Exposure to Kynurenic Acid during Adolescence Increases Sign-Tracking and Impairs Long-Term Potentiation in Adulthood

Changes in brain reward systems are thought to contribute significantly to the cognitive and behavioral impairments of schizophrenia, as well as the propensity to develop co-occurring substance abuse disorders. Presently, there are few treatments for persons with a dual diagnosis and little is known about the neural substrates that underlie co-occurring schizophrenia and substance abuse. One goal of the present study was to determine if a change in the concentration of kynurenic acid (KYNA), a tryptophan metabolite that is increased in the brains of people with schizophrenia, affects reward-related behavior. KYNA is an endogenous antagonist of NMDA glutamate receptors and α7 nicotinic acetylcholine receptors, both of which are critically involved in neurodevelopment, plasticity, and behavior. In Experiment 1, rats were treated throughout adolescence with L-kynurenine (L-KYN), the precursor of KYNA. As adults, the rats were tested drug-free in an autoshaping procedure in which a lever was paired with food. Rats treated with L-KYN during adolescence exhibited increased sign-tracking behavior (lever pressing) when they were tested as adults. Sign-tracking is thought to reflect the lever acquiring incentive salience (motivational value) as a result of its pairing with reward. Thus, KYNA exposure may increase the incentive salience of cues associated with reward, perhaps contributing to an increase in sensitivity to drug-related cues in persons with schizophrenia. In Experiment 2, we tested the effects of exposure to KYNA during adolescence on hippocampal long-term potentiation (LTP). Rats treated with L-KYN exhibited no LTP after a burst of high-frequency stimulation that was sufficient to produce robust LTP in vehicle-treated rats. This finding represents the first demonstrated consequence of elevated KYNA concentration during development and provides insight into the basis for cognitive and behavioral deficits that result from exposure to KYNA during adolescence

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: A comparative risk assessment

Background: High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four cardiometabolic risk factors for all countries and regions from 1980 to 2010. Methods: We used data for exposure to risk factors by country, age group, and sex from pooled analyses of population-based health surveys. We obtained relative risks for the effects of risk factors on cause-specific mortality from meta-analyses of large prospective studies. We calculated the population attributable fractions for each risk factor alone, and for the combination of all risk factors, accounting for multicausality and for mediation of the effects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specific population attributable fractions by the number of disease-specific deaths. We obtained cause-specific mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the final estimates. Findings: In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After accounting for multicausality, 63% (10·8 million deaths, 95% CI 10·1-11·5) of deaths from these diseases in 2010 were attributable to the combined effect of these four metabolic risk factors, compared with 67% (7·1 million deaths, 6·6-7·6) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country level, age-standardised death rates from these diseases attributable to the combined effects of these four risk factors surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France, Japan, the Netherlands, Singapore, South Korea, and Spain. Interpretation: The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of the 21st century are high blood pressure and an increasing effect of obesity and diabetes. The mortality burden of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the global response to non-communicable diseases. Funding: UK Medical Research Council, US National Institutes of Health. © 2014 Elsevier Ltd

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Brain-derived neurotrophic factor attenuates mouse cerebellar granule cell GABAA receptor-mediated responses via postsynaptic mechanisms

In addition to exerting long-term neurotrophic influences on developmental process such as neuronal survival and neuritic outgrowth, brain-derived neurotrophic factor (BDNF) has been reported to modulate synaptic transmission in the short-term. Considerable evidence indicates that BDNF acutely modulates NMDA receptor-mediated synaptic activity. However, whether BDNF modulates inhibitory synaptic transmission remains to be firmly established. In the present study, we examined the effect of acute BDNF exposure on GABA-evoked whole-cell responses as well as GABAergic synaptic activity in cultured mouse cerebellar granule cells. GABA-evoked responses were reduced by 39.5 ± 4.7 % upon acute and focal application of BDNF (100 ng ml−1). The reduction of the GABA response recovered only partially even minutes after removal of BDNF. TrkB-IgG and K252a, but not K252b, prevented the BDNF-induced attenuation of the GABA response. BDNF exposure shifted the cumulative peak amplitude distribution leftward for both spontaneous IPSCs (sIPSCs) and miniature IPSCs (mIPSCs) without affecting the rise time and decay time constants. Acute exposure to BDNF also resulted in internalization of GABAA receptors in cultured cerebellar granule cells, as reflected by diminished immunostaining with an antibody against the GABAA receptor β2/3 subunit. Although the BDNF-induced GABAA receptor internalization was sensitive to K252a, it did not become manifest until 5 min after exposure to BDNF. Therefore, receptor internalization alone cannot account for the prompt BDNF-induced attenuation of GABA-mediated activity. We conclude that BDNF modulates GABAA receptor-mediated activity through TrkB receptor signalling that triggers a kinase-dependent short latency effect and a delayed longer latency effect hallmarked by receptor internalization

