Honors & Awards
Travel award from the American College of Neuropsychopharmacology, American College of Neuropsychopharmacology (2016)
1st place in the university entrance examination among Chemistry majors, University of Sao Paulo (2000)
Best poster award, Amygdala Gordon Research Conference (08/21/2015)
Travel award for the Society for Free Radical Research International meeting, Society for Free Radical Research International (2004)
Antoine Lavoisier award for being the Valedictorian of chemistry majors of the class of 2000, University of Sao Paulo-Dept. of Chemistry (2004)
2nd place on the University-wide Annual Neuroscience poster show, Columbia University (2008)
Kavli graduate student travel award, Kavli Institute (2010)
PhD thesis unanimously approved "with distinction" by thesis committee, Columbia University (2010)
Walter V. and Idun Berry postdoctoral fellowship, Walter V. and Idun Berry Foundation (2012 - 2015)
NARSAD Young Investigator award, Brain and Behavior Research Foundation (2015- 2017)
K99/R00 Transitional award, National Institutes of Health/National Institute of Mental Health (NIH / NIMH) (2015-2020)
Bachelor of Science, University of Sao Paulo, Chemistry (2004)
Doctor of Philosophy, Columbia University (2011)
Karl Deisseroth, Postdoctoral Research Mentor
Basomedial amygdala mediates top-down control of anxiety and fear.
2015; 527 (7577): 179-185
Anxiety-related conditions are among the most difficult neuropsychiatric diseases to treat pharmacologically, but respond to cognitive therapies. There has therefore been interest in identifying relevant top-down pathways from cognitive control regions in medial prefrontal cortex (mPFC). Identification of such pathways could contribute to our understanding of the cognitive regulation of affect, and provide pathways for intervention. Previous studies have suggested that dorsal and ventral mPFC subregions exert opposing effects on fear, as do subregions of other structures. However, precise causal targets for top-down connections among these diverse possibilities have not been established. Here we show that the basomedial amygdala (BMA) represents the major target of ventral mPFC in amygdala in mice. Moreover, BMA neurons differentiate safe and aversive environments, and BMA activation decreases fear-related freezing and high-anxiety states. Lastly, we show that the ventral mPFC-BMA projection implements top-down control of anxiety state and learned freezing, both at baseline and in stress-induced anxiety, defining a broadly relevant new top-down behavioural regulation pathway.
View details for DOI 10.1038/nature15698
View details for PubMedID 26536109
Diverging neural pathways assemble a behavioural state from separable features in anxiety
2013; 496 (7444): 219-223
Behavioural states in mammals, such as the anxious state, are characterized by several features that are coordinately regulated by diverse nervous system outputs, ranging from behavioural choice patterns to changes in physiology (in anxiety, exemplified respectively by risk-avoidance and respiratory rate alterations). Here we investigate if and how defined neural projections arising from a single coordinating brain region in mice could mediate diverse features of anxiety. Integrating behavioural assays, in vivo and in vitro electrophysiology, respiratory physiology and optogenetics, we identify a surprising new role for the bed nucleus of the stria terminalis (BNST) in the coordinated modulation of diverse anxiety features. First, two BNST subregions were unexpectedly found to exert opposite effects on the anxious state: oval BNST activity promoted several independent anxious state features, whereas anterodorsal BNST-associated activity exerted anxiolytic influence for the same features. Notably, we found that three distinct anterodorsal BNST efferent projections-to the lateral hypothalamus, parabrachial nucleus and ventral tegmental area-each implemented an independent feature of anxiolysis: reduced risk-avoidance, reduced respiratory rate, and increased positive valence, respectively. Furthermore, selective inhibition of corresponding circuit elements in freely moving mice showed opposing behavioural effects compared with excitation, and in vivo recordings during free behaviour showed native spiking patterns in anterodorsal BNST neurons that differentiated safe and anxiogenic environments. These results demonstrate that distinct BNST subregions exert opposite effects in modulating anxiety, establish separable anxiolytic roles for different anterodorsal BNST projections, and illustrate circuit mechanisms underlying selection of features for the assembly of the anxious state.
