Hippocampal Neural Network Research Articles

Unveiling the impact of low-frequency electrical stimulation on network synchronization and learning behavior in cultured hippocampal neural networks

Understanding the dynamics of neural networks and their response to external stimuli is crucial for unraveling the mechanisms associated with learning processes. In this study, we hypothesized that electrical stimulation (ES) would lead to significant alterations in the activity patterns of hippocampal neuronal networks and investigated the effects of low-frequency ES on hippocampal neuronal populations using the microelectrode arrays (MEAs). Our findings revealed significant alterations in the activity of hippocampal neuronal networks following low-frequency ES trainings. Post-stimulation, the neural activity exhibited an organized burst firing pattern characterized by increased spike and burst firings, increased synchronization, and enhanced learning behaviors. Analysis of peri-stimulus time histograms (PSTHs) further revealed that low-frequency ES (1Hz) significantly enhanced neural plasticity, thereby facilitating the learning process of cultured neurons, whereas high-frequency ES (>10Hz) impeded this process. Moreover, we observed a substantial increase in correlations and connectivity within neuronal networks following ES trainings. These alterations in network properties indicated enhanced synaptic plasticity and emphasized the positive impact of low-frequency ES on hippocampal neural activities, contributing to the brain's capacity for learning and memory.

Differences in the consolidation by spontaneous and evoked ripples in the presence of active dendrites.

Ripples are a typical form of neural activity in hippocampal neural networks associated with the replay of episodic memories during sleep as well as sleep-related plasticity and memory consolidation. The emergence of ripples has been observed both dependent as well as independent of input from other brain areas and often coincides with dendritic spikes. Yet, it is unclear how input-evoked and spontaneous ripples as well as dendritic excitability affect plasticity and consolidation. Here, we use mathematical modeling to compare these cases. We find that consolidation as well as the emergence of spontaneous ripples depends on a reliable propagation of activity in feed-forward structures which constitute memory representations. This propagation is facilitated by excitable dendrites, which entail that a few strong synapses are sufficient to trigger neuronal firing. In this situation, stimulation-evoked ripples lead to the potentiation of weak synapses within the feed-forward structure and, thus, to a consolidation of a more general sequence memory. However, spontaneous ripples that occur without stimulation, only consolidate a sparse backbone of the existing strong feed-forward structure. Based on this, we test a recently hypothesized scenario in which the excitability of dendrites is transiently enhanced after learning, and show that such a transient increase can strengthen, restructure and consolidate even weak hippocampal memories, which would be forgotten otherwise. Hence, a transient increase in dendritic excitability would indeed provide a mechanism for stabilizing memories.

ВЛИЯНИЕ ОКСИДАТИВНОГО СТРЕССА НА ФУНКЦИОНИРОВАНИЕ ГЛУТАМАТНЫХ РЕЦЕПТОРОВ ГИППОКАМПА

. In this work, we propose a model approach for analysis of the properties of hippocampal neural networks containing modified glutamate receptors. Molecular dynamics modeling of NMDA and AMPA receptors containing damage caused by the action of free radicals was carried out. The study of network activity of neurons with altered receptor structure was carried out in models of neural network CA3 of the hippocampus region. As a result of studying the properties of the neural network of the hippocampus with a modified structure of glutamate receptors, the electrophysiological characteristics of the known model of neural networks were obtained depending on the structure of the ion channel of the receptor. Based on the analysis of changes in the conductance of the ion channel, differences in the amplitude of the theta and gamma frequency ranges in neural networks with different model structures of AMPA and NMDA receptors were revealed. During the analysis of the network activity of neurons, changes in the conductance of the ion channel of glutamate receptors and local potential were revealed depending on the type of damage. With a significant decrease in the conductivity of the ion channel of the glutamate receptor in the neural network, a decrease in the amplitude of the theta-frequency and an increase in the gamma-frequency ranges is observed. In the case of damage to the TYR731 and CYS765 NMDA receptor in the neural network, an increase in the amplitude of the theta and gamma frequency ranges takes place.

