Hippocampal Synchronization Research Articles

Chemogenetic silencing reveals presynaptic Gi/o protein-mediated inhibition of developing hippocampal synchrony in vivo

Recent advances in understanding how neuronal activity shapes developing brain circuits increasingly rely on Gi/o-dependent inhibitory chemogenetic tools (Gi-DREADDs). However, their mechanisms ofaction and efficacy in neurons with immature Gi/o signaling are elusive. Here, we express the Gi-DREADD hM4Di in glutamatergic telencephalic neurons and analyze its impact on CA1 pyramidal neurons in neonatal mice. Using acousto-optic two-photon Ca2+ imaging, we report that activation of hM4Di leads to a complete arrest of spontaneous synchrony in CA1 invitro. We demonstrate that hM4Di does not cause somatic hyperpolarization or shunting but rather mediates presynaptic silencing of glutamatergic neurotransmission. Invivo, inhibition through hM4Di potently suppresses early sharp waves (eSPWs) and discontinuous oscillatory network activity in CA1 of head-fixed mice before eye opening. Our findings provide insights into the role of Gi/o signaling in synchronized activity in the neonatal hippocampus and bear relevance for applying chemogenetic silencing at early developmental stages.

Disrupted hippocampal synchrony following maternal immune activation in a rat model.

Maternal immune activation (MIA) is a risk factor for schizophrenia and other neurodevelopmental disorders. MIA in rats models a number of the brain and behavioral changes that are observed in schizophrenia, including impaired memory. Recent studies in the MIA model have shown that the firing of the hippocampal place cells that are involved in memory processes appear relatively normal, but with abnormalities in the temporal ordering of firing. In this study, we re-analyzed data from prior hippocampal electrophysiological recordings of MIA and control animals to determine whether temporal dysfunction was evident. We find that there is a decreased ratio of slow to fast gamma power, resulting from an increase in fast gamma power and a tendency toward reduced slow gamma power in MIA rats. Moreover, we observe a robust reduction in spectral coherence between hippocampal theta and both fast and slow gamma rhythms, as well as changes in the phase of theta at which fast gamma occurs. We also find the phasic organization of place cell phase precession on the theta wave to be abnormal in MIA rats. Lastly, we observe that the local field potential of MIA rats contains more frequent sharp-wave ripple events, and that place cells were more likely to fire spikes during ripples in these animals than control. These findings provide further evidence of desynchrony in MIA animals and may point to circuit-level changes that underlie failures to integrate and encode information in schizophrenia.

Retrosplenial and Hippocampal Synchrony during Retrieval of Old Memories in Macaques.

Memory for events from the distant past relies on multiple brain regions, but little is known about the underlying neural dynamics that give rise to such abilities. We recorded neural activity in the hippocampus and retrosplenial cortex of two female rhesus macaques as they visually selected targets in year-old and newly acquired object-scene associations. Whereas hippocampal activity was unchanging with memory age, the retrosplenial cortex responded with greater magnitude alpha oscillations (10-15 Hz) and greater phase locking to memory-guided eye movements during retrieval of old events. A similar old-memory enhancement was observed in the anterior cingulate cortex but in a beta2/gamma band (28-35 Hz). In contrast, remote retrieval was associated with decreased gamma-band synchrony between the hippocampus and each neocortical area. The increasing retrosplenial alpha oscillation and decreasing hippocampocortical synchrony with memory age may signify a shift in frank memory allocation or, alternatively, changes in selection among distributed memory representations in the primate brain.SIGNIFICANCE STATEMENT Memory depends on multiple brain regions, whose involvement is thought to change with time. Here, we recorded neuronal population activity from the hippocampus and retrosplenial cortex as nonhuman primates searched for objects embedded in scenes. These memoranda were either newly presented or a year old. Remembering old material drove stronger oscillations in the retrosplenial cortex and led to a greater locking of neural activity to search movements. Remembering new material revealed stronger oscillatory synchrony between the hippocampus and retrosplenial cortex. These results suggest that with age, memories may come to rely more exclusively on neocortical oscillations for retrieval and search guidance and less on long-range coupling with the hippocampus.

Mecamylamine inhibits seizure-like activity in CA1-CA3 hippocampus through antagonism to nicotinic receptors.