View details for DOI 10.1038/nature12018
View details for Web of Science ID 000317346300041
Single Units in the Medial Prefrontal Cortex with Anxiety-Related Firing Patterns Are Preferentially Influenced by Ventral Hippocampal Activity
2011; 71 (5): 898-910
The medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC) functionally interact during innate anxiety tasks. To explore the consequences of this interaction, we examined task-related firing of single units from the mPFC of mice exploring standard and modified versions of the elevated plus maze (EPM), an innate anxiety paradigm. Hippocampal local field potentials (LFPs) were simultaneously monitored. The population of mPFC units distinguished between safe and aversive locations within the maze, regardless of the nature of the anxiogenic stimulus. Strikingly, mPFC units with stronger task-related activity were more strongly coupled to theta-frequency activity in the vHPC LFP. Lastly, task-related activity was inversely correlated with behavioral measures of anxiety. These results clarify the role of the vHPC-mPFC circuit in innate anxiety and underscore how specific inputs may be involved in the generation of behaviorally relevant neural activity within the mPFC.
View details for DOI 10.1016/j.neuron.2011.07.027
View details for Web of Science ID 000294877900014
View details for PubMedID 21903082
Synchronized Activity between the Ventral Hippocampus and the Medial Prefrontal Cortex during Anxiety
2010; 65 (2): 257-269
The ventral hippocampus, unlike its dorsal counterpart, is required for anxiety-like behavior. The means by which it acts are unknown. We hypothesized that the hippocampus synchronizes with downstream targets that influence anxiety, such as the medial prefrontal cortex (mPFC). To test this hypothesis, we recorded mPFC and hippocampal activity in mice exposed to two anxiogenic arenas. Theta-frequency activity in the mPFC and ventral, but not dorsal, hippocampus was highly correlated at baseline, and this correlation increased in both anxiogenic environments. Increases in mPFC theta power predicted avoidance of the aversive compartments of each arena and were larger in serotonin 1A receptor knockout mice, a genetic model of increased anxiety-like behavior. These results suggest a role for theta-frequency synchronization between the ventral hippocampus and the mPFC in anxiety. They are consistent with the notion that such synchronization is a general mechanism by which the hippocampus communicates with downstream structures of behavioral relevance.
View details for DOI 10.1016/j.neuron.2009.12.002
View details for Web of Science ID 000274136100012
View details for PubMedID 20152131
Wiring and Molecular Features of Prefrontal Ensembles Representing Distinct Experiences
2016; 165 (7): 1776-1788
A major challenge in understanding the cellular diversity of the brain has been linking activity during behavior with standard cellular typology. For example, it has not been possible to determine whether principal neurons in prefrontal cortex active during distinct experiences represent separable cell types, and it is not known whether these differentially active cells exert distinct causal influences on behavior. Here, we develop quantitative hydrogel-based technologies to connect activity in cells reporting on behavioral experience with measures for both brain-wide wiring and molecular phenotype. We find that positive and negative-valence experiences in prefrontal cortex are represented by cell populations that differ in their causal impact on behavior, long-range wiring, and gene expression profiles, with the major discriminant being expression of the adaptation-linked gene NPAS4. These findings illuminate cellular logic of prefrontal cortex information processing and natural adaptive behavior and may point the way to cell-type-specific understanding and treatment of disease-associated states.
View details for DOI 10.1016/j.cell.2016.05.010
View details for Web of Science ID 000378062000026
View details for PubMedID 27238022
- Basomedial amygdala mediates top-down control of anxiety and fear NATURE 2015; 527 (7577): 179-?
Natural Neural Projection Dynamics Underlying Social Behavior
2014; 157 (7): 1535-1551
Social interaction is a complex behavior essential for many species and is impaired in major neuropsychiatric disorders. Pharmacological studies have implicated certain neurotransmitter systems in social behavior, but circuit-level understanding of endogenous neural activity during social interaction is lacking. We therefore developed and applied a new methodology, termed fiber photometry, to optically record natural neural activity in genetically and connectivity-defined projections to elucidate the real-time role of specified pathways in mammalian behavior. Fiber photometry revealed that activity dynamics of a ventral tegmental area (VTA)-to-nucleus accumbens (NAc) projection could encode and predict key features of social, but not novel object, interaction. Consistent with this observation, optogenetic control of cells specifically contributing to this projection was sufficient to modulate social behavior, which was mediated by type 1 dopamine receptor signaling downstream in the NAc. Direct observation of deep projection-specific activity in this way captures a fundamental and previously inaccessible dimension of mammalian circuit dynamics.