Coexisting fast–slow dendritic traveling waves in a 3D-array electric field coupled neuronal network

Coexistence of fast and slow traveling waves without synaptic transmission has been found in hhhippocampal tissues, which is closely related to both normal brain activity and abnormal neural activity such as epileptic discharge. However, the propagation mechanism behind this coexistence phenomenon remains unclear. In this paper, a three-dimensional electric field coupled hippocampal neural network is established to investigate generation of coexisting spontaneous fast and slow traveling waves. This model captures two types of dendritic traveling waves propagating in both transverse and longitude directions: the N-methyl-D-aspartate (NMDA)-dependent wave with a speed of about 0.1 m/s and the Ca-dependent wave with a speed of about 0.009 m/s. These traveling waves are synaptic-independent and could be conducted only by the electric fields generated by neighboring neurons, which are basically consistent with the in vitro data measured experiments. It is also found that the slow Ca wave could trigger generation of fast NMDA waves in the propagation path of slow waves whereas fast NMDA waves cannot affect the propagation of slow Ca waves. These results suggest that dendritic Ca waves could acted as the source of the coexistence fast and slow waves. Furthermore, we also confirm the impact of cellular spacing heterogeneity on the onset of coexisting fast and slow waves. The local region with decreasing distances among neighbor neurons is more liable to promote the onset of spontaneous slow waves which, as sources, excite propagation of fast waves. These modeling studies provide possible biophysical mechanisms underlying the neural dynamics of spontaneous traveling waves in brain tissues.

Tuning Microelectrodes' Impedance to Improve Fast Ripples Recording.

Epilepsy is a chronic neurological disorder characterized by recurrent seizures resulting from abnormal neuronal hyperexcitability. In the case of pharmacoresistant epilepsy requiring resection surgery, the identification of the Epileptogenic Zone (EZ) is critical. Fast Ripples (FRs; 200-600 Hz) are one of the promising biomarkers that can aid in EZ delineation. However, recording FRs requires physically small electrodes. These microelectrodes suffer from high impedance, which significantly impacts FRs' observability and detection. In this study, we investigated the potential of a conductive polymer coating to enhance FR observability. We employed biophysical modeling to compare two types of microelectrodes: Gold (Au) and Au coated with the conductive polymer poly(3,4-ethylenedioxythiophene)-poly(styrene sulfonate) (Au/PEDOT:PSS). These electrodes were then implanted into the CA1 hippocampal neural network of epileptic mice to record FRs during epileptogenesis. The results showed that the polymer-coated electrodes had a two-order lower impedance as well as a higher transfer function amplitude and cut-off frequency. Consequently, FRs recorded with the PEDOT:PSS-coated microelectrode yielded significantly higher signal energy compared to the uncoated one. The PEDOT:PSS coating improved the observability of the recorded FRs and thus their detection. This work paves the way for the development of signal-specific microelectrode designs that allow for better targeting of pathological biomarkers.

Increased A1 astrocyte activation-driven hippocampal neural network abnormality mediates delirium-like behavior in aged mice undergoing cardiac surgery.

Delirium is the most common neurological complication after cardiac surgery with adverse impacts on surgical outcomes. Advanced age is an independent risk factor for delirium occurrence but its underlying mechanisms are not fully understood. Although increased A1 astrocytes and abnormal hippocampal networks are involved in neurodegenerative diseases, whether A1 astrocytes and hippocampal network changes are involved in the delirium-like behavior of aged mice remains unknown. In the present study, a mice model of myocardial ischemia-reperfusion mimicking cardiac surgery and various assessments were used to investigate the different susceptibility of the occurrence of delirium-like behavior between young and aged mice and the underlying mechanisms. The results showed that surgery significantly increased hippocampal A1 astrocyte activation in aged compared to young mice. The high neuroinflammatory state induced by surgery resulted in glutamate accumulation in the extrasynaptic space, which subsequently decreased the excitability of pyramidal neurons and increased the PV interneurons inhibition through enhancing N-methyl-D-aspartate receptors' tonic currents in the hippocampus. These further induced the abnormal activities of the hippocampal neural networks and consequently contributed to delirium-like behavior in aged mice. Notably, the intraperitoneal administration of exendin-4, a glucagon-like peptide-1 receptor agonist, downregulated A1 astrocyte activation and alleviated delirium-like behavior in aged mice, while IL-1α, TNF-α, and C1q in combination administered intracerebroventricularly upregulated A1 astrocyte activation and induced delirium-like behavior in young mice. Therefore, our study suggested that cardiac surgery increased A1 astrocyte activation which subsequently impaired the hippocampal neural networks and triggered delirium development.

