Hippocampal Local Field Potentials Research Articles

Theta Phase Precession and the Dynamics of Spatiotemporal Asymmetry in Hippocampal Place Fields

A consistently observed characteristic of hippocampal place fields is the shifting of the field's center of mass and the subsequent development of asymmetry. This is evidenced by the expansion of the place field in an asymmetric manner over repeated traversals, wherein a rat's initial entry into the field prompts a low firing rate that substantially increases as it exits. Our study delves deeper into these spatiotemporal asymmetries of place field spiking, specifically examining their relationship with theta oscillations and disentangling the effects from environmental factors. Analysis of neuronal data from a T-maze alternation task revealed a distinct non-uniform firing pattern of place cells. This pattern was markedly skewed in relation to the phases of theta cycles, indicating a phase precession effect. We found that as the rat navigates through the place field, there is a systematic advancement of spike timing, with action potentials tending to cluster in the early phases of theta during the exit phase of the field. Such temporal coordination of spikes suggests that the timing of neural activity within theta cycles is as integral as spatial location, influencing the dynamics of place field expansion and potentially affecting the hippocampal local field potential. This discovery underscores the role of theta phase precession in spatial encoding, proposing a novel temporal component that could underpin the cognitive map within the hippocampus. R01 MH126236 R01 AG055544. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Analysis of hippocampal local field potentials by diffusion mapped delay coordinates

Spatial navigation through novel spaces and to known goal locations recruits multiple integrated structures in the mammalian brain. Within this extended network, the hippocampus enables formation and retrieval of cognitive spatial maps and contributes to decision making at choice points. Exploration and navigation to known goal locations produce synchronous activity of hippocampal neurons resulting in rhythmic oscillation events in local networks. Power of specific oscillatory frequencies and numbers of these events recorded in local field potentials correlate with distinct cognitive aspects of spatial navigation. Typically, oscillatory power in brain circuits is analyzed with Fourier transforms or short-time Fourier methods, which involve assumptions about the signal that are likely not true and fail to succinctly capture potentially informative features. To avoid such assumptions, we applied a method that combines manifold discovery techniques with dynamical systems theory, namely diffusion maps and Takens’ time-delay embedding theory, that avoids limitations seen in traditional methods. This method, called diffusion mapped delay coordinates (DMDC), when applied to hippocampal signals recorded from juvenile rats freely navigating a Y-maze, replicates some outcomes seen with standard approaches and identifies age differences in dynamic states that traditional analyses are unable to detect. Thus, DMDC may serve as a suitable complement to more traditional analyses of LFPs recorded from behaving subjects that may enhance information yield.

Sleep-slow oscillation-spindle coupling precedes spindle-ripple coupling during development.

Sleep supports systems memory consolidation through the precise temporal coordination of specific oscillatory events during slow-wave sleep, i.e. the neocortical slow oscillations (SOs), thalamic spindles, and hippocampal ripples. Beneficial effects of sleep on memory are also observed in infants, although the contributing regions, especially hippocampus and frontal cortex, are immature. Here, we examined in rats the development of these oscillatory events and their coupling during early life. EEG and hippocampal local field potentials were recorded during sleep in male rats at postnatal days (PD)26 and 32, roughly corresponding to early (1-2 years) and late (9-10 years) human childhood, and in a group of adult rats (14-18 weeks, corresponding to ~22-29 years in humans). SO and spindle amplitudes generally increased from PD26 to PD32. In parallel, frontocortical EEG spindles increased in density and frequency, while changes in hippocampal ripples remained nonsignificant. The proportion of SOs co-occurring with spindles also increased from PD26 to PD32. Whereas parietal cortical spindles were phase-locked to the depolarizing SO-upstate already at PD26, over frontal cortex SO-spindle phase-locking emerged not until PD32. Co-occurrence of hippocampal ripples with spindles was higher during childhood than in adult rats, but significant phase-locking of ripples to the excitable spindle troughs was observed only in adult rats. Results indicate a protracted development of synchronized thalamocortical processing specifically in frontocortical networks (i.e. frontal SO-spindle coupling). However, synchronization within thalamocortical networks generally precedes synchronization of thalamocortical with hippocampal processing as reflected by the delayed occurrence of spindle-ripple phase-coupling.