View details for DOI 10.1016/j.cell.2014.05.017
View details for Web of Science ID 000340941900010
Distributed circuits underlying anxiety
FRONTIERS IN BEHAVIORAL NEUROSCIENCE
Anxiety is of paramount importance for animals, as it allows assessment of the environment while minimizing exposure to potential threats. Furthermore, anxiety disorders are highly prevalent. Consequently, the neural circuitry underlying anxiety has been a topic of great interest. In this mini review, we will discuss current views on anxiety circuits. We will focus on rodent anxiety paradigms, but we will also consider results from human neuroimaging and clinical studies. We briefly review studies demonstrating the central role that the amygdala and the bed nucleus of the stria terminals (BNST) play in modulating anxiety and present evidence showing how the bed nucleus uses different output pathways to influence specific features of anxiolysis. Lastly, we propose that several brain regions, such as the medial prefrontal cortex (mPFC) and the ventral hippocampus (vHPC), act in a coordinated fashion with the amygdala and BNST, forming a distributed network of interconnected structures that control anxiety both in rodents and humans.
View details for DOI 10.3389/fnbeh.2014.00112
View details for Web of Science ID 000333558500001
View details for PubMedID 24744710
Dopamine neurons modulate neural encoding and expression of depression-related behaviour
2013; 493 (7433): 537-?
Major depression is characterized by diverse debilitating symptoms that include hopelessness and anhedonia. Dopamine neurons involved in reward and motivation are among many neural populations that have been hypothesized to be relevant, and certain antidepressant treatments, including medications and brain stimulation therapies, can influence the complex dopamine system. Until now it has not been possible to test this hypothesis directly, even in animal models, as existing therapeutic interventions are unable to specifically target dopamine neurons. Here we investigated directly the causal contributions of defined dopamine neurons to multidimensional depression-like phenotypes induced by chronic mild stress, by integrating behavioural, pharmacological, optogenetic and electrophysiological methods in freely moving rodents. We found that bidirectional control (inhibition or excitation) of specified midbrain dopamine neurons immediately and bidirectionally modulates (induces or relieves) multiple independent depression symptoms caused by chronic stress. By probing the circuit implementation of these effects, we observed that optogenetic recruitment of these dopamine neurons potently alters the neural encoding of depression-related behaviours in the downstream nucleus accumbens of freely moving rodents, suggesting that processes affecting depression symptoms may involve alterations in the neural encoding of action in limbic circuitry.
View details for DOI 10.1038/nature11740
View details for Web of Science ID 000313871400039
View details for PubMedID 23235822
A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge
2012; 492 (7429): 428-432
The prefrontal cortex (PFC) is thought to participate in high-level control of the generation of behaviours (including the decision to execute actions); indeed, imaging and lesion studies in human beings have revealed that PFC dysfunction can lead to either impulsive states with increased tendency to initiate action, or to amotivational states characterized by symptoms such as reduced activity, hopelessness and depressed mood. Considering the opposite valence of these two phenotypes as well as the broad complexity of other tasks attributed to PFC, we sought to elucidate the PFC circuitry that favours effortful behavioural responses to challenging situations. Here we develop and use a quantitative method for the continuous assessment and control of active response to a behavioural challenge, synchronized with single-unit electrophysiology and optogenetics in freely moving rats. In recording from the medial PFC (mPFC), we observed that many neurons were not simply movement-related in their spike-firing patterns but instead were selectively modulated from moment to moment, according to the animal's decision to act in a challenging situation. Surprisingly, we next found that direct activation of principal neurons in the mPFC had no detectable causal effect on this behaviour. We tested whether this behaviour could be causally mediated by only a subclass of mPFC cells defined by specific downstream wiring. Indeed, by leveraging optogenetic projection-targeting to control cells with specific efferent wiring patterns, we found that selective activation of those mPFC cells projecting to the brainstem dorsal raphe nucleus (DRN), a serotonergic nucleus implicated in major depressive disorder, induced a profound, rapid and reversible effect on selection of the active behavioural state. These results may be of importance in understanding the neural circuitry underlying normal and pathological patterns of action selection and motivation in behaviour.