Progressive development of synchronous activity in the hippocampal neuronal network is modulated by GluK1 kainate receptors

Kainate receptors are potent modulators of circuit excitability and have been repeatedly implicated in pathophysiological synchronization of limbic networks. While the role of aberrant GluK2 subunit containing KARs in generation of epileptiform hypersynchronous activity is well described, the contribution of other KAR subtypes, including GluK1 subunit containing KARs remain less well understood. To investigate the contribution of GluK1 KARs in developmental and pathological synchronization of the hippocampal neural network, we used multielectrode array recordings on organotypic hippocampal slices that display first multi-unit activity and later spontaneous population discharges resembling ictal-like epileptiform activity (IEA). Chronic blockage of GluK1 activity using selective antagonist ACET or lentivirally delivered shRNA significantly delayed developmental synchronization of the hippocampal CA3 network and generation of IEA. GluK1 overexpression, on the other hand, had no significant effect on occurrence of IEA, but enhanced the size of the neuron population participating in the population discharges. Correlation analysis indicated that local knockdown of GluK1 locally in the CA3 neurons reduced their functional connectivity, while GluK1 overexpression increased the connectivity to both CA1 and DG. These data suggest that GluK1 KARs regulate functional connectivity between the excitatory neurons, possibly via morphological changes in glutamatergic circuit, affecting synchronization of neuronal populations. The significant effects of GluK1 manipulations on network activity call for further research on GluK1 KAR as potential targets for antiepileptic treatments, particularly during the early postnatal development when GluK1 KARs are strongly expressed in the limbic neural networks.

Emergent structural and functional properties of hippocampal multi-cellular aggregates.

Hippocampal neural networks are distinctly capable of integrating multi-modal sensory inputs to drive memory formation. Neuroscientific investigations using simplified in vitro models have greatly relied on planar (2D) neuronal cultures made from dissociated tissue. While these models have served as simple, cost-effective, and high-throughput tools for examining various morphological and electrophysiological characteristics of hippocampal networks, 2D cultures fail to reconstitute critical elements of the brain microenvironment that may be necessary for the emergence of sophisticated integrative network properties. To address this, we utilized a forced aggregation technique to generate high-density (>100,000 cells/mm3) multi-cellular three-dimensional aggregates using rodent embryonic hippocampal tissue. We contrasted the emergent structural and functional properties of aggregated (3D) and dissociated (2D) cultures over 28 days in vitro (DIV). Hippocampal aggregates displayed robust axonal fasciculation across large distances and significant neuronal polarization, i.e., spatial segregation of dendrites and axons, at earlier time points compared to dissociated cultures. Moreover, we found that astrocytes in aggregate cultures self-organized into non-overlapping quasi-domains and developed highly stellate morphologies resembling astrocyte structures in vivo. We maintained cultures on multi-electrode arrays (MEAs) to assess spontaneous electrophysiological activity for up to 28 DIV. We found that 3D networks of aggregated cultures developed highly synchronized networks and with high burstiness by 28 DIV. We also demonstrated that dual-aggregate networks became active by 7 DIV, in contrast to single-aggregate networks which became active and developed synchronous bursting activity with repeating motifs by 14 DIV. Taken together, our findings demonstrate that the high-density, multi-cellular, 3D microenvironment of hippocampal aggregates supports the recapitulation of emergent biofidelic morphological and functional properties. Our findings suggest that neural aggregates may be used as segregated, modular building blocks for the development of complex, multi-nodal neural network topologies.

