored as potential neuroprotective agents for dopaminergic neurons. However, it is not known if the neuroprotective effects of pan-histone deacetylase (HDAC) inhibition are a general phenomenon or if these effects require inhibition of specific classes of HDACs. Here, we examine the ability of class-specific HDIs to promote neurite growth in a variety of cellular contexts. We find that MC1568, a class IIa-specific HDI, promotes neurite growth and arbourisation and protects neurite arbours against neurotoxic insult. Furthermore, we show that class IIa-specific HDAC inhibition results in activation of the canonical Smad signalling pathway, which is known to promote the survival and growth of midbrain dopaminergic neurons. These results demonstrate the potential of class IIa-specific HDIs as regulators of neuronal structure and suggest they should be examined in animal models of Parkinson’s disease as the next stage in rationalising their use as a potential therapy for this disorder.