Cholinergic modulation of hippocampal network function is implicated in multiple behavioral and cognitive states. Activation of nicotinic and muscarinic acetylcholine receptors affects neuronal excitability, synaptic transmission and rhythmic oscillations in the hippocampus. In this work, we studied the ability of the cholinergic system to sustain hippocampal epileptiform activity independently from glutamate and GABA transmission. Simultaneous CA3 and CA1 field potential recordings were obtained during the perfusion of hippocampal slices with the aCSF containing AMPA, NMDA and GABA receptor antagonists. Under these conditions, spontaneous epileptiform discharges synchronous between CA3 and CA1 were recorded. Epileptiform discharges were blocked by addition of the calcium-channel blocker Cd2+ and disappeared in CA1 after a surgical cut between CA3 and CA1. Cholinergic antagonist mecamylamine abolished CA3-CA1 synchronous epileptiform discharges, while antagonists of α7 and α4β2 nAChRs, MLA and DhβE, had no effect. Our results suggest that activation of nicotinic acetylcholine receptors can sustain CA3-CA1 synchronous epileptiform activity independently from AMPA, NMDA and GABA transmission. In addition, mecamylamine, but not α7 and α4β2 nAChRs antagonists, reduced bicuculline-induced seizure-like activity. The ability of mecamylamine to decrease hippocampal network synchronization might be associated with its therapeutic effects in a wide variety of CNS disorders including addiction, depression and anxiety.

Awake delta and theta-rhythmic hippocampal network modes during intermittent locomotor behaviors in the rat.

Delta-frequency network activity is commonly associated with sleep or behavioral disengagement accompanied by a dearth of cortical spiking, but delta in awake behaving animals is not well understood. We show that hippocampal (HC) synchronization in the delta frequency band (1-4 Hz) is related to animals' locomotor behavior using detailed analyses of the HC local field potential (LFP) and simultaneous head- and body-tracking data. In contrast to running-speed modulation of the theta rhythm (6-10 Hz), delta was most prominent when animals were stationary or moving slowly, that is, when theta and fast gamma (65-120 Hz) were weak, and often developed rapidly when animals paused briefly between runs. We next combined time-frequency decomposition of the LFP with hierarchical clustering algorithms to categorize momentary estimations of the power spectral density (PSD) into putative modes of HC activity. Delta and theta power were strikingly orthogonal across spectral modes, as well as across bouts of precisely defined running and stationary behavior. Delta-band and theta-band coherences between HC recording sites were monotonically related to theta-delta ratios across modes; and whereas theta coherence between HC and medial prefrontal cortex (mPFC) increased during running, delta-band coherence between mPFC and HC increased during stationary bouts. Taken together, our findings suggest that delta-dominated network modes (and corresponding mPFC-HC couplings) represent functionally distinct circuit dynamics that are temporally and behaviorally interspersed among theta-dominated modes during navigation. As such, delta modes could play a fundamental role in coordinating encoding and retrieval mechanisms or decision-making processes at a timescale that segments event sequences within behavioral episodes. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Prefrontal–hippocampal functional connectivity encodes recognition memory and is impaired in intellectual disability

Down syndrome (DS) is the most common form of intellectual disability. The cognitive alterations in DS are thought to depend on brain regions critical for learning and memory such as the prefrontal cortex (PFC) and the hippocampus (HPC). Neuroimaging studies suggest that increased brain connectivity correlates with lower intelligence quotients (IQ) in individuals with DS; however, its contribution to cognitive impairment is unresolved. We recorded neural activity in the PFC and HPC of the trisomic Ts65Dn mouse model of DS during quiet wakefulness, natural sleep, and the performance of a memory test. During rest, trisomic mice showed increased theta oscillations and cross-frequency coupling in the PFC and HPC while prefrontal-hippocampal synchronization was strengthened, suggesting hypersynchronous local and cross-regional processing. During sleep, slow waves were reduced, and gamma oscillations amplified in Ts65Dn mice, likely reflecting prolonged light sleep. Moreover, hippocampal sharp-wave ripples were disrupted, which may have further contributed to deficient memory consolidation. Memory performance in euploid mice correlated strongly with functional connectivity measures that indicated a hippocampal control over memory acquisition and retrieval at theta and gamma frequencies, respectively. By contrast, trisomic mice exhibited poor memory abilities and disordered prefrontal-hippocampal functional connectivity. Memory performance and key neurophysiological alterations were rescued after 1 month of chronic administration of a green tea extract containing epigallocatequin-3-gallate (EGCG), which improves executive function in young adults with DS and Ts65Dn mice. Our findings suggest that abnormal prefrontal-hippocampal circuit dynamics are candidate neural mechanisms for memory impairment in DS.

