Contribution of GABAergic neurotransmission to microcircuits of amygdala and hippocampus in health and disease

Lead Research Organisation: University of Oxford

Abstract

I study two areas of the mammalian brain known as amygdala and hippocampus. These brain regions are of fundamental importance in cognitive functions such as learning, memory, fear and emotional states in health and psychiatric diseases. The amygdala and the hippocampus are composed of several distinct types of nerve cells. About 20% of them release and use a substance called GABA to communicate with other nerve cells. This neurotransmitter normally reduces the activity of nerve cells and plays key roles in the normal brain and in the diseased brain. To define the functions of the amygdala and hippocampus under normal conditions and in experimental models of psychiatric diseases, it is important to characterise the types of GABA cells, their structure, and their molecular properties. My work identifies specific types of GABA cells which have clear roles in behaviour and are related to psychiatric disorders and the study of them can lead to the identification exciting novel principles of how neurons communicate with each other. For example, I study a type of nerve cell in the amygdala which is of paramount importance for fear extinction, a process that extinguishes fear once fear associations have been learned. Fear extinction is the corner-stone of the psychological therapy of anxiety because the inability to extinguish fear responses is a trait of several anxiety disorders. As the amygdala and hippocampus are associated with post-traumatic stress disorders and other anxiety conditions, this project may also advance not only the knowledge of fundamental neuroscience, but also help to elucidate the mechanisms of action of widely used drugs such as anaesthetics, anticonvulsants and anxiolytics.

Technical Summary

The hippocampus and the amygdala are two interconnected mammalian brain areas of fundamental importance in healthy cognitive functions such as episodic memory formation and fear learning, and directly affected in neurodegenerative diseases. A number of neurons of the hippocampus (about 10%) and amygdala (about 30%) release the classical inhibitory neurotransmitter GABA. These cells have key roles in the correct function of neuronal circuits as exemplified by their various and profound effects on the activity of target neurons. For example, GABAergic cells set the timing of neuronal oscillations at various frequencies including 4-8 Hz theta and 30-80 Hz gamma rhythms. Notably these oscillations are disrupted in several neurological diseases. The high specificity of the axonal and dendritic patterns of GABAergic cells suggests a precisely defined, highly controlled, functionally important division of labour among them. Specific types of interneurons exclusively target the dendrites of postsynaptic neurons. It is likely that the activity of such dendritic-targeting interneurons poorly influences the membrane potential in the soma and initial segment of the axon, and rather controls the generation of dendritic activity of postsynaptic cells. Furthermore, these neurons may regulate the release of glutamate from nearby excitatory fibres via a metabotropic action. At network level, GABA released from dendritic targeting interneurons is likely to play a predominant role in shaping oscillatory patterns in the theta frequency range. Our initial studies in the hippocampus demonstrate that dendritic-targeting interneurons can elicit a phasic GABAergic synaptic response in postsynaptic cells, which is about 5-10 times slower than the classical fast inhibitory response. The so-called neurogliaform and ivy cells have been identified so far as the cell types that generate this slow synaptic response in the hippocampus. We will continue studying the action of dendritic targeting interneurons of the hippocampus and we will extend this analysis to the GABAeric cells of basolateral and paracapsular nuclei of the amygdala. We will test the hypothesis that these interneurons release a GABA waveform with a broad and persistent spatiotemporal profile causing synaptic responses with slow kinetics. To this end, we will study the concentration/duration profile of GABA at the synaptic cleft and the GABA-A receptor subunit composition. The synaptic responses will also be recorded at dendritic sites of postsynaptic cells without altering the intracellular milieu by using optical methods. Furthermore, the hypothesis that nitric oxide and neuropeptide Y positive cells generate this response in the amygdala will be tested. In complementary experiments, dendritic targeting GABAergic cells will be recorded in vivo to understand their physiological role within the network.

Publications

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Bienvenu TC (2015) Large intercalated neurons of amygdala relay noxious sensory information. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Blaesse P (2015) µ-Opioid Receptor-Mediated Inhibition of Intercalated Neurons and Effect on Synaptic Transmission to the Central Amygdala. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Bocchio M (2016) Serotonin, Amygdala and Fear: Assembling the Puzzle. in Frontiers in neural circuits

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Bocchio M (2015) Increased Serotonin Transporter Expression Reduces Fear and Recruitment of Parvalbumin Interneurons of the Amygdala. in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

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Bocchio M (2014) Oscillatory substrates of fear and safety. in Neuron

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Capogna M (2013) Which molecules regulate synaptic brain asymmetries? in The Journal of Physiology

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Capogna M (2014) GABAergic cell type diversity in the basolateral amygdala in Current Opinion in Neurobiology

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Li G (2014) Firing of hippocampal neurogliaform cells induces suppression of synaptic inhibition. in The Journal of neuroscience : the official journal of the Society for Neuroscience

 
Description Wellcome Trust Project Grant (Volume transmission of GABAergic signalling enabled by hippocampal neurogliaform cells)
Amount £172,279 (GBP)
Funding ID 093242 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2012 
End 12/2013
 