View details for DOI 10.1038/nature11617
View details for Web of Science ID 000312488200056
View details for PubMedID 23160494
Disrupted Activity in the Hippocampal-Accumbens Circuit of Type III Neuregulin 1 Mutant Mice
2011; 36 (2): 488-496
Neuregulin 1 (Nrg1), a schizophrenia susceptibility gene, is involved in fundamental aspects of neurodevelopment. Mice lacking any one of the several isoforms of Nrg1 have a variety of schizophrenia-related phenotypes, including deficits in working memory and sensorimotor gating, loss of spines in pyramidal neurons in the ventral subiculum, loss of dendrites in cortical pyramidal cells, loss of parvalbumin-positive interneurons in the prefrontal cortex, and altered plasticity in corticolimbic synapses. Mice heterozygous for a disruption in exon 7 of the Nrg1 gene lack Type III (cysteine-rich-domain-containing) isoforms and have sensorimotor gating deficits that may involve changes in the activity of a circuit involving projections from the ventral hippocampus (vHPC) to medium spiny neurons in the nucleus accumbens (nACC). To explore the neural basis of these deficits, we examined electrophysiological activity in the nACC and vHPC of these mice. Under urethane anesthesia, bursts of spontaneous activity propagated from the vHPC to the nACC in both wild-type and mutant mice. However, these bursts were weaker in mutant nACC, with reduced local field potential amplitude and spiking activity. Single units in mutant nACC fired less frequently within the bursts, and more frequently outside of the bursts. Moreover, within-burst nACC spiking was less modulated by vHPC activity, as determined by phase-locking to the low-frequency oscillatory components of the bursts. These data suggest that the efficacy of vHPC input to the nACC is reduced in the Type III Nrg1 heterozygotes, supporting a role for Nrg1 in the functional profile of hippocampal-accumbens synapses.
View details for DOI 10.1038/npp.2010.180
View details for Web of Science ID 000285292200010
View details for PubMedID 20927045
Cross-correlation of instantaneous amplitudes of field potential oscillations: A straightforward method to estimate the directionality and lag between brain areas
JOURNAL OF NEUROSCIENCE METHODS
2010; 191 (2): 191-200
Researchers performing multi-site recordings are often interested in identifying the directionality of functional connectivity and estimating lags between sites. Current techniques for determining directionality require spike trains or involve multivariate autoregressive modeling. However, it is often difficult to sample large numbers of spikes from multiple areas simultaneously, and modeling can be sensitive to noise. A simple, model-independent method to estimate directionality and lag using local field potentials (LFPs) would be of general interest. Here we describe such a method using the cross-correlation of the instantaneous amplitudes of filtered LFPs. The method involves four steps. First, LFPs are band-pass filtered; second, the instantaneous amplitude of the filtered signals is calculated; third, these amplitudes are cross-correlated and the lag at which the cross-correlation peak occurs is determined; fourth, the distribution of lags obtained is tested to determine if it differs from zero. This method was applied to LFPs recorded from the ventral hippocampus and the medial prefrontal cortex in awake behaving mice. The results demonstrate that the hippocampus leads the mPFC, in good agreement with the time lag calculated from the phase locking of mPFC spikes to vHPC LFP oscillations in the same dataset. We also compare the amplitude cross-correlation method to partial directed coherence, a commonly used multivariate autoregressive model-dependent method, and find that the former is more robust to the effects of noise. These data suggest that the cross-correlation of instantaneous amplitude of filtered LFPs is a valid method to study the direction of flow of information across brain areas.
View details for DOI 10.1016/j.jneumeth.2010.06.019
View details for Web of Science ID 000281927100006
View details for PubMedID 20600317
Intracellular Ca2+ Regulation During Neuronal Differentiation of Murine Embryonal Carcinoma and Mesenchymal Stem Cells
STEM CELLS AND DEVELOPMENT
2010; 19 (3): 379-393
Changes in intracellular Ca(2+) concentration ([Ca(2+)](i)) play a central role in neuronal differentiation. However, Ca(2+) signaling in this process remains poorly understood and it is unknown whether embryonic and adult stem cells share the same signaling pathways. To clarify this issue, neuronal differentiation was analyzed in two cell lines: embryonic P19 carcinoma stem cells (CSCs) and adult murine bone-marrow mesenchymal stem cells (MSC). We studied Ca(2+) release from the endoplasmic reticulum via intracellular ryanodine-sensitive (RyR) and IP(3)-sensitive (IP(3)R) receptors. We observed that caffeine, a RyR agonist, induced a [Ca(2+)](i) response that increased throughout neuronal differentiation. We also demonstrated a functional coupling between RyRs and L- but not with N-, P-, or Q-type Ca(v)1 Ca(2+) channels, both in embryonal CSC and adult MSC. We also found that agonists of L-type channels and of RyRs increase neurogenesis and neuronal differentiation, while antagonists of these channels have the opposite effect. Thus, our data demonstrate that in both cell lines RyRs control internal Ca(2+) release following voltage-dependent Ca(2+) entry via L-type Ca(2+) channels. This study shows that both in embryonal CSC and adult MSC [Ca(2+)](i) is controlled by a common pathway, indicating that coupling of L-type Ca(2+) channels and RyRs may be a conserved mechanism necessary for neuronal differentiation.