The Dorsal Hippocampus Neuronal Lesion Does not Affect Theta Activity in the Cortical Network

The hippocampal theta activity represents the oscillatory field potentials within the range of 4–10 Hz, which mainly appears during wakefulness and rapid eye moment (REM) sleep. The synchronization of theta activity between the hippocampus and other parts of the brain is essential for learning and memory. Theta waves can be recorded from the different cortical areas, which exhibit a consistent phase relationship with hippocampal rhythmicity. It has been postulated that the synchronized theta activity in the cortico-hippocampal networks could be essential for communication of memory information between hippocampus and cortex. It is, however, not known if the dorsal hippocampus (DH) contributes in propagating theta waves in the cortical network. In this study, we have investigated the effects of DH lesion on theta activity during different vigilant states in the frontoparietal cortical network. Rats were surgically prepared for chronic polysomnographic recordings and drug injections. After recovery from surgery, animals were divided into two groups: (a) DH-non-lesioned and (b) DH-lesioned groups. DH was lesioned with microinjection of ibotenic acid. We found that the DH neuronal damage did not significantly alter cortical EEG theta activity. There were only marginal changes in the power of theta (5–9 Hz) and high-frequency oscillatory waves (10–40 Hz) that too only during REM sleep in the DH-lesioned animals. Although the hippocampal theta rhythm plays an important role the cortical–hippocampal synchrony, it is likely that in the absence of DH, the cortical theta oscillation can be modulated by some non-hippocampal theta generators such as the septum-diagonal band of Broca or the supramammillary body.

Impaired hippocampal-cortical coupling but preserved local synchrony during sleep in APP/PS1 mice modeling Alzheimer\u2019s disease

Sleep, in addition to its brain restorative processes, plays an important role in memory transfer from its temporary store in the hippocampus to the more permanent storage in the neocortex. Alzheimer’s disease (AD) affects memory and sleep. The aim of this study was to explore disturbances in global and local synchrony patterns between brain regions in the APP/PS1 mouse model of the AD during natural sleep. We used 8 male APPswe/PS1dE9 mice and 6 wild-type littermates, aged 5–6 months, with multiple electrode bundles implanted into cortical regions, thalamus and hippocampus. We measured video-EEG in freely moving animals and analyzed synchrony during NREM vs REM sleep. Global synchrony between medial frontal cortex and hippocampus measured with magnitude-squared coherence was slightly decreased in delta range during NREM stage of sleep in APP/PS1 mice. In contrast, local hippocampal synchrony measured with cross-frequency coupling remained intact. Ripple structure or frequency did not differ between the genotypes. However, the coupling of the spindle-band power peak in the medial prefrontal cortex to hippocampal ripples was significantly decreased compared to wild-type animals. The delicate timing of hippocampal ripples, frontal delta, and corticothalamic spindle oscillations may be the first sign of impaired memory in amyloid plaque-forming transgenic mice.

Optogenetic Entrainment of Hippocampal Theta Oscillations in Behaving Mice

Extensive data on relationships of neural network oscillations to behavior and organization of neuronal discharge across brain regions call for new tools to selectively manipulate brain rhythms. Here we describe an approach combining projection-specific optogenetics with extracellular electrophysiology for high-fidelity control of hippocampal theta oscillations (5-10 Hz) in behaving mice. The specificity of the optogenetic entrainment is achieved by targeting channelrhodopsin-2 (ChR2) to the GABAergic population of medial septal cells, crucially involved in the generation of hippocampal theta oscillations, and a local synchronized activation of a subset of inhibitory septal afferents in the hippocampus. The efficacy of the optogenetic rhythm control is verified by a simultaneous monitoring of the local field potential (LFP) across lamina of the CA1 area and/or of neuronal discharge. Using this readily implementable preparation we show efficacy of various optogenetic stimulation protocols for induction of theta oscillations and for the manipulation of their frequency and regularity. Finally, a combination of the theta rhythm control with projection-specific inhibition addresses the readout of particular aspects of the hippocampal synchronization by efferent regions.