MTL neurons phase-lock to human hippocampal theta.

Memory formation depends on neural activity across a network of regions, including the hippocampus and broader medial temporal lobe (MTL). Interactions between these regions have been studied indirectly using functional MRI, but the bases for interregional communication at a cellular level remain poorly understood. Here, we evaluate the hypothesis that oscillatory currents in the hippocampus synchronize the firing of neurons both within and outside the hippocampus. We recorded extracellular spikes from 1854 single- and multi-units simultaneously with hippocampal local field potentials (LFPs) in 28 neurosurgical patients who completed virtual navigation experiments. A majority of hippocampal neurons phase-locked to oscillations in the slow (2-4 Hz) or fast (6-10 Hz) theta bands, with a significant subset exhibiting nested slow theta × beta frequency (13-20 Hz) phase-locking. Outside of the hippocampus, phase-locking to hippocampal oscillations occurred only at theta frequencies and primarily among neurons in the entorhinal cortex and amygdala. Moreover, extrahippocampal neurons phase-locked to hippocampal theta even when theta did not appear locally. These results indicate that spike-time synchronization with hippocampal theta is a defining feature of neuronal activity in the hippocampus and structurally connected MTL regions. Theta phase-locking could mediate flexible communication with the hippocampus to influence the content and quality of memories.

Postnatal Maturation of Membrane Potential Dynamics during in Vivo Hippocampal Ripples.

Sharp-wave ripples (SWRs) are transient high-frequency oscillations of local field potentials (LFPs) in the hippocampus and play a critical role in memory consolidation. During SWRs, CA1 pyramidal cells exhibit rapid spike sequences that often replay the sequential activity that occurred during behavior. This temporally organized firing activity gradually emerges during 2 weeks after the eye opening; however, it remains unclear how the organized spikes during SWRs mature at the intracellular membrane potential (Vm) level. Here, we recorded Vm of CA1 pyramidal cells simultaneously with hippocampal LFPs from anesthetized immature mice of either sex after the developmental emergence of SWRs. On postnatal days 16 and 17, Vm dynamics around SWRs were premature, characterized by prolonged depolarizations without either pre- or post-SWR hyperpolarizations. The biphasic hyperpolarizations, features typical of adult SWR-relevant Vm, formed by approximately postnatal day 30. This Vm maturation was associated with an increase in SWR-associated inhibitory inputs to pyramidal cells. Thus, the development of SWR-relevant inhibition restricts the temporal windows for spikes of pyramidal cells and allows CA1 pyramidal cells to organize their spike sequences during SWRs.SIGNIFICANCE STATEMENT Sharp-wave ripples (SWRs) are prominent hippocampal oscillations and play a critical role in memory consolidation. During SWRs, hippocampal neurons synchronously emit spikes with organized temporal patterns. This temporal structure of spikes during SWRs develops during the third and fourth postnatal weeks, but the underlying mechanisms are not well understood. Here, we recorded in vivo membrane potentials from hippocampal neurons in premature mice and suggest that the maturation of SWR-associated inhibition enables hippocampal neurons to produce precisely controlled spike times during SWRs.

Effects of theta phase precessing optogenetic intervention on hippocampal neuronal reactivation and spatial maps

As animals explore environments, hippocampal place cells sequentially fire at progressively earlier phases of theta oscillations in hippocampal local field potentials. In this study, we evaluated the network-level significance of theta phase-entrained neuronal activity in organizing place cell spike patterns. A closed-loop system was developed in which optogenetic stimulation with a temporal pattern replicating theta phase precession is delivered to hippocampal CA1 neurons when rats traversed a particular region on a linear track. Place cells that had place fields during phase precessing stimulation, but not random phase stimulation, showed stronger reactivation during hippocampal sharp-wave ripples in a subsequent rest period. After the rest period, place cells with place fields that emerged during phase precessing stimulation showed more stable place fields. These results imply that neuronal reactivation and stability of spatial maps are mediated by theta phase precession in the hippocampus.

