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This thesis examines the influence of stress on the activity of hippocampal CA1 area. The main task was to determine whether the stress load affects the changes of the local metabolism of glucocorticoids, and whether the levels of corticosteroid receptors in the CA1 hippocampus are modulated in response to stress. In order to answer these questions, the experiments were carried out using three different rat strains - Fisher, Lewis and Wistar which differ in their activities of hypothalamic-pituitary-adrenal axis. Our results demonstrate that stress has no effect on expression of MR mRNA. Conversely, stress reduces the levels of GR mRNA in CA1 area of the dorsal hippocampus. Moreover, we confirmed that the Lewis and Wistar rats didn't change metabolism of glucocorticoids after stress response. By the Fisher rats increased levels of 11β-HSD1 mRNA expression and therefore increased the metabolism of corticosterone.

Leung, Kin Ling. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 133-162). / Abstracts in English and Chinese. / CONTENTS --- p.i / ACKNOWLEDGEMENTS --- p.ii / ABBREVIATIONS --- p.iii / ABSTRACT --- p.vi / 論文摘要 --- p.ix / Chapter CHAPTER 1 --- INTRODUCTION --- p.1 / Chapter 1.1 --- Obstructive sleep apnea syndrome --- p.1 / Chapter 1.1.1 --- Symptoms of OSA --- p.2 / Chapter 1.1.2 --- Causes of OSA --- p.5 / Chapter 1.1.3 --- Complications of OSA --- p.6 / Chapter 1.1.4 --- Episodic hypoxia profile --- p.9 / Chapter 1.2 --- Hippocampus --- p.12 / Chapter 1.2.1 --- General structure of hippocampus --- p.12 / Chapter 1.2.2 --- The neuronal circuitry of hippocampus --- p.17 / Chapter 1.2.3 --- Cell types of hippocampus --- p.21 / Chapter 1.2.4 --- Functions of hippocampus --- p.24 / Chapter 1.3 --- Memory Formation and long term potentiation --- p.27 / Chapter 1.4 --- Neurotrophins --- p.33 / Chapter 1.5 --- Brain-derived neurotrophic factor (BDNF) --- p.38 / Chapter 1.5.1 --- Molecular characteristics of BDNF --- p.38 / Chapter 1.5.3 --- Functions of BDNF --- p.46 / Chapter 1.5.4 --- BDNF and neuronal plasticity --- p.46 / Chapter 1.6 --- Tissue plasminogen activator - plasmin system --- p.51 / Chapter 1.6.1 --- Molecular characteristics of tissue plasminogen activator - plasmin system --- p.51 / Chapter 1.6.2 --- Functions of tissue plasminogen activator - plasmin system --- p.54 / Chapter 1.7 --- Aim of the study --- p.59 / Chapter CHAPTER 2 --- MATERIALS AND METHODS --- p.61 / Chapter 2.1 --- Animal model of obstructive sleep apnea --- p.61 / Chapter 2.1.1 --- Intermittent hypoxia --- p.61 / Chapter 2.2 --- Electrophysiological recordings --- p.65 / Chapter 2.2.1 --- Preparation of brain slices --- p.65 / Chapter 2.2.1 --- Visualization of hippocampus CA1 Neurons --- p.66 / Chapter 2.2.3 --- Patch-clamp recordings --- p.66 / Chapter 2.3 --- Protein analysis - ELISA --- p.71 / Chapter 2.3.1 --- Isolation of mouse hippocampus total protein --- p.71 / Chapter 2.3.2 --- ELISA --- p.72 / Chapter 2.3 --- Protein analysis (II) - Western blot --- p.74 / Chapter 2.4.1 --- Isolation of mouse hippocampus total protein --- p.74 / Chapter 2.4.2 --- Western blot analysis --- p.75 / Chapter 2.5 --- Data analysis --- p.78 / Chapter CHAPTER 3 --- RESULTS --- p.79 / Chapter 3.1 --- Effect of intermittent hypoxia on passive and active properties of hippocampal CA1 neurons --- p.79 / Chapter 3.1.1 --- Passive properties --- p.79 / Chapter 3.1.2 --- Membrane excitability --- p.83 / Chapter 3.1.3 --- Action potential characteristics --- p.93 / Chapter 3.2 --- Effect of intermittent hypoxia on the expression of BDNF and related proteins --- p.104 / Chapter 3.2.1 --- "Levels of total BDNF, NGF, NT-3 and NT-4/5" --- p.104 / Chapter 3.2.2 --- Recovery study of the expression of BDNF after IH treatment --- p.110 / Chapter 3.2.3 --- Differential effect of IH on pro-BDNF and mature BDNF --- p.114 / Chapter 3.2.4 --- "Expressions of tissue plasminogen activator, plasmin and plasminogen" --- p.117 / Chapter Chapter 4 --- Discussion --- p.121 / Chapter 4.1 --- Changes in neuronal excitability of CA1 neurons under intermittent hypoxia --- p.121 / Chapter 4.2 --- Intermittent hypoxia-induced changes in BDNF level --- p.127 / Chapter 4.3 --- Conclusion --- p.130 / REFERENCES --- p.133