Optogenetic Entrainment of Hippocampal Theta Oscillations in Behaving Mice.

Extensive data on relationships of neural network oscillations to behavior and organization of neuronal discharge across brain regions call for new tools to selectively manipulate brain rhythms. Here we describe an approach combining projection-specific optogenetics with extracellular electrophysiology for high-fidelity control of hippocampal theta oscillations (5-10 Hz) in behaving mice. The specificity of the optogenetic entrainment is achieved by targeting channelrhodopsin-2 (ChR2) to the GABAergic population of medial septal cells, crucially involved in the generation of hippocampal theta oscillations, and a local synchronized activation of a subset of inhibitory septal afferents in the hippocampus. The efficacy of the optogenetic rhythm control is verified by a simultaneous monitoring of the local field potential (LFP) across lamina of the CA1 area and/or of neuronal discharge. Using this readily implementable preparation we show efficacy of various optogenetic stimulation protocols for induction of theta oscillations and for the manipulation of their frequency and regularity. Finally, a combination of the theta rhythm control with projection-specific inhibition addresses the readout of particular aspects of the hippocampal synchronization by efferent regions.

Resting-state fMRI study of brain activation using low-intensity repetitive transcranial magnetic stimulation in rats

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique used to treat many neuropsychiatric conditions. However, the mechanisms underlying its mode of action are still unclear. This is the first rodent study using resting-state functional MRI (rs-fMRI) to examine low-intensity (LI) rTMS effects, in an effort to provide a direct means of comparison between rodent and human studies. Using anaesthetised Sprague-Dawley rats, rs-fMRI data were acquired before and after control or LI-rTMS at 1 Hz, 10 Hz, continuous theta burst stimulation (cTBS) or biomimetic high-frequency stimulation (BHFS). Independent component analysis revealed LI-rTMS-induced changes in the resting-state networks (RSN): (i) in the somatosensory cortex, the synchrony of resting activity decreased ipsilaterally following 10 Hz and bilaterally following 1 Hz stimulation and BHFS, and increased ipsilaterally following cTBS; (ii) the motor cortex showed bilateral changes following 1 Hz and 10 Hz stimulation, a contralateral decrease in synchrony following BHFS, and an ipsilateral increase following cTBS; and (iii) hippocampal synchrony decreased ipsilaterally following 10 Hz, and bilaterally following 1 Hz stimulation and BHFS. The present findings demonstrate that LI-rTMS modulates functional links within the rat RSN with frequency-specific outcomes, and the observed changes are similar to those described in humans following rTMS.

GABAergic Neurons in the Rat Medial Septal Complex Express Relaxin-3 Receptor (RXFP3) mRNA.

The medial septum (MS) complex modulates hippocampal function and related behaviors. Septohippocampal projections promote and control different forms of hippocampal synchronization. Specifically, GABAergic and cholinergic projections targeting the hippocampal formation from the MS provide bursting discharges to promote theta rhythm, or tonic activity to promote gamma oscillations. In turn, the MS is targeted by ascending projections from the hypothalamus and brainstem. One of these projections arises from the nucleus incertus in the pontine tegmentum, which contains GABA neurons that co-express the neuropeptide relaxin-3 (Rln3). Both stimulation of the nucleus incertus and septal infusion of Rln3 receptor agonist peptides promotes hippocampal theta rhythm. The Gi/o-protein-coupled receptor, relaxin-family peptide receptor 3 (RXFP3), is the cognate receptor for Rln3 and identification of the transmitter phenotype of neurons expressing RXFP3 in the septohippocampal system can provide further insights into the role of Rln3 transmission in the promotion of septohippocampal theta rhythm. Therefore, we used RNAscope multiplex in situ hybridization to characterize the septal neurons expressing Rxfp3 mRNA in the rat. Our results demonstrate that Rxfp3 mRNA is abundantly expressed in vesicular GABA transporter (vGAT) mRNA- and parvalbumin (PV) mRNA-positive GABA neurons in MS, whereas ChAT mRNA-positive acetylcholine neurons lack Rxfp3 mRNA. Approximately 75% of Rxfp3 mRNA-positive neurons expressed vGAT mRNA (and 22% were PV mRNA-positive), while the remaining 25% expressed Rxfp3 mRNA only, consistent with a potential glutamatergic phenotype. Similar proportions were observed in the posterior septum. The occurrence of RXFP3 in PV-positive GABAergic neurons gives support to a role for the Rln3-RXFP3 system in septohippocampal theta rhythm.