A Role of the Hippocampus in Perception and Memory of Odors. Hypothetical Neural Mechanism

Abstract—A mechanism for the interdependent functioning of the olfactory and hippocampal neural networks has been proposed. In this functioning, a significant role belongs to the long-term changes in the efficacy of connections between neurons from these networks, as well as from the ventral part of the basal ganglia, the frontal neocortical areas, the reuniens and mediodorsal thalamic nuclei. Odors are involved in spatial mapping and navigation since these two kinds of information are processed simultaneously and interdependently. The proposed mechanism for the formation of representations of “odor–object–place” associations in the activity of neurons from different hippocampal fields may underlie the participation of odors in the definition of “place fields”. The CA2 hippocampal field makes an important contribution to this process, facilitating the memorization and retrieval of information related to odors and their location. Due to hippocampal projections to olfactory structures, a spatial mapping of the environment is also formed in the activity of neurons in the piriform cortex. According to the proposed mechanism, damage to various parts of the analyzed chains, as well as weakening of neurogenesis in the dentate gyrus and olfactory bulb, should impair odor perception and memory for odors. This consequence is consistent with olfactory deficits in various neurodegenerative and viral diseases, as well as in aging.

Seizure-induced hilar ectopic granule cells in the adult dentate gyrus.

Epilepsy is a chronic neurological disorder characterized by hypersynchronous spontaneous recurrent seizures, and affects approximately 50 million people worldwide. Cumulative evidence has revealed that epileptogenic insult temporarily increases neurogenesis in the hippocampus; however, a fraction of the newly generated neurons are integrated abnormally into the existing neural circuits. The abnormal neurogenesis, including ectopic localization of newborn neurons in the hilus, formation of abnormal basal dendrites, and disorganization of the apical dendrites, rewires hippocampal neural networks and leads to the development of spontaneous seizures. The central roles of hilar ectopic granule cells in regulating hippocampal excitability have been suggested. In this review, we introduce recent findings about the migration of newborn granule cells to the dentate hilus after seizures and the roles of seizure-induced ectopic granule cells in the epileptic brain. In addition, we delineate possible intrinsic and extrinsic mechanisms underlying this abnormality. Finally, we suggest that the regulation of seizure-induced ectopic cells can be a promising target for epilepsy therapy and provide perspectives on future research directions.

Microglial motility is modulated by neuronal activity and correlates with dendritic spine plasticity in the hippocampus of awake mice.

Microglia, the resident immune cells of the brain, play a complex role in health and disease. They actively survey the brain parenchyma by physically interacting with other cells and structurally shaping the brain. Yet, the mechanisms underlying microglial motility and significance for synapse stability, especially in the hippocampus during adulthood, remain widely unresolved. Here, we investigated the effect of neuronal activity on microglial motility and the implications for the formation and survival of dendritic spines on hippocampal CA1 neurons in vivo. We used repetitive two-photon in vivo imaging in the hippocampus of awake and anesthetized mice to simultaneously study the motility of microglia and their interaction with dendritic spines. We found that CA3 to CA1 input is sufficient to modulate microglial process motility. Simultaneously, more dendritic spines emerged in mice after awake compared to anesthetized imaging. Interestingly, the rate of microglial contacts with individual dendritic spines and dendrites was associated with the stability, removal, and emergence of dendritic spines. These results suggest that microglia might sense neuronal activity via neurotransmitter release and actively participate in synaptic rewiring of the hippocampal neural network during adulthood. Further, this study has profound relevance for hippocampal learning and memory processes.

