Andrew N. Coogan

The P38 mitogen-activated protein kinase inhibitor SB203580 antagonizes the inhibitory effects of interleukin-1β on long-term potentiation in the rat dentate gyrus in vitro

Levels of the pro-inflammatory cytokine interleukin-1beta are known to be elevated in patients with chronic disorders such as Alzheimers disease. We have investigated the effects of interleukin-1beta on long-term potentiation and N-methyl-D-aspartate receptor-mediated field potentials in the rat dentate gyrus in vitro utilizing field extracellular recordings obtained from the middle third of the molecular layer of the dentate gyrus. Presynaptic stimulation was applied to the commissural/association pathway at a frequency of 0.05 Hz and at a distance of 50 microm from the granule cell body layer. As previously reported, interleukin-1beta (1 ng/ml) caused an inhibition of long-term potentiation (108+/-2% of baseline 1 h following application of tetanic stimulation compared with 145+/-5% in vehicle control slices). This action of interleukin-1beta on long-term potentiation, as well as an inhibition of N-methyl-D aspartate receptor-mediated field potentials, was attenuated by pre-treatment of slices with the p38 mitogen-associated protein kinase inhibitor SB203580 (1 microM). SB203580 alone had no significant affect on long-term potentiation, but did cause an increase in baseline synaptic transmission [107+/-2% of baseline, 1 h after SB203580 (1 microM) treatment]. The p42/44 mitogen-activated protein kinase cascade inhibitor PD98059 (50 microM) did not inhibit the interleukin-1beta-induced inhibition of N-methyl-D-aspartate receptor-mediated field potentials. The cyclooxygenase inhibitor indomethacin (50 microM) was found to attenuate the interleukin-1beta-induced effects on both long-term potentiation and N-methyl-D-aspartate receptor-mediated field potentials. The lipid second messenger analogue C2 ceramide (20 microM) was found to attenuate the expression of long-term potentiation (108+/-3% of baseline 1 h following tetanic stimulation), and this effect was not blocked by pre-treatment with SB203580. To investigate a possible role for interleukin-1beta in the normal expression of long-term potentiation, the interleukin-1 receptor antagonist (25 ng/ml) was applied during the maintenance phase of long-term potentiation. This was found to depress the sustained expression of long-term potentiation (116+/-6% of baseline 1 h following tetanic stimulation). Our results indicate possible signalling mechanisms by which interleukin-1beta at pathophysiological concentrations may serve to inhibit long-term potentiation, and also suggests a role for IL-1beta in the physiological expression of synaptic plasticity in the rat dentate gyrus in vitro.

Anatomical and functional brain imaging in adult attention-deficit/hyperactivity disorder (ADHD) - A neurological view

In this review, we discuss current structural and functional imaging data on ADHD in a neurological and neuroanatomical framework. At present, the literature on adult ADHD is somewhat sparse, and so results from imaging have to therefore be considered mainly from the childhood or adolescence perspective. Most work has considered the impairment of executive functions (motor execution, inhibition, working memory), and as such a number of attention networks and their anatomical correlates are discussed in this review (e. g. the cerebello-(thalamo-)-striato-cortical network seems to play a pivotal role in ADHD pathology from childhood to adulthood).The core findings in ADHD imaging are alterations in the architecture and function of prefrontal cortex and cerebellum. The dorsal part of anterior cingulated cortex (dACC) is an important region for decision making, and executive control is impaired in adult ADHD. Finally, dysfunction of basal ganglia is a consistent finding in childhood and adulthood ADHD, reflecting dysregulation of fronto-striatal circuitry. The cerebellum, and its role in affect and cognition, is also persistently implicated in the pathology of ADHD.

Impact of aging on diurnal expression patterns of CLOCK and BMAL1 in the mouse brain

Mammalian circadian rhythms are generated by a network of transcriptional and translational loops in the expression of a panel of clock genes in various brain and peripheral sites. Many of the output rhythms controlled by this system are significantly affected by ageing, although the mechanisms of age-related circadian dysfunction remain opaque. The aim of this study was to investigate the effect of aging on the daily oscillation of two clock gene proteins (CLOCK, BMAL1) in the mouse brain. Clock gene protein expression in the brain was measured by means of immunohistochemistry in groups of young (4 months) and older (16 months) mice sampled every 4h over a 24-h cycle. CLOCK and BMAL1 were constitutively expressed in the suprachiasmatic nucleus (SCN; the master circadian pacemaker) in young adult animals. We report novel rhythmic expression of CLOCK and BMAL1 in a number of extra-SCN sites in the young mouse brain, including the hippocampus, amygdala and the paraventricular, arcuate and dorsomedial nuclei of the hypothalamus. Aging altered the amplitude and/or phase of expression in these regions. These results indicate hitherto unreported expression patterns of CLOCK and BMAL1 in non-SCN brain circadian oscillators, and suggest that alterations of these patterns may contribute to age-related circadian dysfunction.