Supramammillary serotonin reduction alters place learning and concomitant hippocampal, septal, and supramammillar theta activity in a Morris water maze

Hippocampal theta activity is related to spatial information processing, and high-frequency theta activity, in particular, has been linked to efficient spatial memory performance. Theta activity is regulated by the synchronizing ascending system (SAS), which includes mesencephalic and diencephalic relays. The supramamillary nucleus (SUMn) is located between the reticularis pontis oralis and the medial septum (MS), in close relation with the posterior hypothalamic nucleus (PHn), all of which are part of this ascending system. It has been proposed that the SUMn plays a role in the modulation of hippocampal theta-frequency; this could occur through direct connections between the SUMn and the hippocampus or through the influence of the SUMn on the MS. Serotonergic raphe neurons prominently innervate the hippocampus and several components of the SAS, including the SUMn. Serotonin desynchronizes hippocampal theta activity, and it has been proposed that serotonin may regulate learning through the modulation of hippocampal synchrony. In agreement with this hypothesis, serotonin depletion in the SUMn/PHn results in deficient spatial learning and alterations in CA1 theta activity-related learning in a Morris water maze. Because it has been reported that SUMn inactivation with lidocaine impairs the consolidation of reference memory, we asked whether changes in hippocampal theta activity related to learning would occur through serotonin depletion in the SUMn, together with deficiencies in memory. We infused 5,7-DHT bilaterally into the SUMn in rats and evaluated place learning in the standard Morris water maze task. Hippocampal (CA1 and dentate gyrus), septal and SUMn EEG were recorded during training of the test. The EEG power in each region and the coherence between the different regions were evaluated. Serotonin depletion in the SUMn induced deficient spatial learning and altered the expression of hippocampal high-frequency theta activity. These results provide evidence in support of a role for serotonin as a modulator of hippocampal learning, acting through changes in the synchronicity evoked in several relays of the SAS.

Status epilepticus results in region-specific alterations in seizure susceptibility along the hippocampal longitudinal axis

Temporal lobe epilepsy (TLE) is the most common epilepsy syndrome in adults. In particular, the hippocampus is highly susceptible to abnormal synchronization. Recent advances in the surgical treatment of patients with refractory TLE have shown that multiple hippocampal transections can effectively control seizures. It has been suggested that in TLE the synchrony in the longitudinal connections is required for seizure generation; however the physiological background for the increase in hippocampal synchronization along the longitudinal axis is not fully understood. The hippocampus varies in seizure susceptibility along its longitudinal axis with the ventral hippocampus (VH) region being more seizure-prone and susceptible to neuronal damage than the dorsal hippocampus (DH). In the present study we studied seizure susceptibility along the longitudinal axis of the hippocampus following pilocarpine-induced status epilepticus (SE). In control conditions the VH generates epileptiform activity (EA) more frequently than the DH when exposed to a low Mg(2+)/1Ca(2+)/5K(+) solution. Following SE the probability of inducing epileptiform activity (EA) is similar in the VH and DH slices. This SE-induced change is due to an increase in the proportion of DH slices responding to the low Mg(2+)/1Ca(2+)/5K(+) solution with EA. Moreover, both the VH and DH show similar responses to a low Mg(2+)/1Ca(2+)/5K(+) solution. These findings indicate that the hippocampus undergoes significant functional changes following SE, which may provide the necessary increase of synchrony along the longitudinal axis to generate seizures in TLE.

Reversal of theta rhythm flow through intact hippocampal circuits.