ВЛИЯНИЕ МОДУЛЯТОРОВ НА АКТИВАЦИЮ РЕЦЕПТОРА NMDA

In this paper, we have proposed a model approach for analyzing the properties of hippocampal neural networks with different types of NMDA receptors: GluN1/GluN2A, GluN1/GluN2B, GluN1/GluN2A/GluN2B. Molecular dynamics modeling of the activation of the ion channel of NMDA receptors modified by the action of allosteric modulators was carried out. The study of the network activity of neurons with a modified structure of NMDA receptors was carried out in models of neural networks in the CA1 and CA3 regions of the hippocampus. As a result of studying the properties of the neural network of the hippocampus with a modified structure of NMDA receptors, the electrophysiological characteristics of the neural network model were obtained depending on the structure of the ion channel of the NMDA receptor. Based on the analysis of changes in the conductivities of the ion channel and the binding of magnesium ions, differences in the amplitude of the theta and gamma frequency ranges in neural networks with different model structures of NMDA receptors were revealed. Analysis of the network activity of neurons with different types of NMDA revealed minor changes in the ion channel conductance and local potential depending on the subunits that make up the receptor and the type of modulator. Under the influence of Ro 25-6981 and ketamine for the diheteromeric model of the GluN1/GluN2A NMDA receptor, a decrease in the amplitude of the theta-frequency ranges and an increase in the gamma-frequency ranges were observed in comparison with the native forms of the receptor. For the GluN1/GluN2A/GluN2B trigger heteromer, there is an increase in theta frequency and a decrease in the gamma frequency compared to GluN1/GluN2B. In the absence of ketamine, for the GluN1/GluN2A and GluN1/GluN2A/GluN2B NMDA receptor models, an increase in the amplitude of theta-frequency and gamma-frequency ranges was observed compared to the native forms of the NMDA receptor.

The dysfunction of mGluRIIs is involved in the disorder of hippocampal neural network in diabetic mice model.

Cognitive dysfunction is a high incidence of diabetes mellitus (DM). However, the relationship between DM-induced cognitive defect and neuronal network oscillations is still unknown. In this study, adult male C57BL/6J mice were intraperitoneally injected with streptozotocin (STZ) to duplicate DM. After 12weeks, local field potentials were recorded in the perforant fiber pathway (PP) and dentate gyrus (DG) regions. Data showed that mice in the STZ group exhibited impairment of spatial learning and memory by the Morris Water Mazetest. The low gamma (LG) and high gamma (HG) power were increased in the PP and DG areas of the STZ group. Moreover, the phase synchronization and the information flow at theta and LG rhythms between the PP and DG areas were decreased, and the theta-LG phase-amplitude coupling strength was markedly reduced in the PPregion, DG region, and the PP-DG pathway in the STZ group. Additionally, the concentration of glutamate was increased by thehigh-performance liquid chromatography. Moreover, the NR2B and PSD95 expressions were markedly reduced, and the Akt/GSK-3β pathway was inhibited. Interestingly, the expressions of mGluRIIs (mGluR2 and mGluR3) were significantly decreased. The reduction of mGluRIIs may limit their function, such as restricting presynaptic glutamate release and reversing the dysfunction of NR2B via Akt/GSK-3β signaling pathway. In conclusion, our data suggest that DM alters the hippocampal neural network partly related to the dysfunction of mGluRIIs.

In vivo Chronic Two-Photon Imaging of Microglia in the Mouse Hippocampus.

Microglia, the only immune cells resident in the brain, actively participate in neural circuit maintenance by modifying synapses and neuronal excitability. Recent studies have revealed the differential gene expression and functional heterogeneity of microglia in different brain regions. The unique functions of the hippocampal neural network in learning and memory may be associated with the active roles of microglia in synapse remodeling. However, inflammatory responses induced by surgical procedures have been problematic in the two-photon microscopic analysis of hippocampal microglia. Here, a method is presented that enables the chronic observation of microglia in all layers of the hippocampal CA1 through an imaging window. This method allows the analysis of morphological changes in microglial processes for more than 1 month. Long-term and high-resolution imaging of the resting microglia requires minimally invasive surgical procedures, appropriate objective lens selection, and optimized imaging techniques. The transient inflammatory response of hippocampal microglia may prevent imaging immediately after surgery, but the microglia restore their quiescent morphology within a few weeks. Furthermore, imaging neurons simultaneously with microglia allows us to analyze the interactions of multiple cell types in the hippocampus. This technique may provide essential information about microglial function in the hippocampus.