Inhibition of ANXA2 activity attenuates epileptic susceptibility and GluA1 phosphorylation.

Annexin A2 (ANXA2) participates in the pathology of a variety of diseases. Nevertheless, the impact of ANXA2 on epilepsy remains to be clarified. Hence, the study aimed at investigating the underlying role of ANXA2 in epilepsy through behavioral, electrophysiological, and pathological analyses. It was found that ANXA2 was markedly upregulated in the cortical tissues of temporal lobe epilepsy patients (TLE), kainic acid (KA)-induced epilepsy mice, and in a seizure-like model in vitro. ANXA2 silencing in mice suppressed first seizure latency, number of seizures, and seizure duration in behavioral analysis. In addition, abnormal brain discharges were less frequent and shorter in the hippocampal local field potential (LFP) record. Furthermore, the results showed that the frequency of miniature excitatory postsynaptic currents was decreased in ANXA2 knockdown mice, indicating that the excitatory synaptic transmission is reduced. Co-immunoprecipitation (COIP) experiments demonstrated that ANXA2 interacted with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit GluA1. Moreover, ANXA2 knockdown decreased GluA1 expression on the cell surface and its phosphorylation onserine 831 and serine 845, related to the decreased phosphorylation levels mediated by protein kinases A and C (PKA and PKC). This study covers a previously unknown and key function of ANXA2 in epilepsy. These findings indicate that ANXA2 can regulate excitatory synaptic activity mediated by AMPAR subunit GluA1 to improve seizure activity, which can provide novel insights for the treatment and prevention of epilepsy.

TRPC4 Channel Knockdown in the Hippocampal CA1 Region Impairs Modulation of Beta Oscillations in Novel Context.

Hippocampal local field potentials (LFP) are highly related to behavior and memory functions. It has been shown that beta band LFP oscillations are correlated with contextual novelty and mnemonic performance. Evidence suggests that changes in neuromodulators, such as acetylcholine and dopamine, during exploration in a novel environment underlie changes in LFP. However, potential downstream mechanisms through which neuromodulators may alter the beta band oscillation in vivo remain to be fully understood. In this paper, we study the role of the membrane cationic channel TRPC4, which is modulated by various neuromodulators through G-protein-coupled receptors, by combining shRNA-mediated TRPC4 knockdown (KD) with LFP measurements in the CA1 region of the hippocampus in behaving mice. We demonstrate that the increased beta oscillation power seen in the control group mice in a novel environment is absent in the TRPC4 KD group. A similar loss of modulation was also seen in the low-gamma band oscillations in the TRPC4 KD group. These results demonstrate that TRPC4 channels are involved in the novelty-induced modulation of beta and low-gamma oscillations in the CA1 region.

Amyloid-β Protein Precursor Regulates Electrophysiological Properties in the Hippocampus via Altered Kv1.4 Expression and Function in Mice.

Amyloid-β protein precursor (AβPP) is enriched in neurons. However, the mechanism underlying AβPP regulation of neuronal activity is poorly understood. Potassium channels are critically involved in neuronal excitability. In hippocampus, A-type potassium channels are highly expressed and involved in determining neuronal spiking. We explored hippocampal local field potential (LFP) and spiking in the presence and absence of AβPP, and the potential involvement of an A-type potassium channel. We used in vivo extracellular recording and whole-cell patch-clamp recording to determine neuronal activity, current density of A-type potassium currents, and western blot to detect changes in related protein levels. Abnormal LFP was observed in AβPP-/- mice, including reduced beta and gamma power, and increased epsilon and ripple power. The firing rate of glutamatergic neurons reduced significantly, in line with an increased action potential rheobase. Given that A-type potassium channels regulate neuronal firing, we measured the protein levels and function of two major A-type potassium channels and found that the post-transcriptional level of Kv1.4, but not Kv4.2, was significantly increased in the AβPP-/- mice. This resulted in a marked increase in the peak time of A-type transient outward potassium currents in both glutamatergic and gamma-aminobutyric acid-ergic (GABAergic) neurons. Furthermore, a mechanistic experiment using human embryonic kidney 293 (HEK293) cells revealed that the AβPP deficiency-induced increase in Kv1.4 may not involve protein-protein interaction between AβPP and Kv1.4. This study suggests that AβPP modulates neuronal firing and oscillatory activity in the hippocampus, and Kv1.4 may be involved in mediating the modulation.

