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The Role of Serotonin in Cortical Excitability and Network Dynamics THE ROLE OF SEROTONIN IN CORTICAL EXCITABILITY AND NETWORK DYNAMICS By PAVEL ANATOLYEVICH PUZEREY Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Thesis Advisor: Roberto Fernández Gálan Department of Neurosciences CASE WESTERN RESERVE UNIVERSITY January 2015 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis of Pavel Anatolyevich Puzerey Candidate for the doctoral degree*. David Friel (Chair of thesis committee) Roberto Galan Evan Deneris Christopher Wilson (date) November 11th, 2014 * We also certify that written approval has been obtained for any proprietary material contained herein. ii DEDICATION This dissertation is dedicated to my loving family. Your unyielding support and confidence in my resolve kept me afloat in these rough waters. iii TABLE OF CONTENTS List of Tables viii List of Figures ix Acknowledgements x Abstract xi Chapter 1: Introduction Overview 1 Anatomical Organization of the Cerebral Cortex 2 Dynamics of Cortical Activity 4 Neuromodulation in the Cortex 9 Serotonin as a Modulator of Cortical Neuronal Excitability 13 Serotonin as a Modulator of Cortical Network Activity 16 Chapter 2: Elevated serotonergic signaling amplifies synaptic noise and facilitates the emergence of epileptiform network oscillations Summary 20 Introduction 20 Materials and Methods Thalamocortical Slice Preparation 24 In Vitro Electrophysiology 24 Data Analysis and Statistics 26 Spectral Analysis 28 Computational Model 28 iv Seizure Induction 31 In Vivo Electrophysiology 32 Biocytin Staining, Histology, and Imaging 33 Results Spontaneous synaptic activity in the mouse neocortex 34 is partially mediated by 5–HT in vitro Augmenting endogenous 5–HT signaling transforms 37 cortical network dynamics via 5–HT2 and 5–HT3 receptors Fluoxetine enhances excitatory synaptic inputs 40 mediating cortical network activity Enhanced excitatory coupling and synaptic noise 42 are sufficient to simulate fluoxetine–modulated network activity in a model of a cortical microcircuit In vivo blockade of 5–HT2R activity delays 48 behavioral and electrographic seizure onset and reduces seizure incidence Discussion 50 Figures 2.1–2.5 63 Table 2.1 73 Chapter 3: Constitutive deletion of Pet–1 leads to altered cell–intrinsic, synaptic, and network excitability in mouse cortex Summary 75 Introduction 76 Materials and Methods Thalamocortical Slice Preparation 78 In Vitro Electrophysiology 79 Seizure Induction 81 v Data Analysis and Statistics 82 Results Cell–intrinsic parameters of neuronal excitability 83 are altered in Pet–1 knock–out mice Cortical pyramidal cells exhibit increased 85 spontaneous synaptic activity in Pet–1 knock–out mice Cortical network excitability is enhanced in Pet–1 86 knock–out mice Susceptibility to convulsant–induced seizures is 88 unchanged in Pet–1 knock–out mice Discussion 90 Figures 3.1–3.4 96 Chapter 4: On How Correlations between Excitatory and Inhibitory Synaptic Inputs Maximize the Information Rate of Neuronal Firing Summary 104 Introduction 105 Materials and Methods Synaptic Inputs 109 Analytical Expression for the Cross–Correlogram 110 of the Synaptic Inputs Single Compartment Model 111 Determination of Information Rates 112 Results Magnitude, kinetics, and temporal correlation 115 of synaptic excitation and inhibition Spiking behavior of a stochastic Hodgkin–Huxley 116 vi neuron in response to kinetically variant synaptic inputs Entropy of neural spike trains 118 Information rate of spike trains is insensitive to 119 synaptic kinetics and the relative delay of synaptic inhibition in the balanced conductances regime Information rate of spike trains exhibits dependence 120 on synaptic kinetics at short delays for inhibition in the balanced currents regime Discussion 122 Figures 4.1–4.5 130 Chapter 5: General Discussion Thesis Overview 140 On Noise 144 Serotonin as a neuromodulator of cortical network activity 147 Serotonin and Epilepsy 152 Bibliography 155 vii LIST OF TABLES Table 2.1 Parameter values for computational model presented in Fig 2.4 73 viii LIST OF FIGURES Figure 1: Circuit diagram of a canonical cortical microcircuit 19 with presently known cellular and subcellular 5-HT receptor expression profiles Figure 2.1: Spontaneous excitatory transmitter release is 63 mediated in part by 5–HT3 receptors in mouse neocortex Figure 2.2: Elevated endogenous 5–HT in cortical slices 65 enhances network excitability and transforms network dynamics Figure 2.3: Enhanced synaptic excitation onto cortical 67 neurons underlies transformation of network dynamics in the presence of fluoxetine Figure 2.4: Computational model of a cortical network 69 accounts for the emergence of fast runs with increased synaptic noise and excitatory coupling Figure 2.5: 