Neuroimmunology of the circadian clock

Circadian timekeeping is a ubiquitous feature of all eukaryotes which allows for the imposition of a biologically appropriate temporal architecture on an animals physiology, behavior and metabolism. There is growing evidence that in mammals the processes of circadian timing are under the influence of the immune system. Such a role for the neuroimmune regulation of the circadian clock has inferences for phenomena such as sickness behavior. Conversely, there is also accumulating evidence for a circadian influence on immune function, raising the likelihood that there is a bidirectional communication between the circadian and immune systems. In this review, we examine the evidence for these interactions, including circadian rhythmicity in models of disease and immune challenge, distribution of cytokines and their receptors in the suprachiasmatic nucleus of the hypothalamus, the site of the master circadian pacemaker, and the evidence for endogenous circadian timekeeping in immune cells.

Aberrant Gating of Photic Input to the Suprachiasmatic Circadian Pacemaker of Mice Lacking the VPAC2 Receptor

VIP acting via the VPAC2 receptor is implicated as a key signaling pathway in the maintenance and resetting of the hypothalamic suprachiasmatic nuclei (SCN) circadian pacemaker; circadian rhythms in SCN clock gene expression and wheel-running behavior are abolished in mice lacking the VPAC2 receptor (Vipr2–/–). Here, using immunohistochemical detection of pERK (phosphorylated extracellular signal-regulated kinases 1/2) and c-FOS, we tested whether the gating of photic input to the SCN is maintained in these apparently arrhythmic Vipr2–/– mice. Under light/dark and constant darkness, spontaneous expression of pERK and c-FOS in the wild-type mouse SCN was significantly elevated during subjective day compared with subjective night; no diurnal or circadian variation in pERK or c-FOS was detected in the SCN of Vipr2–/– mice. In constant darkness, light pulses given during the subjective night but not the subjective day significantly increased expression of pERK and c-FOS in the wild-type SCN. In contrast, light pulses given during both subjective day and subjective night robustly increased expression of pERK and c-FOS in the Vipr2–/– mouse SCN. Although photic stimuli activate intracellular pathways within the SCN of Vipr2–/– mice, they do not engage the core clock mechanisms. The absence of photic gating, together with the general lack of overt rhythms in circadian output, strongly suggests that the SCN circadian pacemaker is completely dysfunctional in the Vipr2–/– mouse.

The Circadian System in Alzheimer’s Disease: Disturbances, Mechanisms, and Opportunities

Alzheimers disease (AD) is a devastating neurodegenerative condition associated with severe cognitive and behavioral impairments. Circadian rhythms are recurring cycles that display periods of approximately 24 hours and are driven by an endogenous circadian timekeeping system centered on the suprachiasmatic nucleus of the hypothalamus. We review the compelling evidence that circadian rhythms are significantly disturbed in AD and that such disturbance is of significant clinical importance in terms of behavioral symptoms. We also detail findings from neuropathological studies of brain areas associated with the circadian system in postmortem studies, the use of animal models of AD in the investigation of circadian processes, and the evidence that chronotherapeutic approaches aimed at bolstering weakened circadian rhythms in AD produce beneficial outcomes. We argue that further investigation in such areas is warranted and highlight areas for future research that might prove fruitful in ultimately providing new treatment options for this most serious and intractable of conditions.

Circadian control of innate immunity in macrophages by miR-155 targeting Bmal1.

Significance The circadian clock allows an organism to anticipate daily changes imposed by the environment. The response to LPS is altered depending on time of day; however, the molecular mechanisms underlying this are unclear. We find that the clock in myeloid cells plays a role in LPS-induced sepsis by altering NF-κB activity and the induction of the microRNA miR-155. LPS causes the repression of BMAL1 via the targeting of miR-155 to two seed sequences in the 3′-untranslated region of Bmal1. Lack of miR-155 has profound effects on circadian function and circadian induction of cytokines by LPS. Thus, the molecular clock is using miR-155 as an important regulatory component to control inflammation variably across the circadian day in myeloid cells. The response to an innate immune challenge is conditioned by the time of day, but the molecular basis for this remains unclear. In myeloid cells, there is a temporal regulation to induction by lipopolysaccharide (LPS) of the proinflammatory microRNA miR-155 that correlates inversely with levels of BMAL1. BMAL1 in the myeloid lineage inhibits activation of NF-κB and miR-155 induction and protects mice from LPS-induced sepsis. Bmal1 has two miR-155–binding sites in its 3′-UTR, and, in response to LPS, miR-155 binds to these two target sites, leading to suppression of Bmal1 mRNA and protein in mice and humans. miR-155 deletion perturbs circadian function, gives rise to a shorter circadian day, and ablates the circadian effect on cytokine responses to LPS. Thus, the molecular clock controls miR-155 induction that can repress BMAL1 directly. This leads to an innate immune response that is variably responsive to challenges across the circadian day.