View details for DOI 10.1089/scd.2008.0289
View details for Web of Science ID 000275579000011
View details for PubMedID 19032055
Influence of spontaneous calcium events on cell-cycle progression in embryonal carcinoma and adult stem cells
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
2010; 1803 (2): 246-260
Spontaneous Ca(2+) events have been observed in diverse stem cell lines, including carcinoma and mesenchymal stem cells. Interestingly, during cell cycle progression, cells exhibit Ca(2+) transients during the G(1) to S transition, suggesting that these oscillations may play a role in cell cycle progression. We aimed to study the influence of promoting and blocking calcium oscillations in cell proliferation and cell cycle progression, both in neural progenitor and undifferentiated cells. We also identified which calcium stores are required for maintaining these oscillations. Both in neural progenitor and undifferentiated cells calcium oscillations were restricted to the G1/S transition, suggesting a role for these events in progression of the cell cycle. Maintenance of the oscillations required calcium influx only through inositol 1,4,5-triphosphate receptors (IP(3)Rs) and L-type channels in undifferentiated cells, while neural progenitor cells also utilized ryanodine-sensitive stores. Interestingly, promoting calcium oscillations through IP(3)R agonists increased both proliferation and levels of cell cycle regulators such as cyclins A and E. Conversely, blocking calcium events with IP(3)R antagonists had the opposite effect in both undifferentiated and neural progenitor cells. This suggests that calcium events created by IP(3)Rs may be involved in cell cycle progression and proliferation, possibly due to regulation of cyclin levels, both in undifferentiated cells and in neural progenitor cells.
View details for DOI 10.1016/j.bbamcr.2009.11.008
View details for Web of Science ID 000276538000011
View details for PubMedID 19958796
Cholinergic receptor pathways involved in apoptosis, cell proliferation and neuronal differentiation
CELL COMMUNICATION AND SIGNALING
Acetylcholine (ACh) has been shown to modulate neuronal differentiation during early development. Both muscarinic and nicotinic acetylcholine receptors (AChRs) regulate a wide variety of physiological responses, including apoptosis, cellular proliferation and neuronal differentiation. However, the intracellular mechanisms underlying these effects of AChR signaling are not fully understood. It is known that activation of AChRs increase cellular proliferation and neurogenesis and that regulation of intracellular calcium through AChRs may underlie the many functions of ACh. Intriguingly, activation of diverse signaling molecules such as Ras-mitogen-activated protein kinase, phosphatidylinositol 3-kinase-Akt, protein kinase C and c-Src is modulated by AChRs. Here we discuss the roles of ACh in neuronal differentiation, cell proliferation and apoptosis. We also discuss the pathways involved in these processes, as well as the effects of novel endogenous AChRs agonists and strategies to enhance neuronal-differentiation of stem and neural progenitor cells. Further understanding of the intracellular mechanisms underlying AChR signaling may provide insights for novel therapeutic strategies, as abnormal AChR activity is present in many diseases.
View details for DOI 10.1186/1478-811X-7-20
View details for Web of Science ID 000271932400001
View details for PubMedID 19712465
Mechanism of acetylcholine-induced calcium signaling during neuronal differentiation of P19 embryonal carcinoma cells in vitro
2008; 43 (2): 107-121
Muscarinic (mAChRs) and nicotinic acetylcholine receptors (nAChRs) are involved in various physiological processes, including neuronal development. We provide evidence for expression of functional nicotinic and muscarinic receptors during differentiation of P19 carcinoma embryonic cells, as an in vitro model of early neurogenesis. We have detected expression and activity of alpha(2)-alpha(7), beta(2), beta(4) nAChR and M1-M5 mAChR subtypes during neuronal differentiation. Nicotinic alpha(3) and beta(2) mRNA transcription was induced by addition of retinoic acid to P19 cells. Gene expression of alpha(2), alpha(4)-alpha(7), beta(4) nAChR subunits decreased during initial differentiation and increased again when P19 cells underwent final maturation. Receptor response in terms of nicotinic agonist-evoked Ca(2+) flux was observed in embryonic and neuronal-differentiated cells. Muscarinic receptor response, merely present in undifferentiated P19 cells, increased during neuronal differentiation. The nAChR-induced elevation of intracellular calcium ([Ca(2+)](i)) response in undifferentiated cells was due to Ca(2+) influx. In differentiated P19 neurons the nAChR-induced [Ca(2+)](i) response was reduced following pretreatment with ryanodine, while the mAChR-induced response was unaffected indicating the contribution of Ca(2+) release from ryanodine-sensitive stores to nAChR- but not mAChR-mediated Ca(2+) responses. The presence of functional nAChRs in embryonic cells suggests that these receptors are involved in triggering Ca(2+) waves during initial neuronal differentiation.