HIV is capable of causing a set of neurological diseases collectively termed the HIV Associated Neurocognitive Disorders (HAND). Worsening pathology is observed in HIV+ individuals who use opioid drugs. Memory problems are often observed in HAND, implicating HIV pathology in the hippocampus, and are also known to be exacerbated by morphine use. HIV-1 Tat was demonstrated to reduce spatial memory performance in multiple tasks, and individual subsets of CA1 interneurons were found to be selectively vulnerable to the effects of Tat, notably nNOS+/NPY- interneurons of the pyramidal layer and stratum radiatum, PV+ neurons of the pyramidal layer, and SST+ neurons of stratum oriens. Each of these interneuron subsets are hypothesized to form part of a microcircuit involved in memory formation. Electrophysiological assessment of hippocampal pyramidal neurons with Tat and morphine together revealed that Tat caused a reduction in firing frequency, however, chronic morphine exposure did not have any effect. When morphine was removed after chronic exposure, non-interacting effects of Tat and morphine withholding on firing frequency were observed, suggesting that a homeostatic rebalancing of CA1 excitation/inhibition balance takes place in response to chronic morphine exposure independently of any Tat effects. Additionally, differential morphological effects of Tat and morphine were observed in each of the three major dendritic compartments, with SR being less affected, suggesting complex circuit responses to these insults reflecting local change and potentially changes in inputs from other brain regions. Behaviorally, Tat and morphine interactions occur in spatial memory, with morphine potentially obviating Tat effects.

Over time astrocytes have been thought to function in an auxiliary manner, providing neurons with metabolic and structural support. However, recent research suggests they may play a fundamental role in the generation and propagation of focal epileptic seizures by causing synchronized electrical bursts in neurons. It would be helpful to have a simple mathematical model that represents this dynamic and incorporates these updated experimental results. We have created a two-compartment model of a typical neuron found in the hippocampal CA1 region, an area often thought to be the origin of these seizures. The focus is on properly modeling the astrocytic input to examine the pathological excitation of these neurons and subsequent transmission of the signals. In particular, we consider the intracellular astrocytic calcium fluctuations which are associated with slow inward currents in neighbouring neurons. Using our model, a variety of experimental results are reproduced, and comments are made about the potential differences between graded and “all-or-none” astrocytes.

Over time astrocytes have been thought to function in an auxiliary manner, providing neurons with metabolic and structural support. However, recent research suggests they may play a fundamental role in the generation and propagation of focal epileptic seizures by causing synchronized electrical bursts in neurons. It would be helpful to have a simple mathematical model that represents this dynamic and incorporates these updated experimental results. We have created a two-compartment model of a typical neuron found in the hippocampal CA1 region, an area often thought to be the origin of these seizures. The focus is on properly modeling the astrocytic input to examine the pathological excitation of these neurons and subsequent transmission of the signals. In particular, we consider the intracellular astrocytic calcium fluctuations which are associated with slow inward currents in neighbouring neurons. Using our model, a variety of experimental results are reproduced, and comments are made about the potential differences between graded and “all-or-none” astrocytes.