Accelerating Maturation of Spatial Memory Systems by Experience: Evidence from Sleep Oscillation Signatures of Memory Processing.

During early development, memory systems gradually mature over time, in parallel with the gradual accumulation of knowledge. Yet, it is unknown whether and to what extent maturation is driven by discrete experience. Sleep is thought to contribute to the formation of long-term memory and knowledge through a systems consolidation process that is driven by specific sleep oscillations (i.e., ripples, spindles, and slow oscillations) in cortical and hippocampal networks. Based on these oscillatory signatures, we show here in rats that discrete spatial experience speeds the functional maturation of spatial memory systems during development. Juvenile male rats were exposed for 5 min periods to changes in the spatial configuration of two identical objects on postnatal day (PD)25, PD27, and PD29 (Spatial experience group), while a Control group was exposed on these occasions to the same two objects without changing their positions. On PD31, both groups were tested on a classical Object Place Recognition (OPR) task with a 3 h retention interval during which the sleep-associated EEG and hippocampal local field potentials were recorded. On PD31, consistent with forgoing studies, Control rats still did not express OPR memory. By contrast, rats with Spatial experience formed significant OPR memory and, in parallel, displayed an increased percentage of hippocampal ripples coupled to parietal slow oscillation-spindle complexes, and a stronger ripple-spindle phase-locking during the retention sleep. Our findings support the idea that experience promotes the maturation of memory systems during development by enhancing cortico-hippocampal information exchange and the formation of integrated knowledge representations during sleep.SIGNIFICANCE STATEMENT Cognitive and memory capabilities mature early in life. We show here that and how discrete spatial experience contributes to this process. Using a simple recognition paradigm in developing rats, we found that exposure of the rat pups to three short-lasting experiences enhances spatial memory capabilities to adult-like levels. The adult-like capability of building spatial memory was connected to a more precise coupling of ripples in the hippocampus with slow oscillation-spindle complexes in the thalamo-cortical system when the memory was formed during sleep. Our findings support the view that discrete experience accelerates maturation of cognitive and memory capabilities by enhancing the dialogue between hippocampus and cortex when these experiences are reprocessed during sleep.

Ellagic acid alleviates motor, cognitive and hippocampal electrical activity deficits in the male rats with 2-vessel occlusion cerebral ischemia/reperfusion.

Cerebral ischemia/reperfusion (I/R) has been known as a major cause of inability and mortality worldwide. Ellagic acid (EA) has many pharmacological effects including antioxidant, antithrombotic and neurorestoration activities. The aim of this study was evaluation of the effects of EA on motor and cognitive behaviors, hippocampal local field potential (LFP), brain oxidative stress in male rats with cerebral 2-vessel occlusion ischemia/reperfusion (2VO I/R). Forty-eight male Wistar rats (250-300 g) were assigned into six groups. 1) The Sham: rats were treated with DMSO10%/normal saline as solvent of EA 3 times daily for 1 week; 2) I/R+Veh; I/R rats received vehicle; 3-5) EA-treated groups: I/R rats received 50, 75, or 100 mg/kg EA; and 6) Cont+EA100: intact rats received EA. The cerebral 2VO I/R was made by the bilateral common carotid arteries closing for 20 min followed by reperfusion. The behavioral tests and hippocampal LFP recording were performed after treatment with EA. The oxidative stress parameters were assayed by special ELISA kits. Cerebral 2VO I/R significantly decreased motor coordination, memory and hippocampal LFP and significantly increased oxidative stress. Treatment with EA improved all I/R complications. The current findings showed that treatment of I/R rats with EA could reverse cognitive and motor functions, and improve the LFP and oxidative stress markers. So, effects of EA on cognitive and motor function may at least in part, be due to its antioxidative actions.