View details for DOI 10.1016/j.ceca.2007.04.007
View details for Web of Science ID 000254158600002
View details for PubMedID 17662384
The dual face of endogenous alpha-aminoketones: Pro-oxidizing metabolic weapons
COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY
2007; 146 (1-2): 88-110
Amino metabolites with potential prooxidant properties, particularly alpha-aminocarbonyls, are the focus of this review. Among them we emphasize 5-aminolevulinic acid (a heme precursor formed from succinyl-CoA and glycine), aminoacetone (a threonine and glycine metabolite), and hexosamines and hexosimines, formed by Schiff condensation of hexoses with basic amino acid residues of proteins. All these metabolites were shown, in vitro, to undergo enolization and subsequent aerobic oxidation, yielding oxyradicals and highly cyto- and genotoxic alpha-oxoaldehydes. Their metabolic roles in health and disease are examined here and compared in humans and experimental animals, including rats, quail, and octopus. In the past two decades, we have concentrated on two endogenous alpha-aminoketones: (i) 5-aminolevulinic acid (ALA), accumulated in acquired (e.g., lead poisoning) and inborn (e.g., intermittent acute porphyria) porphyric disorders, and (ii) aminoacetone (AA), putatively overproduced in diabetes mellitus and cri-du-chat syndrome. ALA and AA have been implicated as contributing sources of oxyradicals and oxidative stress in these diseases. The end product of ALA oxidation, 4,5-dioxovaleric acid (DOVA), is able to alkylate DNA guanine moieties, promote protein cross-linking, and damage GABAergic receptors of rat brain synaptosome preparations. In turn, methylglyoxal (MG), the end product of AA oxidation, is also highly cytotoxic and able to release iron from ferritin and copper from ceruloplasmin, and to aggregate proteins. This review covers chemical and biochemical aspects of these alpha-aminoketones and their putative roles in the oxidative stress associated with porphyrias, tyrosinosis, diabetes, and cri-du-chat. In addition, we comment briefly on a side prooxidant behaviour of hexosamines, that are known to constitute building blocks of several glycoproteins and to be involved in Schiff base-mediated enzymatic reactions.
View details for DOI 10.1016/j.cbpc.2006.07.004
View details for Web of Science ID 000248881200007
View details for PubMedID 16920403
5-Aminolevulinate and 4,5-dioxovalerate ions decrease GABA(A) receptor density in neuronal cells, synaptosomes and rat brain
2006; 1093: 95-104
Porphyrias are heme-associated metabolic disorders such as intermittent acute porphyria (IAP) and lead poisoning, where 5-aminolevulinate (ALA) accumulates. Effects of ALA on the CNS have been explained by ALA binding to GABA(A) receptors, followed by receptor lesions from oxyradicals and 4, 5-dioxovalerate (DOVA) generated from metal-catalyzed ALA oxidation by oxygen. We have characterized the effects of ALA and DOVA on GABA(A) receptor density in synaptosomes and neurons in vitro and also in brains of rats treated with ALA or succinylacetone methyl ester (SAME), a tyrosine catabolite derivative able to induce ALA accumulation. Radiolabeling assays revealed that following exposure to DOVA the concentration of synaptosomal GABAergic sites decreased by approximately 50%. Pretreatment with DOVA resulted in less GABA(A) receptor density in P19 and WERI cells and altered cell morphology. Furthermore, exposure to DOVA also induced a 5-fold increase in WERI cell mortality rate. Treatment with ALA resulted in loss of neuronal morphology and decrease of GABA(A) density in P19 neuronal cells. ALA and SAME treatment diminished the density of GABAergic receptors in the habenular complex and the parabigeminal nucleus of rat brain as studied by immunohistochemical procedures. Our results strongly suggest that ALA- and DOVA-promoted damage to GABA(A) receptors may contribute to the neurological manifestations of AIP and plumbism.
View details for DOI 10.1016/j.brainres.2006.03.103
View details for Web of Science ID 000239068100010
View details for PubMedID 16701578