Οι ιπποκάμπιες συνάψεις επιδεικνύουν σημαντική ικανότητα για μακρόχρονη πλαστικότητα, η οποία θεωρείται ότι είναι η βάση της μνήμης και της μάθησης. Υπάρχουν ολοένα και αυξανόμενες αποδείξεις ότι αυτή η ικανότητα διαφέρει κατά μήκος του ιπποκάμπου, με τις συνάψεις της CA1 περιοχής του κοιλιακού ιπποκάμπου να επιδεικνύουν σημαντικά μικρότερη ικανότητα για μακρόχρονη ενίσχυση (LTP) σε σύγκριση με τις αντίστοιχες συνάψεις του ραχιαίου ιπποκάμπου, όταν ενεργοποιούνται με υψηλόσυχνο ερεθισμό. Στην παρούσα εργασία, δείχνουμε ότι μία μικρή συχνότητα ερεθισμού, των 10 Hz, επάγει μακρόχρονη ενίσχυση πιο αξιόπιστα στην περιοχή CA1 του ραχιαίου απ' ό,τι του κοιλιακού ιπποκάμπου. Προτείνουμε ότι η δραστηριότητα που επάγεται από του υποδοχείς α5GABAA παίζει έναν σημαντικό ρόλο στην ρύθμιση του κατωφλίου επαγωγής του LTP ειδικά στις συνάψεις της περιοχής CA1 του κοιλιακού ιπποκάμπου. Αυτό το γεγονός μπορεί να έχει σημαντικές συνέπειες για την λειτουργική εξειδίκευση κατά μήκος του ιπποκάμπου. / The hippocampal synapses display conspicuous ability for long-term plasticity which is thought to underlie learning and memory. Growing evidence shows that this ability differs along the long axis of the hippocampus, with the ventral CA1 hippocampal synapses displaying remarkably lower ability for long-term potentiation(LTP) compared with their dorsal counterpart when activated with high-frequency stimulation. Here, we show that low frequency, 10Hz stimulation induced LTP more reliably in DH than in VH CA1 field. Blockade of alpha5 subunit-containing GABAA receptors eliminated the difference between DH and VH. We propose that α5GABAA receptor-mediated activity plays a crucial role in regulating the threshold for induction of LTP especially at the ventral CA1 hippocampal synapses. This might have important implications for the functional specialization along the hippocampus.

Xie, Hui. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 91-116). / Abstracts in English and Chinese. / CONTENTS --- p.I / ACKNOWLEDGEMENTS --- p.i / ABSTRACT --- p.ii / 中文摘要 --- p.v / Chapter CHAPTER 1 --- INTRODUCTION --- p.1 / Chapter 1.1 --- Overview of the Study --- p.1 / Chapter 1.2 --- Obstructive Sleep Apnea --- p.4 / Chapter 1.2.1 --- Epidemiology --- p.5 / Chapter 1.2.1.1 --- Prevalence --- p.5 / Chapter 1.2.1.2 --- Risk Factors --- p.6 / Chapter 1.2.2 --- Pathogenesis --- p.8 / Chapter 1.2.3 --- Pathophysiologic Consequences --- p.9 / Chapter 1.2.4 --- Diagnosis --- p.12 / Chapter 1.2.5 --- Treatment --- p.13 / Chapter 1.3 --- Memory and Long-term Potentiation --- p.15 / Chapter 1.3.1 --- Memory --- p.15 / Chapter 1.3.1.1 --- Classification of Memory --- p.15 / Chapter 1.3.1.1 --- Physiology of Memory --- p.17 / Chapter 1.3.2 --- Hippocampus --- p.18 / Chapter 1.3.2.1 --- Anatomy --- p.18 / Chapter 1.3.2.2 --- Hippocampus and Memory --- p.20 / Chapter 1.3.3 --- Long-term Potentiation (LTP) --- p.20 / Chapter 1.3.3.1 --- Discovery of LTP --- p.21 / Chapter 1.3.3.2 --- Types of LTP --- p.22 / Chapter 1.3.3.3 --- Properties of NMDA-LTP --- p.23 / Chapter 1.3.3.4 --- Early Phase LTP and Mechanism --- p.24 / Chapter 1.3.3.5 --- Late Phase LTP and Mechanism --- p.28 / Chapter 1.3.3.6 --- Important Factors in Long-term Potentiation --- p.29 / Chapter 1.4 --- Brain-derived Neurotrophic Factor (BDNF) --- p.33 / Chapter 1.4.1 --- Neurotrophins --- p.33 / Chapter 1.4.2 --- Structure and Expression of BDNF --- p.36 / Chapter 1.4.3 --- BDNF and Synaptic Plasticity --- p.37 / Chapter 1.4.3.1 --- BDNF and E-LTP --- p.38 / Chapter 1.4.3.2 --- BDNF and L-LTP --- p.39 / Chapter CHAPTER 2 --- METHODS --- p.43 / Chapter 2.1 --- Animal model of Obstructive Sleep Apnea --- p.43 / Chapter 2.1.1 --- Chronic Intermittent Hypoxia --- p.43 / Chapter 2.1.2 --- Bodyweight During Hypoxia Treatment --- p.47 / Chapter 2.2 --- Electrophysiological Experiments --- p.47 / Chapter 2.2.1 --- Brain Slice Preparation --- p.47 / Chapter 2.2.2 --- Multi-electrode Recording Setup (MED64) --- p.48 / Chapter 2.2.3 --- Slice Superfusion --- p.51 / Chapter 2.3.4 --- Field Potential Recordings --- p.53 / Chapter 2.3.5 --- LTP Induction Protocol --- p.55 / Chapter 2.3 --- Stereotaxic Surgery --- p.57 / Chapter 2.4 --- Drugs and Data Analysis --- p.58 / Chapter CHAPTER 3 --- RESULTS --- p.59 / Chapter 3.1 --- Validation of the OSA model --- p.59 / Chapter 3.2 --- Optimization for