Activity flow through the hippocampus is thought to arise exclusively from unidirectional excitatory synaptic signaling from CA3 to CA1 to the subiculum. Theta rhythms are important for hippocampal synchronization during episodic memory processing; thus, it is assumed that theta rhythms follow these excitatory feedforward circuits. To the contrary, we found that theta rhythms generated in the rat subiculum flowed backward to actively modulate spike timing and local network rhythms in CA1 and CA3. This reversed signaling involved GABAergic mechanisms. However, when hippocampal circuits were physically limited to a lamellar slab, CA3 outputs synchronized CA1 and the subiculum using excitatory mechanisms, as predicted by classic hippocampal models. Finally, analysis of in vivo recordings revealed that this reversed theta flow was most prominent during REM sleep. These data demonstrate that communication between CA3, CA1 and the subiculum is not exclusively unidirectional or excitatory and that reversed inhibitory theta signaling also contributes to intrahippocampal synchrony.

Compromised maturation of GABAergic inhibition underlies abnormal network activity in the hippocampus of epileptic Ca2+ channel mutant mice, tottering.

Cholinergically induced network activity is a useful analogue of theta rhythms involved in memory processing or epileptiform activity in the hippocampus, providing a powerful tool to elucidate the mechanisms of synchrony in neuronal networks. In absence epilepsy, although its association with cognitive impairments has been reported, the mechanisms underlying hippocampal synchrony remain poorly investigated. Here we simultaneously recorded electrical activities from 64 sites in hippocampal slices of CaV2.1 Ca(2+) channel mutant tottering (tg) mice, a well-established mouse model of spontaneous absence epilepsy, to analyze the spatiotemporal pattern of cholinergically induced hippocampal network activity. The cholinergic agonist carbachol induced oscillatory discharges originating from the CA3 region. In tg/tg mice, this hippocampal network activity was characterized by enhanced occupancy of discharges of relatively high frequency (6-10 Hz) compared to the wild type. Pharmacological analyses of slices, patch clamp electrophysiological characterization of isolated neurons, and altered patterns of hippocampal GABAA receptor subunit and Cl(-) transporter messenger RNA (mRNA) transcript levels revealed that this abnormality is attributable to a developmental retardation of GABAergic inhibition caused by immature intracellular Cl(-) regulation. These results suggest that the inherited CaV2.1 Ca(2+) channel mutation leads to developmental abnormalities in Cl(-) transporter expression and GABAA receptor compositions in hippocampal neurons and that compromised maturation of GABAergic inhibition contributes to the abnormal synchrony in the hippocampus of tg absence epileptic mice.

Recognition memory and theta–gamma interactions in the hippocampus

Neuronal oscillations and cross-frequency interactions in the rat hippocampus relate in important ways to memory processes and serve as a model for studying oscillatory activity in cognition more broadly. We report here that hippocampal synchrony (CA3-CA1 coherence) increased markedly in the low gamma range as rats were exploring novel objects, particularly those for which the rat subsequently showed good memory. The gamma synchrony varied across phases of the theta rhythm such that coherence was highest at the falling slope and trough of the theta wave. Further, the shape of the theta wave was more asymmetric and elongated at the falling slope during exploration of objects for which the rat subsequently showed good memory as compared with objects for which the rat subsequently showed poor memory. The results showed a strong association between event-related gamma synchrony in rat hippocampus and memory encoding for novel objects. In addition, a novel potential mechanism of cross-frequency interactions was observed whereby dynamic alterations in the shape of theta wave related to memory in correspondence with the strength of gamma synchrony. These findings add to our understanding of how theta and gamma oscillations interact in the hippocampus in the service of memory.

Oscillatory coupling within neonatal prefrontal–hippocampal networks is independent of selective removal of GABAergic neurons in the hippocampus

GABAergic neurons have been proposed to control oscillatory entrainment and cognitive processing in prefrontal–hippocampal networks. Co-activation of these networks emerges already during neonatal development, with hippocampal theta bursts driving prefrontal oscillations via axonal projections. The cellular substrate of neonatal prefrontal–hippocampal communication and in particular, the role of GABAergic neurons, is still unknown. Here, we used saporin-conjugated anti-vesicular GABA transporter antibodies to cause selective immunotoxic lesion of GABAergic neurons in the CA1 area of the hippocampus during the first postnatal week. Without affecting the somatic development of rat pups, the lesion impaired the generation of hippocampal sharp waves, but not of theta bursts during neonatal development. Moreover, the oscillatory entrainment and firing of neonatal prefrontal cortex as well as the early prefrontal–hippocampal synchrony were largely independent of GABAergic neurotransmission in the hippocampus. Thus, hippocampal interneurons are critical elements for the ontogeny of hippocampal sharp waves, but seem to not control the directed oscillatory coupling between the neonatal prefrontal cortex and hippocampus.