Actions of the Pro-Inflammatory Cytokine Il-1[beta] on Central Synaptic Transmission

Within the last decade huge advances have been made in the understanding of the interactions between the central nervous system (CNS) and the immune system. Foremost amongst these is the realization that cytokines, classically regarded as mediators and co‐ordinators of the inflammatory and immune responses, can exert a number of neuromodulatory effects within the CNS under both physiological and pathological conditions (for recent reviews see Rothwell & Hopkins, 1995; Rothwell et al. 1997; Rothwell, 1999). Consistent with this, it has been shown that many cytokines and their receptors are present in the brain (Hopkins & Rothwell, 1995). Much attention has focused on the pro‐inflammatory cytokine interleukin‐1 (IL‐1) especially the [beta] variant. IL‐1[beta] has been shown to be produced in the CNS in response to a number of stimuli including peripheral administration of lipopolysaccharide (LPS); traumatic brain injury; acute stress; anorexia and [beta]‐adrenoceptor agonist administration (e.g. Maruta et al. 1997). IL‐1 receptors have also been shown to be present in many brain regions, with high levels in the hippocampus and hypothalamus (Ban et al. 1991). Expression of IL‐1 receptors has also been shown to be upregulated in response to insult, e.g. kainic acid administration (Nishiyori et al. 1997) and expression is higher in aged animals (Murray & Lynch, 1998). However this review will concentrate on the effects of IL‐1[beta] on hippocampal synaptic transmission and long‐term potentiation (LTP), a process long thought to be an important underlying mechanism of learning and memory formation (for review see Bliss & Collingridge, 1993).

A polymorphism at the 3-untranslated region of the CLOCK gene is associated with adult attention-deficit hyperactivity disorder

Attention‐deficit hyperactivity disorder (ADHD) is frequently found in childhood and persists in about 50% of cases into adulthood. Several studies demonstrate a relationship between ADHD, circadian rhythmicity and sleeping disturbances in unmedicated ADHD patients. Since ADHD is a very complex disease with a high genetic load involving multiple genes of moderate effect, we hypothesized a link between adult ADHD and genes involved in the circadian timekeeping system. A 3′‐UTR polymorphism of the circadian locomotor output cycles protein kaput (CLOCK) gene, rs1801260, has been linked to disturbed sleep patterns, although both the C‐allele and more controversially the T‐allele have been proposed as risk factors for different measures of evening preference. This study compared self‐rating and interview based measures of ADHD psychopathology of 143 subjects with and without ADHD with their rs1801260 genotype to test the hypothesis that ADHD is linked to one of the alleles of the CLOCK polymorphism. The T > C single nucleotide polymorphism rs1801260 was genotyped in DNA isolated from blood samples. The associations between genotype and ADHD‐scores were compared using non‐parametric ANCOVA with post hoc pairwise comparisons. There was a strong, significant association (P < 0.001) between each of the adult ADHD assessments and the rs1801260 polymorphism with at least one T‐mutation being the risk allele. This is the first study suggesting that a polymorphism of a gene within the circadian “clock” mechanism is a direct or linked contributing factor in adult ADHD.

Proteomic research in psychiatry

Psychiatric disorders such as Alzheimer’s disease, schizophrenia and mood disorders are severe and disabling conditions of largely unknown origin and poorly understood pathophysiology. An accurate diagnosis and treatment of these disorders is often complicated by their aetiological and clinical heterogeneity. In recent years proteomic technologies based on mass spectrometry have been increasingly used, especially in the search for diagnostic and prognostic biomarkers in neuropsychiatric disorders. Proteomics enable an automated high-throughput protein determination revealing expression levels, post-translational modifications and complex protein-interaction networks. In contrast to other methods such as molecular genetics, proteomics provide the opportunity to determine modifications at the protein level thereby possibly being more closely related to pathophysiological processes underlying the clinical phenomenology of specific psychiatric conditions. In this article we review the theoretical background of proteomics and its most commonly utilized techniques. Furthermore the current impact of proteomic research on diverse psychiatric diseases, such as Alzheimer’s disease, schizophrenia, mood and anxiety disorders, drug abuse and autism, is discussed. Proteomic methods are expected to gain crucial significance in psychiatric research and neuropharmacology over the coming decade.