Maria Braga, D.D.S., Ph.D.
Maria F Braga, D.D.S., Ph.D.
Name: Maria F Braga, D.D.S., Ph.D.
Mechanisms Regulating Neuronal Excitability in the Amygdala: Relevance to Neurological and Psychiatric Disorders and New Therapeutic Strategies
In addition to its role in emotional disorders, the amygdala also plays a central role in epilepsy. The basolateral nucleus of the amygdala (BLA), in particular, is highly prone to generating seizure activity, and, in many models of epilepsy, it is the focal point from where epileptic activity is spread to other brain areas, culminating in status epilepticus. The second research goal in our laboratory is to understand the role of the amygdala in epileptogenesis. Epileptogenesis is the process whereby, after an acute brain insult, such as traumatic brain injury, progressive pathophysiological alterations in neuronal networks occur that lead to the development of epilepsy. We recently identified an important mechanism regulating neuronal excitability and epileptic activity in BLA. We demonstrated that, in the rat BLA, kainate receptors containing the GluR5 subunit (GluR5KRs) regulate GABAergic inhibitory synaptic transmission via both postsynaptic and presynaptic mechanisms. The relevance of these findings to epilepsy is suggested by additional findings that a) activation of GluR5KRs can induce epileptiform activity in in vitro amygdala slices, and epilepsy in vivo, b) expression of these receptors is elevated in epileptic temporal lobe regions, in both humans and rats, c) GluR5-KRs are a primary target of a commonly used antiepileptic drug (topiramate), and d) GluR5-KR antagonists prevent limbic seizures. We are working on identifying the alterations in GABAergic and glutamatergic synaptic transmission, in the BLA, during the course of epileptogenesis, and determining whether changes in the function of GluR5KRs contribute to these alterations. We will also determine whether genetic elimination or pharmacological blockade of GluR5KRs can inhibit epileptogenesis. Unraveling the role of GluR5KRs in the pathogenesis of epilepsy may have significant implications for the discovery of antiepileptogenic drugs that have fewer side effects, as GluR5KR antagonist do not affect normal synaptic transmission and GluR5KRs are not widely distributed in the brain.
In summary, the goal of our research program is to provide the basic knowledge that is necessary for the development of effective therapeutic strategies aimed at preventing or treating certain neurological and psychiatric disorders where dysfunction of the amygdala plays a pivotal, causative role.
The lifetime prevalence of anxiety disorders (generalized anxiety disorder, panic disorder, social phobia, posttraumatic stress disorder, and obsessive-compulsive disorder) is already more than 20% in the general population, and it is only rising. The associated personal and societal burden is considerable. Available psychotropic drug treatments require careful selection and close patient monitoring, and are often ineffective or have serious adverse effects. Dr. Maria Braga and colleagues (APG USUHS) reported a novel mechanism associated with the generation and expression of anxiety, which may potentially lead to the development of new pharmacological treatments for anxiety disorders (The Journal of Neuroscience, 2014 Feb 26;34(9):3130-41).
This study was performed in Dr. Braga’s lab at USU with the participation of 3 neuroscience graduate students*, and was authored by Pidoplichko VI, Aroniadou-Anderjaska V, Prager EM*, Figueiredo TH, Almeida-Suhett CP*, Miller SL*, and Braga MFM. The Society for Neuroscience covered their paper entitled "ASIC1a Activation Enhances Inhibition in the Basolateral Amygdala and Reduces Anxiety" in a press release. The Press Release was also published in ScienceDaily which is one of the Internet's most popular science news web sites. Since starting in 1995, this award-winning site has earned the loyalty of students, researchers, healthcare professionals, government agencies, educators and the general public around the world. Now with more than 3 million monthly visitors, ScienceDaily generates nearly 15 million page views a month and is steadily growing in its global audience. Please see the press release at https://www.eurekalert.org/pub_releases/2014-02/sfn-iba022414.php or you may also contact Dr. Maria Braga to request a pdf copy of the SFN press release.
Below, please find other articles published by Maria's team elucidating new and important mechanisms regulating neuronal excitability in the amygdala, and the discussion of how alterations in these mechanisms play a critical role in anxiety disorders and epilepsy.
NIH Sponsored Selected Publications:
Pidoplichko VI, Aroniadou-Anderjaska V, Prager EM, Figueiredo TH, Almeida-Suhett CP, Miller SL, Braga MF. ASIC1a activation enhances inhibition in the basolateral amygdala and reduces anxiety. J Neurosci. 2014 Feb 26;34(9):3130-41.
Aroniadou-Anderjaska V, Pidoplichko VI, Figueiredo TH, Braga MFM. Oscillatory Synchronous Inhibition in the Basolateral Amygdala and its Primary Dependence on NR2A-containing NMDA Receptors. Neuroscience. 2018 Mar 1;373:145-158.
Pidoplichko VI, Prager EM, Aroniadou-Anderjaska V, Braga MF. α7-Containing nicotinic acetylcholine receptors on interneurons of the basolateral amygdala and their role in the regulation of the network excitability. J Neurophysiol. 2013 Nov;110(10):2358-69.