Description amygdala interneurons 
Organisation University of Oxford
Department MRC Anatomical Neuropharmacology Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution Electrophysiology and anatomy of neurons of rodent amygdala
Collaborator Contribution Anatomy, immunohistochemistry, electron microscopy of neurons of rodent amygdala (Innsbruck Medical University). Help with electrophysiology in vivo (Medical Research Council Anatomical Neuropharmacology Unit).
Impact PMID: 25653362
 
Description amygdala interneurons 
Organisation University of Washington
Department Department of Pharmacology
Country United States 
Sector Academic/University 
PI Contribution Electrophysiology and anatomy of neurons of rodent amygdala
Collaborator Contribution Anatomy, immunohistochemistry, electron microscopy of neurons of rodent amygdala (Innsbruck Medical University). Help with electrophysiology in vivo (Medical Research Council Anatomical Neuropharmacology Unit).
Impact PMID: 25653362
 
Description amygdala interneurons_2 
Organisation University of Münster
Department Institute of Physiology I
Country Germany 
Sector Academic/University 
PI Contribution Electrophysiology and anatomy of neurons of rodent amygdala.
Collaborator Contribution Anatomy, immunohistochemistry and electron microscopy of neurons of rodent amygdala.
Impact PMID: 17916608 PMID: 25972162 PMID: 26402610
 
Description amygdala interneurons_2 
Organisation University of Washington
Department Department of Pharmacology
Country United States 
Sector Academic/University 
PI Contribution Electrophysiology and anatomy of neurons of rodent amygdala.
Collaborator Contribution Anatomy, immunohistochemistry and electron microscopy of neurons of rodent amygdala.
Impact PMID: 17916608 PMID: 25972162 PMID: 26402610
 
Description serotonin 
Organisation University of Oxford
Department Department of Experimental Psychology
Country United Kingdom 
Sector Academic/University 
PI Contribution Electrophysiology of mouse amygdala neurons in vitro Immunohistochemistry of mouse amygdala
Collaborator Contribution Behavioural test in mouse
Impact PMID: 26052039
Start Year 2014
 
Description voltage imaging 
Organisation National Institute of Health and Medical Research (INSERM)
Department Institute of Neuroscience Montpellier
Country France 
Sector Academic/University 
PI Contribution -Voltage imaging recordings from neurons of the hippocampus -Anatomy and immunohistochemistry of neurons recorded with voltage imaging
Collaborator Contribution -Help in voltage-imaging set up -Computer software for voltage-imaging data analysis -Feedback and quality control of voltage imaging data-Help in voltage-imaging set up -Computer software for voltage-imaging data analysis -Feedback and quality control of voltage imaging data
Impact Willadt et al., poster at SFN Meeting S Diego Nov 2010 (Paired recordings of GABAergic cells through voltage sensitive dyes imaging) Li et al., poster at FENS Meeting Barcelona July 2012 (Nitric Oxide Modulates Synaptic Inhibition in the Stratum Lacunosum Moleculare of the Hippocampus)
Start Year 2009
 
Description voltage imaging 
Organisation University of Basel
Department Biozentrum Basel
Country Switzerland 
Sector Academic/University 
PI Contribution -Voltage imaging recordings from neurons of the hippocampus -Anatomy and immunohistochemistry of neurons recorded with voltage imaging
Collaborator Contribution -Help in voltage-imaging set up -Computer software for voltage-imaging data analysis -Feedback and quality control of voltage imaging data-Help in voltage-imaging set up -Computer software for voltage-imaging data analysis -Feedback and quality control of voltage imaging data
Impact Willadt et al., poster at SFN Meeting S Diego Nov 2010 (Paired recordings of GABAergic cells through voltage sensitive dyes imaging) Li et al., poster at FENS Meeting Barcelona July 2012 (Nitric Oxide Modulates Synaptic Inhibition in the Stratum Lacunosum Moleculare of the Hippocampus)
Start Year 2009
 
Description GRC Discussion Leader 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I helped in searching external funds and in organizing the Gordon Research Conference entitled: "Inhibition in the CNS", 2011, Colby College, Waterville, Maine, USA

I helped to organise the Gordon research conference entitled: "Inhibition in the CNS", Bates Coll ME, USA, 2013

I helped to organise the Gordon research conference entitled: "Amygdala in Health and Disease", Stonehill College, MA, USA 2013


Increased international recognition
Year(s) Of Engagement Activity 2011,2013
URL http://www.grc.org/programs.aspx?year=2011&program=inhibition
 
Description MSc Neuroscience Oxford 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact I coordinate the module of Cellular Neuroscience consisting of 8-10 lectures. I give one of these lectures.

MSc students usually apply for PhD studenhsips in Neuroscience in Oxford or elsewhere
Year(s) Of Engagement Activity 2011,2012,2013,2014,2015
URL http://www.ox.ac.uk/admissions/postgraduate_courses/course_guide/neuroscience.html
 
Description Science open days 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I participate and in one year organised (2009) to the Science open day held annually at the MRC, Anatomical Neuropharmacology Unit, Oxford. Typical visit includes: 5-8 schools, 50-120 pupils, 6-14 teachers. The pupils are given opportunity in hands on experience.

Positive feedback from schools and participants.
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013,2014,2015