5–HT2 receptor blockade increases seizure 71 threshold in vivo Figure 3.1: Altered cell–intrinsic excitability in mice lacking Pet–1 96 Figure 3.2: Increased spontaneous excitatory postsynaptic 98 currents in cortical pyramidal cells from Pet–1 knock–out mice Figure 3.3: Enhanced cortical network excitability in mice lacking Pet–1 100 Figure 3.4: Seizure susceptibility is unaltered in mice lacking Pet–1 102 Figure 4.1: Modeling excitatory and inhibitory synaptic inputs 130 Figure 4.2: Firing properties of a stochastic Hodgkin–Huxley 132 neuron in different input regimes Figure 4.3: Entropy of neural spike trains 134 Figure 4.4: Information rates of neural spike trains in the balanced 136 conductances regime Figure 4.5: Information rates of neural spike trains in the balanced 138 currents regime ix ACKNOWLEDGEMENTS First and foremost, I would like to express my gratitude to my advisor, Roberto Galán, for the knowledge and skillsets he has bestowed onto me during my time here. His genuine passion for science, his interest in the success of his students, and his emphasis on scientific independence has been an inspiration to me. Secondly, I would like thank Christopher Wilson, who throughout my time here has been a mentor, a thesis committee member, and a friend. Chris taught me electrophysiological methods in brain slices, a lesson that served as a catalyst for a lifelong interest in neurophysiology. I would like to also thank members of my thesis committee including David Friel and Evan Deneris. In addition, I would like to extend my gratitude to members of the Case community who have provided material, methodological, and intellectual support. These include but are not limited to Michael Decker, Ted Dick, Lynn Landmesser, David Baekey, Cathy Mayer, David Nethery, Yee Hsee Hsieh, Gemma Casadesus, George Dubyak, Isaac Youngstrom, Rishi Dhingra, Becca James, Robert Hyde, Gustav Karl Steinke, Yenan Zhu, Joanna Pucilowska, Joseph Vithayathil, Kathy Lobur, Colleen McLaughlin, and Didi Mamaligas. Finally, I would like to sincerely thank my incredible family and friends who have been my anchor during this challenging period of my life. x The Role of Serotonin in Cortical Excitability and Network Dynamics Abstract by PAVEL ANATOLYEVICH PUZEREY The neocortex is the most recent addition to the vertebrate nervous system, endowing it with a capacity to generate abstract representations of sensory stimuli, mediate complex goal–directed behaviors and store memories of past events as well as numerous other functions. The neuronal activity mediating such functions arises from complex nonlinear interactions between excitatory and inhibitory cell populations within and between cortical regions. These interactions are shaped by the distinct cell–intrinsic excitability of the participating neuronal populations, the properties of the synapses connecting their constituent neurons, and the global network interactions that rise from specific patterns of connectivity. Furthermore, the above properties are all subject to neuromodulation, that is, slow neurochemical control of cell–intrinsic, synaptic, and network excitability. Significant conceptual advances in the study of neuronal networks over the last 40 years have redefined the mantra that “structure begets function,” especially in the context of neuromodulation. Namely, these advances have pointed out that while the anatomy of neuronal networks provides the constraints for their operation, it does not define the specific pattern of activity. xi Network activity, it seems, can be reconfigured with neuromodulation to elicit different dynamics within the same anatomical substrate. Using a combination of patch–clamp recordings in mouse cortical slices, computational modeling, and in vivo acute behavioral seizures I addressed contribution of the monoamine neurotransmitter, serotonin (5– hydroxytryptamine; 5–HT), to the patterning of activity within the neocortex. I first showed that cortical pyramidal cells receive a substantial source of synaptic noise in the form of spontaneous excitatory postsynaptic currents mediated by 5– HT3 receptors, the only ionotropic 5–HT receptor. Secondly, I showed in a slice exhibiting spontaneous network activity that increasing endogenous 5–HT signaling leads to transformation of cortical activity from sparse and temporally random to clustered and periodic dynamics. Two parallel mechanisms acting through two distinct 5–HT receptors, 5–HT2 and 5–HT3, account for such a transformation of cortical network activity. In collaboration with Dr. Michael J. Decker, I also induced acute epileptic seizures in awake and behaving mice while performing cortical electroencephalographic recordings to show that blocking 5– HT2 receptors can substantially delay the onset
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