Studies of Early and Late-phase LTP by MED64 --- p.60 / Chapter 3.2.1 --- Optimization of Brain Slices --- p.60 / Chapter 3.2.2 --- Optimization of Field Potential Recording --- p.62 / Chapter 3.2.3 --- Optimization for LTP Study --- p.65 / Chapter 3.3 --- Effect of Intermittent Hypoxia on Hippocampal LTP --- p.68 / Chapter 3.3.1 --- Early-phase LTP (E-LTP) --- p.68 / Chapter 3.3.2 --- Late-phase LTP (L-LTP) --- p.71 / Chapter 3.4 --- Effect of BDNF on Intermittent Hypoxia-induced LTP Impairment --- p.75 / Chapter 3.4.1 --- BDNF Rescues LTP Impairment --- p.75 / Chapter 3.4.2 --- BDNF prevents LTP Impairment --- p.78 / Chapter CHAPTER 4 --- DISCUSSION --- p.80 / Chapter 4.1 --- Chronic Intermittent Hypoxia Model of OSA in Mice --- p.80 / Chapter 4.2 --- Impairment of LTP Induced by Intermittent Hypoxia --- p.82 / Chapter 4.3 --- The role of BDNF in IH-induced Impairment in Hippocampal Synaptic Plasticity --- p.84 / Chapter 4.4 --- Future Studies --- p.89 / REFERENCE --- p.91

The anterior thalamic nuclei (ATN) are a critical part of an extended hippocampal system that supports key elements of episodic memory. Damage or disconnection of the ATN is a component of clinical conditions associated with severe anterograde amnesisa such as the Korsakoff’s syndrome, thalamic stroke, and neurodegenerative disorders. Previous studies have demonstrated that the ATN and hippocampus are often interdependent, and that ATN damage can result in ‘covert pathology’ in ostensibly healthy distal regions of the extended hippocampal system. Adult male rats with neurotoxic bilateral ATN lesions or sham surgery were post-operatively housed in an enriched environment or standard housing after a lesion-induced spatial working memory deficit had been established. These rats were retested on cross-maze and then trained in radial-arm maze spatial memory tasks. Other enriched rats received pseudo-training only after the enrichment period. The detailed neuromorphology of neurons was subsequently examined in the hippocampal CA1. Soma characteristics were also examined in the retrosplenial granular b cortex and the prelimbic cortex. In Experiment 1, ATN lesions produced clear deficits in both the cross-maze and radial-arm maze tasks and reduced hippocampal CA1 dendritic complexity, length, and spine density, while increasing the average diameter of the dendrites. Post-operative enrichment reversed the ATN lesion-induced deficits in the cross-maze and radial-arm maze, and returned CA1 basal and apical spine density to a level comparable to that of sham standard housed trained rats. The sham enriched rats exhibited improved radial-arm maze performance and increased CA1 branching complexity and spine density in both basal and apical arbors compared to sham standard housed rats. The neuromorphological changes observed in the enriched ATN and sham rats may be in part responsible for the spatial working memory improvements observed. Experiment 2 provided support for this contention by demonstrating that the CA1 spine changes were explicitly relevant to spatial learning and memory, because trained enriched sham and ATN rats had increased spines, particularly in the basal tree when compared to closely comparable pseudo-trained enriched rats. Interestingly, spatial memory training increased the numbers of both thin and mushroom spines, whereas enrichment was only associated with an increase in thin spines. In Experiment 3, ATN lesions increased cell body size in layer II of the retrosplenial granular b cortex, whereas enrichment decreased cell body size in layer V of this region. Neither ATN lesions nor enrichment had any effect on cell body morphology in the prelimbic cortex. The current research provides some of the strongest evidence to date of ATN and hippocampal interdependence within the extended hippocampal system, and provides the first evidence of neuromorphological correlates of recovery after ATN lesions.