Display of consistent ictal networks in refractory mesial temporal lobe epilepsy

ObjectiveExploration of emergent ictal networks was performed in homogeneous subjects with refractory medial temporal lobe epilepsy. MethodsMaximal Synchrony Index (SI) values were calculated for all electrode pairs for each second during 25 seizures and displayed as connectivity animations. Consistent temporal patterns of SI value and spatial connectivity were observed across seizures and subjects, and used to define a sequence of network stages. ResultsHighest SI values were found in electrodes within the area of surgical resection. Analysis of these electrodes by network stage demonstrated lateral temporal cortex dominance at seizure initiation, giving way to hippocampal synchrony during the major portion of the seizure, with lateral temporal regions re-emerging as the seizure terminated. SI values also corresponded to behavioral severity of seizures, and lower SI values were associated with post-surgical seizure freedom. ConclusionSI based methods of network characterization consistently display the intrinsic MTLE ictal network and may be sensitive to clinical features. SignificanceConsistency of EEG-derived network patterns is an important step as network features are applied towards improvement of clinical management. These data confirm consistency of network patterns within and across subjects and support the potential for these methods to distinguish relevant clinical variables.

Ih modulates theta rhythm and synchrony in computer model of CA3

Although the contributions of different hippocampal cell classes to oscillatory activity has been studied, the intrinsic membrane mechanisms contributing to the oscillations and neuronal synchronization are not well understood. The hyperpolarization-activated cation (HCN) channel is a voltage-gated ion channel potentially implicated in epilepsy. Ih, the current produced by HCN channels, plays an important role in regulating neuronal excitability, particularly in hippocampal and neocortical pyramidal neurons. Changes in HCN conductance have been associated with epilepsy, manifesting as discharges with aberrant synchrony [1]. In this study we investigated the role of Ih in pacing network oscillations and synchronizing activity. We studied the effects of modulating both the Ih time-constant and the Ih conductance level in a biophysical computer model of the CA3 region of the hippocampus using the NEURON simulator. Some of the manipulations could be realized in-vitro with pharmacological manipulation via the Ih blocker, ZD7288. Our network consisted of 800 five-compartment pyramidal cells, 200 one-compartment basket cell interneurons, and 200 one-compartment oriens lacunosum-moleculare (O-LM) interneurons. All cells contained leak current, transient sodium current and delayed rectifier current. Additionally, pyramidal cells contained potassium type A current and pyramidal and OLM cells had Ih current. Cell classes were interconnected probabilistically with AMPA/NMDA, and two classes of GABAA synapses. The O-LM cells formed synapses on the distal dendrites of pyramidal cells, while the basket cells synapsed proximally on pyramidal and other basket cells. Pyramidal cells synapsed on both types of interneurons with AMPA/NMDA synapses. All synapses were bombarded with external Poisson inputs to generate network activity. We used Kendall’s tau correlation to measure the synchrony between pairs of pyramidal cells and performed FFT analysis on local field potentials generated by the pyramidal cells to measure rhythmic activity. At baseline, OLM cells fired preferentially at the theta frequency, causing periodic inhibition/disinhibition of pyramidal cells [2]. Although lowering the Ih conductance of pyramidal cell distal dendrites did not change average firing rates of pyramidal cells, the delay to pyramidal cell synchronization increased. Delayed synchronization was associated with a delay in the emergence of pyramidal interneuron network gamma (PING; in PING, pyramidal cells drive basket cells via AMPA/NMDA receptors and basket cells in turn inhibit the pyramidal cells through GABAergic synapses). This mechanism depends on stabilization via pyramidal cell synchronization. Analysis of the simulated local field potential spectral power showed that Ih conductance level correlated with the peak theta rhythm, from ~6.5 - 8.5 Hz. Our model demonstrates that changes in conductance of HCN channels can modulate hippocampal network rhythms and synchrony. These effects could be tested in-vivo and in-vitro, under neuromodulatory or pharmacological control. Our model also predicts that hippocampal networks may become more prone towards epilepsy with alterations in the level of HCN channel expression.