Early Detection of Alzheimer's Disease from Cortical and Hippocampal Local Field Potentials using an Ensembled Machine Learning Model.

Early diagnosis of Alzheimer's disease (AD) is a very challenging problem and has been attempted through data-driven methods in recent years. However, considering the inherent complexity in decoding higher cognitive functions from spontaneous neuronal signals, these data-driven methods benefit from the incorporation of multimodal data. This work proposes an ensembled machine learning model with explainability (EXML) to detect subtle patterns in cortical and hippocampal local field potential signals (LFPs) that can be considered as a potential marker for AD in the early stage of the disease. The LFPs acquired from healthy and two types of AD animal models (n=10 each) using linear multielectrode probes were endorsed by electrocardiogram and respiration signals for their veracity. Feature sets were generated from LFPs in temporal, spatial and spectral domains and were fed into selected machine-learning models for each domain. Using late fusion, the EXML model achieved an overall accuracy of 99.4%. This provided insights into the amyloid plaque deposition process as early as 3 months of the disease onset by identifying the subtle patterns in the network activities. Lastly, the individual and ensemble models were found to be robust when evaluated by randomly masking channels to mimic the presence of artefacts.

Behaviourally modulated hippocampal theta oscillations in the ferret persist during both locomotion and immobility

Theta oscillations are a hallmark of hippocampal activity across mammals and play a critical role in many hippocampal models of memory and spatial navigation. To reconcile the cross-species differences observed in the presence and properties of theta, we recorded hippocampal local field potentials in rats and ferrets during auditory and visual localisation tasks designed to vary locomotion and sensory attention. Here, we show that theta oscillations occur during locomotion in both ferrets and rats, however during periods of immobility, theta oscillations persist in the ferret, contrasting starkly with the switch to large irregular activity (LIA) in the rat. Theta during immobility in the ferret is identified as analogous to Type 2 theta that has been observed in rodents due to its sensitivity to atropine, and is modulated by behavioural state with the strongest theta observed during reward epochs. These results demonstrate that even under similar behavioural conditions, differences exist between species in the relationship between theta and behavioural state.

Muscarinic and N-methyl-D-aspartate receptor blockade reveal differences in hippocampal local field potentials in mice with low cholinergic tone.

We hypothesize that hippocampal local field potentials in acetylcholine (ACh)-deficient mutant mice, compared to wild-type (WT) mice, will show lower sensitivity to muscarinic cholinergic antagonist scopolamine (5mg/kg i.p.) but higher sensitivity to NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP, 10mg/kg i.p.). Recordings were made during walk and awake-immobility (IMM) in WT mice, and in mice with forebrain knockout (KO) of the vesicular acetylcholine transporter (VAChT) gene, or heterozygous knockdown of VAChT gene (KD). Scopolamine or CPP did not significantly alter walk theta frequency, which was higher in KD than WT/KO mice. Scopolamine decreased theta power peak rise during walk in WT/KD mice but not in KO mice, while CPP suppressed theta peak rise more in WT/KO mice than KD mice. During IMM, scopolamine decreased gamma1 (γ1, 30-58 Hz) power more in KD/WT mice than KO mice, while delta (1-4Hz) power and delta-gamma cross-frequency coherence (CFC) were increased in all mouse groups during IMM or walk. During walk, scopolamine increased delta and beta (13-30 Hz) power and decreased gamma2 (γ2, 62-100 Hz) power and theta-γ2 CFC more in WT/KD than KO mice. Theta-γ2, but not theta-γ1, CFC increased with theta-peak-frequency in WT/KD mice, and was suppressed by scopolamine at high theta (8-10Hz) frequency; theta-γ2 CFC in KO mice was not significantly altered by scopolamine. CPP decreased beta and gamma power more in KD/KO mice compared to WT mice, while delta power and delta-gamma CFC were increased in all mouse groups. ACh deficiency exacerbates the attenuation of beta and gamma power by CPP. We conclude that both muscarinic and NMDA transmission contribute toward hippocampal theta, beta, and gamma power, and a decrease in gamma power or theta-gamma CFC may be associated with loss of arousal and cognitive functions.