<i>In vivo</i> Chronic Two-Photon Imaging of Microglia in the Mouse Hippocampus

Microglia, the only immune cells resident in the brain, actively participate in neural circuit maintenance by modifying synapses and neuronal excitability. Recent studies have revealed the differential gene expression and functional heterogeneity of microglia in different brain regions. The unique functions of the hippocampal neural network in learning and memory may be associated with the active roles of microglia in synapse remodeling. However, inflammatory responses induced by surgical procedures have been problematic in the two-photon microscopic analysis of hippocampal microglia. Here, a method is presented that enables the chronic observation of microglia in all layers of the hippocampal CA1 through an imaging window. This method allows the analysis of morphological changes in microglial processes for more than 1 month. Long-term and high-resolution imaging of the resting microglia requires minimally invasive surgical procedures, appropriate objective lens selection, and optimized imaging techniques. The transient inflammatory response of hippocampal microglia may prevent imaging immediately after surgery, but the microglia restore their quiescent morphology within a few weeks. Furthermore, imaging neurons simultaneously with microglia allows us to analyze the interactions of multiple cell types in the hippocampus. This technique may provide essential information about microglial function in the hippocampus.

Controlling synchronization of gamma oscillations by astrocytic modulation in a model hippocampal neural network

Recent in vitro and in vivo experiments demonstrate that astrocytes participate in the maintenance of cortical gamma oscillations and recognition memory. However, the mathematical understanding of the underlying dynamical mechanisms remains largely incomplete. Here we investigate how the interplay of slow modulatory astrocytic signaling with fast synaptic transmission controls coherent oscillations in the network of hippocampal interneurons that receive inputs from pyramidal cells. We show that the astrocytic regulation of signal transmission between neurons improves the firing synchrony and extends the region of coherent oscillations in the biologically relevant values of synaptic conductance. Astrocyte-mediated potentiation of inhibitory synaptic transmission markedly enhances the coherence of network oscillations over a broad range of model parameters. Astrocytic regulation of excitatory synaptic input improves the robustness of interneuron network gamma oscillations induced by physiologically relevant excitatory model drive. These findings suggest a mechanism, by which the astrocytes become involved in cognitive function and information processing through modulating fast neural network dynamics.

Age-related changes in medial septal cholinergic and GABAergic projection neurons and hippocampal neurotransmitter receptors: relationship with memory impairment.

The hippocampus, which provides cognitive functions, has been shown to become highly vulnerable during aging. One important modulator of the hippocampal neural network is the medial septum (MS). The present study attempts to determine how age-related mnemonic dysfunction is associated with neurochemical changes in the septohippocampal (SH) system, using behavioral and immunochemical experiments performed on young-adult, middle-aged and aged rats. According to these behavioral results, the aged and around 52.8% of middle-aged rats (within the "middle-aged-impaired" sub-group) showed both impaired spatial reference memory in the Morris water maze and habituation in the open field. Immunohistochemical studies revealed a significant decrease in the number of MS choline acetyltransferase immunoreactive cells in the aged and all middle-aged rats, in comparison to the young; however the number of gamma-aminobutyric acid-ergic (GABAergic) parvalbumin immunoreactive cells was higher in middle-aged-impaired and older rats compared to young and middle-aged-unimpaired rats. Western Blot analysis moreover showed a decrease in the level of expression of cholinergic, GABAergic and glutamatergic receptors in the hippocampus of middle-aged-impaired and aged rats in contrast to middle-aged-unimpaired and young rats. The present results demonstrate for the first time that a decrease in the expression level of hippocampal receptors in naturally aged rats with impaired cognitive abilities occurs in parallel with an increase in the number of GABAergic neurons in the MS, and it highlights the particular importance of inhibitory signaling in the SH network for memory function.