Aroniadou-Anderjaska V, Pidoplichko VI, Figueiredo TH, Almeida-Suhett CP, Prager EM, Braga MF. Presynaptic facilitation of glutamate release in the basolateral amygdala: a mechanism for the anxiogenic and seizurogenic function of GluK1 receptors. Neuroscience. 2012 Sep 27;221:157-69.
Williams LR, Aroniadou-Anderjaska V, Qashu F, Finne H, Pidoplichko V, Bannon DI, Braga MF. RDX binds to the GABA(A) receptor-convulsant site and blocks GABA(A) receptor-mediated currents in the amygdala: a mechanism for RDX-induced seizures. Environ Health Perspect. 2011 Mar;119(3):357-63.
PROJECT 2: EBBING GABA SUPPLY EXPLAINS WHY MILD TRAUMATIC BRAIN INJURY EFFECTS SLOW TO SHOW
About three quarters of people who suffer mild traumatic brain injury (mTBI)—such as soldiers who survive explosive device blasts and athletes concussed on the playing field—experience memory loss, lack of concentration, increases in anxiety, and changes in hippocampal function, even where no structural damage can be seen. In a consortium organized and led by Dr. Maria Braga (APG - USUSH) through the multi-institutional Center for Neuroscience and Regenerative Medicine (CNRM), research teams from the NIMH (Lee Eiden, PhD, Chief, Section on Molecular Neuroscience and Zheng Li, PhD, Chief, Section on Synapse Development Plasticity) and the Uniformed Services University of the Health Sciences (USUHS) (Maria F. Braga, DDS, PhD and Ann Marini, PhD, MD) have worked together to refine our understanding of how mTBI affects the brain. Working with rat models, the researchers were able to show that even one incident of mild controlled cortical impact (mCCI) can affect inhibitory interneurons’ ability to biosynthesize GABA. The resultant decrease in GABAergic tone subsequently disrupted synaptic transmission, which in turn increased anxiety. The experimenters further demonstrated that, because the loss of GABAergic function is gradual, the effects are frequently not observed until some time after an mTBI incident. These findings suggest that bolstering GABAergic neuronal function could possibly slow or even reverse deleterious changes that occur following mTBI.
Additionally, the USUHS and NIMH researchers used multi-read miRNA analysis (Dr. Li’s lab) and transcriptome microarray analysis, carried out by NIMH post-bac IRTA Cameron Waites (Pat Tilmon Scholar in residence 2013-2015; now completing medical training at Massachusetts General Hospital, Boston) to show that mCCI is immediately followed by cytokine-associated changes in non-neuronal brain compartments and in neuronal miRNA—changes that may be linked to later effects of mTBI on neuronal transmission. If the consortium receives support to continue its study of TBI, the researchers propose to test precisely how initial insult to the brain is linked neurochemically with the cascade that leads to decreased GABAergic function over a period of days, and to altered emotion and behavior over a period of weeks. Establishing and understanding causal links such as these is a first step toward the development of more effective treatments—and perhaps even to reversing adverse neuronal effects of traumatic brain injury.
This Research Program was described in an article in BrainWaves (2016), the NIMH in-house organ for disseminating information about intramural research, including collaborative research. You may contact Maria Braga to request a pdf copy of the BrainWaves article.
USUHS-NIMH CNRM-Sponsored Publications:
Figueiredo TH, Harbert CL, Pidoplichko V, Almeida-Suhett CP, Pan H, Rossetti K, Braga MFM, Marini AM. Alpha-Linolenic Acid Treatment Reduces the Contusion and Prevents the Development of Anxiety-Like Behavior Induced by a Mild Traumatic Brain Injury in Rats. Mol Neurobiol. 2018 Jan;55 (1):187-200.
Camila P. Almeida-Suhett, Eric M. Prager, Volodymyr Pidoplichko, Taiza H. Figueiredo, Ann M. Marini, Zheng Li, Lee E. Eiden, Maria F. M. Braga. GABAergic Interneuronal Loss and Reduced Inhibitory Synaptic Transmission in the Hippocampal CA1 Region after Mild Traumatic Brain Injury. Experimental Neurology Nov 2015(273):11–23.
Samal BB, Waites CK, Almeida-Suhett C, Li Z, Marini AM, Samal NR, Elkahloun A, Braga MF, Eiden LE. Acute Response of the Hippocampal Transcriptome Following Mild Traumatic Brain Injury After Controlled Cortical Impact in the Rat J Mol Neurosci. Oct 2015 (57)2:282-303.
Almeida-Suhett CP, Prager EM, Pidoplichko V, Figueiredo TH, Marini AM, Li Z, Eiden LE, Braga MF. Reduced GABAergic Inhibition in the Basolateral Amygdala and the Development of Anxiety-like Behaviors after Mild Traumatic Brain Injury. PLoS One. Jul 21, 2014(9)7:e102627.
Camila P. Almeida-Suhett, Zheng Li, Ann M. Marini, Maria F.M. Braga, and Lee E. Eiden.