Intricate interactions among constituent components are defining hallmarks of biological systems and sculpt physiology across different scales spanning gene networks to behavioural repertoires. Whereas interactions among channels and receptors define neuronal physiology, interactions among different cells specify the characteristic features of network physiology. From a single-neuron perspective, it is now evident that the somato-dendritic plasma membrane of hippocampus pyramidal neurons is endowed with several voltage-gated ion channels (VGICs) with varying biophysical properties and sub cellular expression profiles. Structural and physiological interactions among these channels define generation and propagation of electrical signals, thereby transforming neuronal dendrites to actively excitable membrane endowed with complex computational capabilities. In parallel to this complex network of plasma membrane channels is an elegantly placed continuous intraneuronal membrane of the endoplasmic reticulum (ER) that runs throughout the neuronal morphology. Akin to the plasma membrane, the ER is also endowed with a variety of channels and receptors, prominent among them being the inositol trisphosphate (InsP3) receptors (InsP3Rs) and ryanodine receptors (RyR), both of which are calcium release channels. Physiological interactions among these receptors transform the ER into a calcium excitable membrane, capable of active propagation of calcium waves and of spatiotemporal integration of neuronal signals. Thus, a neuron is endowed with two continuously parallel excitable membranes that actively participate in the bidirectional flow of intraneuronal information, through interactions among different channels and receptors on either membrane. Although the interactions among sets of channels and receptors present individually on either membrane are very well characterized, our understanding of cross-membrane interactions among channels and receptors across these two membranes has been very limited. Recent literature has emphasized the critical nature of such cross-membrane interactions and the several physiological roles played by such interactions. Such cross-channel interactions include ER depletion-induced signaling involving store-operated calcium channels, generation and propagation of calcium waves through interactions between plasma membrane and ER membrane receptors, and the plasticity of plasma membrane VGICs and receptors induced by ER Ca2+. Such tight interactions between these two membranes have highlighted several roles of the ER in the integration of intraneuronal information, in regulating signalling microdomains and in regulating the downstream signaling pathways that are regulated by these Ca2+ signals. Yet, our understanding about the functional interactions between the ion channels and receptors present on either of these membranes is very limited from the perspective of the combinatorial possibilities that encompass the span of channels and receptors across these two membranes. In this context, the first part of this thesis deals with two specific instances of such cross-membrane functional interactions, presented as two subparts with each probing different direction of impact. Specifically, whereas the first of these subparts deals with the impact of plasma membrane VGICs on the physiology of ER receptors, the second subpart presents an instance of the effect of ER receptor activation on plasma membrane VGIC. In the first subpart of the thesis, we establish a novel role for the A-type potassium current in regulating the release of calcium through inositol triphosphate receptors (InsP3R) that reside on the endoplasmic reticulum (ER) of hippocampus pyramidal neurons. Specifically, the A-type potassium current has been implicated in the regulation of several physiological processes including the regulation of calcium influx through voltage-gated calcium channels (VGCCs). Given the dependence of InsP3R open probability on cytosolic calcium concentration ([Ca2+]c) we asked if this regulation of calcium influx by A-type potassium current could translate into the regulation of release of calcium through InsP3Rs by the A-type potassium current. To answer this, we constructed morphologically realistic, conductance-based neuronal models equipped with kinetic schemes that govern several calcium signalling modules and pathways, and constrained the distributions and properties of constitutive components by experimental measurements from these neurons. Employing these models, we establish a bell-shaped dependence of calcium release through InsP3Rs on the density of A-type potassium current, during the propagation of an intraneuronal calcium wave initiated through established protocols. Exploring the sensitivities of calcium wave