Short-Term Epileptiform Activity Potentiates Excitatory Synapses but Does Not Affect Intrinsic Membrane Properties of Pyramidal Neurons in the Rat Hippocampus In Vitro.

Even brief epileptic seizures can lead to activity-dependent structural remodeling of neural circuitry. Animal models show that the functional plasticity of synapses and changes in the intrinsic excitability of neurons can be crucial for epileptogenesis. However, the exact mechanisms underlying epileptogenesis remain unclear. We induced epileptiform activity in rat hippocampal slices for 15 min using a 4-aminopyridine (4-AP) in vitro model and observed hippocampal hyperexcitability for at least 1 h. We tested several possible mechanisms of this hyperexcitability, including changes in intrinsic membrane properties of neurons and presynaptic and postsynaptic alterations. Neither input resistance nor other essential biophysical properties of hippocampal CA1 pyramidal neurons were affected by epileptiform activity. The glutamate release probability also remained unchanged, as the frequency of miniature EPSCs and the paired amplitude ratio of evoked responses did not change after epileptiform activity. However, we found an increase in the AMPA/NMDA ratio, suggesting alterations in the properties of postsynaptic glutamatergic receptors. Thus, the increase in excitability of hippocampal neural networks is realized through postsynaptic mechanisms. In contrast, the intrinsic membrane properties of neurons and the probability of glutamate release from presynaptic terminals are not affected in a 4-AP model.

Developmental Changes in Early Sharp Waves in the Hippocampus of Neonatal Rats

Synchronized activity the hallmark of neural networks. Early sharp waves (eSPW) form one type of synchronized activity – these are synchronized network discharges of neuronal ensembles seen in the developing hippocampus. Despite the fact that eSPW may play a central role in coordinating neural activity and forming hippocampal functions, little is known of changes in eSPW during early postnatal development. Our experiments on neonatal rat pups using multichannel extracellular electrodes showed that during the first two weeks of postnatal life, along with reductions in the duration of eSPW, there were increases in their frequency and amplitude. We also found an increase in extracellular recorded activity of neurons in the pyramidal layer of the hippocampus. These data lead to the suggestion that the dynamics of changes in eSPW and overall network hippocampal activity are associated with the development of the hippocampal neural network and bottom-up neuromodulator projections.

Delta-opioid receptor-mediated modulation of excitability of individual hippocampal neurons: mechanisms involved.

Delta-opioid receptor (DOR)-mediated modulation of hippocampal neural networks is involved in emotions, cognition, and in pathophysiology and treatment of mood disorders. In this study, we examined the effects of DOR agonist (SNC80) and antagonist (naltrindole) on the excitability of individual hippocampal neurons. Primary neuronal cultures were prepared from hippocampi of newborn rats and cultivated in vitro for 8-14days (DIV8-14). The effects of SNC80 naltrindole on evoked and spontaneous action potentials (APs) were measured at DIV8-9 and DIV13-14, respectively. SNC80 (100µM) potentiated spontaneous AP firing and stimulated sodium current; naltrindole had opposite effects. The stimulatory effect of 100µM of SNC80 was revoked by pre-administration of 1µM of naltrindole. SNC80 and naltrindole induced similar inhibitory effects on the evoked AP firing and on the calcium current. Further, SNC80 inhibited both peak and sustained potassium currents. Naltrindole had no effect on potassium currents. We suggest that the effects of naltrindole and high concentration of SNC80 on the sodium currents are mediated via DORs and underlying the changes in spontaneous activity. The inhibitory effects of SNC80 on calcium and potassium currents might also be DOR-dependent; these currents might mediate SNC80 effect on the evoked AP firing. The inhibitory effects of naltrindole on calcium and of low doses of SNC80 on sodium currents might be however DOR independent. The behavioral effects of SNC80 and naltrindole, observed in previous studies, might be mediated, at least in part, via the modulatory effect of these ligands on the excitability of hippocampal neurons.