Temporal Course of Changes in Gene Expression Suggests a Cytokine-Related Mechanism for Long-Term Hippocampal Alteration after Controlled Cortical Impact. J Neurotrauma Apr 1 2014 (31)7:683-690.
Zhonghua Hu, Danni Yu, Camila Almeida-Suhett, Kang Tu, Ann M. Marini, Lee Eiden,
Maria F. Braga, Jun Zhu, Zheng Li. Expression of miRNAs and Their Cooperative Regulation of the Pathophysiology in Traumatic Brain Injury. PLoS One 2012(7)6:e39357.
PROJECT 3: NEW DRUG STRIKES NERVE AGENT
Nerve agents are deadly chemical weapons that are presently a serious threat to military and civilian populations. Nerve agents have been used in the Iraq-Iran war, against Kurdish civilians, in terrorist attacks in Japan, and most recently, the world has witnessed, once again, the devastating effects of nerve agent attacks against civilians in Syria and in England. Currently FDA-approved medical countermeasures are inadequate in counteracting many of the acute intoxication symptoms, including arresting nerve agent-induced seizures (status epilepticus), and preventing brain damage, which leads to long-term neurological and neuropsychiatric disorders. Dr. Maria Braga and colleagues (APG USUHS) has discovered that Tezampanel (also known as LY- 293,558), an antagonist of the GluK1 Kainate Receptors and AMPA receptors, is very effective against nerve agent-induced seizures and neuropathology. Maria Braga conceived the initial idea in 2006, and obtained support from the National Institute of Neurological Disorders and Stroke (NINDS) to demonstrate the proof-of-concept. Since then, and with continuous support from NINDS, Maria and her team have conducted extensive pre-clinical studies demonstrating the effectiveness of Tezampanel against these weapons of mass destruction, even when the drug was administered with a significant delay after exposure to a nerve agent. Encouraged by the very promising results of her investigations, Maria convinced Eli Lilly to form a new company (Proniras) to further develop Tezampanel. On Friday, April 25, 2018, it was announced that the Biomedical Advanced Research and Development Authority (BARDA) has awarded a $89.5 million contract to Proniras for the advanced research development of Tezampanel (also known as LY- 293,558), for the treatment of nerve agent induced-seizures that are refractory to benzodiazepines. These further studies are likely to result in the development of a novel, safe and effective therapeutic treatment against nerve agent-induced seizures and brain damage that will enhance our treatment response capabilities during an emergency.
This Research Program was described in an article in DVIDS – Defense Visual Information Distribution Service (2018). DVIDS is a state-of-the-art, 24/7 operation owned by DMA (Defense Media Activity) that provides a timely, accurate and reliable connection between the media around the world and the military serving at home and abroad. Please see the press release at https://www.dvidshub.net/news/289618/new-drug-strikes-nerve-agent or you may contact Maria Braga to request a pdf copy of the DVIDS article.
NIH/DTRA Sponsored Selected Publications:
Figueiredo TH, Apland JP, Braga MFM, Marini AM. Acute and long-term consequences of exposure to organophosphate nerve agents in humans. Epilepsia. 2018 Oct;59 Suppl 2:92-99.
Apland JP, Aroniadou-Anderjaska V, Figueiredo TH, Pidoplichko VI, Rossetti K, Braga MFM. Comparing the Antiseizure and Neuroprotective Efficacy of LY293558, Diazepam, Caramiphen, and LY293558-Caramiphen Combination against Soman in a Rat Model Relevant to the Pediatric Population. J Pharmacol Exp Ther. 2018 May;365(2):314-326
Aroniadou-Anderjaska V, Figueiredo TH, Apland JP, Prager EM, Pidoplichko VI, Miller SL, Braga MF. Long-term neuropathological and behavioral impairments after exposure to nerve agents. Ann N Y Acad Sci. 2016 Jun;1374(1):17-28.
Prager EM, Aroniadou-Anderjaska V, Almeida-Suhett CP, Figueiredo TH, Apland JP, Rossetti F, Olsen CH, Braga MF. The recovery of acetylcholinesterase activity and the progression of neuropathological and pathophysiological alterations in the rat basolateral amygdala after soman-induced status epilepticus: relation to anxiety-like behavior. Neuropharmacology. 2014 Jun;81:64-74.
Prager EM, Figueiredo TH, Long RP 2nd, Aroniadou-Anderjaska V, Apland JP, Braga MF. LY293558 prevents soman-induced pathophysiological alterations in the basolateral amygdala and the development of anxiety. Neuropharmacology. 2015 Feb;89:11-8.
Prager EM, Pidoplichko VI, Aroniadou-Anderjaska V, Apland JP, Braga MF. Pathophysiological mechanisms underlying increased anxiety after soman exposure: reduced GABAergic inhibition in the basolateral amygdala. Neurotoxicology. 2014 Sep;44:335-43
Figueiredo TH, Aroniadou-Anderjaska V, Qashu F, Apland JP, Pidoplichko V, Stevens D, Ferrara TM, Braga MF. Neuroprotective efficacy of caramiphen against soman and mechanisms of its action. British Journal of Pharmacology 2011 Nov;164(5):1495-505.