initiation and propagation to several underlying parameters, we found that ER calcium release critically depends on dendrite diameter and wave initiation occurred at branch points as a consequence of high surface area to volume ratio of oblique dendrites. Further, analogous to the role of A-type potassium channels in regulating spike latency, we found that an increase in the density of A-type potassium channels led to increases in the latency and the temporal spread of a propagating calcium wave. Next, we incorporated kinetic models for the metabotropic glutamate receptor (miler) signalling components and a calcium-controlled plasticity rule into our model and demonstrate that the presence of mGluRs induced a leftward shift in a BCM-like synaptic plasticity profile. Finally, we show that the A-type potassium current could regulate the relative contribution of ER calcium to synaptic plasticity induced either through 900 pulses of various stimulus frequencies or through theta burst stimulation. These results establish a novel form of interaction between active dendrites and the ER membrane and suggest that A-type K+ channels are ideally placed for inhibiting the suppression of InsP3Rs in thin-caliber dendrites. Furthermore, they uncover a powerful mechanism that could regulate biophysical/biochemical signal integration and steer the spatiotemporal spread of signalling micro domains through changes in dendritic excitability. In the second subpart, we turned our focus to the role of calcium released through InsP3Rs in regulating the properties of VGICs present on the plasma membrane, thereby altering neuronal intrinsic properties that are dependent on these VGICs. Specifically, the synaptic plasticity literature has focused on establishing necessity and sufficiency as two essential and distinct features in causally relating a signalling molecule to plasticity induction, an approach that has been surprisingly lacking in the intrinsic plasticity literature. Here, we complemented the recently established necessity of inositol trisphosphate (InsP3) receptors (InsP3R) in a form of intrinsic plasticity by asking if ER InsP3R activation was sufficient to induce plasticity in intrinsic properties of hippocampus neurons. To do this, we employed whole-cell patch-clamp recordings to infuse D-myo-InsP3, the endogenous ligand for InsP3Rs, into hippocampus pyramidal neurons and assessed the impact of InsP3R activation on neuronal intrinsic properties. We found that such activation reduced input resistance, maximal impedance amplitude and temporal summation, but increased resonance frequency, resonance strength, sag ratio, and impedance phase lead of hippocampus pyramidal neurons. Strikingly, the magnitude of plasticity in all these measurements was dependent upon [InsP3], emphasizing the graded dependence of such plasticity on InsP3R activation. Mechanistically, we found that this InsP3-induced plasticity depended on hyperpolarization-activated cyclic-nucleotide gated (HCN) channels. Moreover, this calcium-dependent form of plasticity was critically reliant on the release of calcium through InsP3Rs, the influx of calcium through N-methyl-D -aspartate receptors and voltage-gated calcium channels, and on the protein kinase A pathway. These results delineate a causal role for InsP3Rs in graded adaptation of neuronal response dynamics through changes in plasma membrane ion channels, thereby revealing novel regulatory roles for the endoplasmic reticulum in neural coding and homeostasis. Whereas the first part of the thesis dealt with bidirectional interactions between ER membrane and plasma membrane channels/receptors within a neuron, second part focuses on cross-cellular interactions, specifically between ER membrane on astrocytes and dendritic plasma membrane of neurons. Specifically, the universality of ER-dependent calcium signalling ensures that its critical influence extends to regulating the physiology of astrocytes, an abundant form of glial cells in the hippocampus. Due to the presence of calcium release channels on ER membrane, astrocytes are calcium excitable, whereby they respond to neuronal activity by increase in their cytosolic calcium levels. Specifically, astrocytes respond to the release of neurotransmitters from neuronal presynaptic terminals through activation of metabotropic receptors expressed on their