Neurotrophin receptors regulate synaptic development in the murine cerebellum

Thesis (Ph. D.)--University of Rochester. School of Medicine and Dentistry. Interdepartmental Graduate Program in Neuroscience, 2008.Neurotrophins, notably brain-derived neurotrophic factor (BDNF), regulate many aspects of neuronal development and modulate synaptic transmission and plasticity. BDNF signals through one of two types of receptors, TrkB and p75NTR. These receptors can either signal independently or as co-receptors forming a high-affinity binding-complex that mediates the effects of TrkB. In this thesis, we tested the hypothesis that the neurotrophins are critical for synaptic development within the central nervous system. We used the developing murine cerebellum as a model for synaptogenesis, focusing on the neurotrophin receptors TrkB and p75NTR and employed transgenic mice hypomorphic or null for TrkB expression and mice null for p75NTR expression. Specifically, we explored the influence of neurotrophins on (1) pruning of nascent excitatory synaptic connections and (2) the development of inhibitory synaptic transmission. To study the role of neurotrophins in synaptic pruning, we studied the developing climbing fiber-Purkinje cell synapse in TrkB mutant and p75NTR knockout mice. Pruning of the climbing fiber-Purkinje cell synapse consists of two processes: synapse elimination and synapse translocation. Initially, Purkinje cells are innervated by multiple climbing fibers, and, subsequently, supernumerary climbing fibers are culled until mature Purkinje cells are mono-innervated. Concomitant with synapse elimination, climbing fiber contacts translocate from the soma to the dendrites of the Purkinje cells. Our results indicated that diminished expression of TrkB in the immature cerebellum resulted in innervation by multiple climbing fibers beyond the normal developmental time frame. This incomplete synapse elimination manifests behaviorally as ataxia. Conversely, in the developing cerebellum of p75NTR knockout mice, despite normal synapse elimination, we found specific deficits in soma-to-dendrite translocation of climbing fiber terminals on Purkinje cells. Thus, TrkB and p75NTR sub serve separate roles but work in concert to shape the development of the climbing fiber-Purkinje cell synapses. To study the role of neurotrophins in inhibitory synaptogenesis, we monitored inhibitory synaptic transmission in Purkinje cells in the developing cerebellum of TrkB mutant mice. The development of spontaneous inhibitory post-synaptic currents (sIPSCs) was assessed in acute cerebellar slices using whole-cell patch-clamp recording of Purkinje cells. sIPSCs were monitored when inhibitory synaptic inputs onto Purkinje cells are derived from recurrent collaterals and when the first synapses from GABAergic interneurons become invested on Purkinje cells. In the absence of TrkB, sIPSCs displayed decreased decay time, decreased amplitude, and decreased frequency and rise time. This suggests that TrkB is necessary for the proper development of inhibitory synaptic transmission. Our results demonstrate that TrkB regulates both excitatory and inhibitory synaptic development. Furthermore, TrkB and p75NTR regulate separate components of pruning, working in concert to shape nascent excitatory synapses. These results underscore the importance of neurotrophins in regulating multiple phases of synaptic development within the central nervous system

GABA and GABAergic Interneurons During Corticogenesis: MigrationFunctional Maturation, and Consequences of Gestational Ethanol Exposure,

Thesis (Ph.D.)--University of Rochester. School of Medicine and Dentistry. Dept. of Interdepartmental Graduate Program in Neuroscience, 2008.Migration during corticogenesis plays an important role in orchestrating the assembly of cortical neurons within the laminated layout of the neocortex. Pyramidal cells migrate radially from the ventricular zone of the cortex while the majority of GABAergic neurons migrate tangentially from the medial ganglionic eminence (MGE). One of the factors that has been postulated to regulate the migration of cortical cells is the neurotransmitter GABA due to the early expression of GABA and its receptor, before the formation of synapses. The results of experiments present in this thesis uncover a role for GABA in regulating the migration of primordial GABAergic cells, mainly those arising from the MGE, as well as a developmentally dynamic expression of GABAA receptor subunits in this population of cells. Transgenic mice lines in which the expression of GFP is driven by either the expression of the GABA-producing enzyme, glutamic acid decarboxylase (GAD), or the gene Lhx6, whose CNS expression is limited to cells derived from the MGE, were used to examine the in vivo disposition of putative GABAergic cells or MGE-derived cells, respectively. A combination of experimental approaches including slice cultures, whole-cell patch clamp recording, immunohistochemistry and single-cell RT-PCR, were used to demonstrate the presence of ambient GABA along the tangential migratory path of MGE-derived cells. We demonstrate further that ambient GABA, through activation of GABAA receptors modulates the cortical entry of tangentially migrating MGE-derived cells. Increases or decreases in ambient levels of GABA or GABAA receptor function can increase or decrease the number of MGE-derived cells that enter into the neocortex, respectively. MGE-derived cells acquire increased sensitivity to GABA as they migrate, and this observation led to revealing the dynamic expression of GABAA receptor number and isoforms in tangentially migrating MGE-derived cells. Errors in the migration process and subsequent development of cortical cells, specifically GABAergic cortical interneurons, have been implicated in disorders with developmentally etiology such as schizophrenia, epilepsy, and autism, as well in consequences of prenatal exposure to teratogens, notably ethanol. Previous studies have suggested that prenatal exposure to ethanol compromises GABAergic transmission. In this light, this thesis tested the hypothesis that prenatal exprosure to ethanol affects the tangential migration and development of primordial cortical GABAergic interneurons through ethanol’s interaction with the developing GABAergic system. Our results demonstrate an increase in tangential migration, resulting in a net increase in the number of MGEderived cells with in utero ethanol exposure. This ethanol-induced increase in migration occurs concurrently with an increase in ambient GABA along the migratory path and alterations in the subunit composition of GABAA receptors expressed by MGE-derived cells. Our data implicate GABA as an important regulation of corticogenesis and establish the basic framework for investigating how cortical development might be affected by maternal ethanol consumption