plasma membrane. Such activation results in the mobilization of cytosolic InsP3 and subsequent release of calcium through InsP3 on the astrocytes ER membrane. These ER-dependent [Ca2+]c elevations in astrocytes then result in the release of gliotransmitters from astrocytes, which bind to corresponding receptors located on neuronal plasma membrane resulting in voltage-deflections and/or activation of signaling pathways in the neuron. Although it is well established that gliotransmission constitutes an important communication channel between astrocytes and neurons, the impact of gliotransmission on neurons have largely been centered at the cell body of the neurons. Consequently, the impact of the activation of astrocytic InsP3R on neuronal dendrites, and the role of dendritic active conductances in regulating this impact have been lacking. This lacuna in mapping the spatial spread of gliotransmission in neurons is especially striking because most afferent synapses impinge on neuronal dendrites, and a significant proportion of information processing in neurons is performed in their dendritic arborization. Additionally, given that active dendritic conductances play a pivotal role in regulating the impact of fast synaptic neurotransmission on neurons, we hypothesized that such active-dendritic regulation should extend to the impact of slower extrasynaptic gliotransmission on neurons. The second part of the thesis is devoted to testing this hypothesis using dendritic and paired astrocyte-neuron electrophysiological recordings, where we also investigate the specific roles of active dendritic conductances in regulating the impact of gliotransmission initiated through activation of astrocytic InsP3Rs. In testing this hypothesis, in the second part of the thesis, we first demonstrate a significantly large increase in the amplitude of astrocytically originating spontaneous slow excitatory potentials (SEP) in distal dendrites compared to their perisomatic counterparts. Employing specific neuronal infusion of pharmacological agents, we show that blocking HCN channels increased the frequency, rise-time and width of dendritically-recorded spontaneous SEPs, whereas blockade of A-type potassium channels enhanced their amplitude. Next, through paired neuron-astrocytes recordings, we show that our conclusions on the differential roles of HCN and A-type potassium channels in modulating spontaneous SEPs also extended to SEPs induced through infusion of InsP3 in a nearby astrocyte. Additionally, employing subtype-specific receptor blockers during paired neuron-astrocyte recordings, we provide evidence that GluN2B-and GluN2D-containing NMDARs predominantly mediate perisomatic and dendritic SEPs, respectively. Finally, using morphologically realistic conductance-based computational models, we quantitatively demonstrate that dendritic conductances play an active role in mediating compartmentalization of the neuronal impact of gliotransmission. These results unveil an important role for active dendrites in regulating the impact of gliotransmission on neurons, and suggest astrocytes as a source of dendritic plateau potentials that have been implicated in localized plasticity and place cell formation. This thesis is organized into six chapters as follows: Chapter 1 lays the motivations for the questions addressed in the thesis apart from providing the highlights of the results presented here. Chapter 2 provides the background literature for the thesis, introducing facts and concepts that forms the foundation on which the rest of the chapters are built upon. In chapter 3, we present quantitative analyses of the physiological interactions between A-type potassium conductances and InsP3Rs in CA1 pyramidal neurons. In chapter 4, using electrophysiological recordings, we investigate the role of calcium released through InsP3Rs in induction of plasticity of intrinsic response dynamics, and demonstrate that this form of plasticity is consequent to changes in neuronal HCN channels. In chapter 5, we systematically map the spatial dynamics of the impact of gliotransmission on neurons across the somato-apical trunk, also unveiling the role of neuronal HCN and A-type potassium channels in compartmentalizing such impact. Finally, chapter 6 concludes the thesis highlighting its major contributions and discussing directions of future research.