Huygens synchronization of medial septal pacemaker neurons generates hippocampal theta oscillation.

Episodic learning and memory retrieval are dependent on hippocampal theta oscillation, thought to rely on the GABAergic network of the medial septum (MS). To test how this network achieves theta synchrony, we recorded MS neurons and hippocampal local field potential simultaneously in anesthetized and awake mice and rats. We show that MS pacemakers synchronize their individual rhythmicity frequencies, akin to coupled pendulum clocks as observed by Huygens. We optogenetically identified them as parvalbumin-expressing GABAergic neurons, while MS glutamatergic neurons provide tonic excitation sufficient to induce theta. In accordance, waxing and waning tonic excitation is sufficient to toggle between theta and non-theta states in a network model of single-compartment inhibitory pacemaker neurons. These results provide experimental and theoretical support to a frequency-synchronization mechanism for pacing hippocampal theta, which may serve as an inspirational prototype for synchronization processes in the central nervous system from Nematoda to Arthropoda to Chordate and Vertebrate phyla.

Theta rhythmicity governs human behavior and hippocampal signals during memory-dependent tasks

Memory formation and reinstatement are thought to lock to the hippocampal theta rhythm, predicting that encoding and retrieval processes appear rhythmic themselves. Here, we show that rhythmicity can be observed in behavioral responses from memory tasks, where participants indicate, using button presses, the timing of encoding and recall of cue-object associative memories. We find no evidence for rhythmicity in button presses for visual tasks using the same stimuli, or for questions about already retrieved objects. The oscillations for correctly remembered trials center in the slow theta frequency range (1-5 Hz). Using intracranial EEG recordings, we show that the memory task induces temporally extended phase consistency in hippocampal local field potentials at slow theta frequencies, but significantly more for remembered than forgotten trials, providing a potential mechanistic underpinning for the theta oscillations found in behavioral responses.

Sevoflurane Increases Hippocampal Theta Oscillations and Impairs Memory Via TASK-3 Channels.

Sevoflurane can induce memory impairment during clinical anesthesia; however, the underlying mechanisms are largely unknown. TASK-3 channels are one of the potential targets of sevoflurane. Accumulating evidence supports a negative role of intracranial theta rhythms (4–12 Hz) in memory formation. Here, we investigated whether TASK-3 channels contribute to sevoflurane-induced memory impairment by regulating hippocampal theta rhythms. In this study, the memory performance of mice was tested by contextual fear conditioning and inhibitory avoidance experiments. The hippocampal local field potentials (LFPs) were recorded from chronically implanted electrodes located in CA3 region. The results showed that sevoflurane concentration-dependently impaired the memory function of mice, as evidenced by the decreased time mice spent on freezing and reduced latencies for mice to enter the shock compartment. Our electrophysiological results revealed that sevoflurane also enhanced the spectral power of hippocampal LFPs (1–30 Hz), particularly in memory-related theta rhythms (4–12 Hz). These effects were mitigated by viral-mediated knockdown of TASK-3 channels in the hippocampal CA3 region. The knockdown of hippocampal TASK-3 channels significantly reduced the enhancing effect of sevoflurane on hippocampal theta rhythms and alleviated sevoflurane-induced memory impairment. Our data indicate that sevoflurane can increase hippocampal theta oscillations and impair memory function via TASK-3 channels.

G-alpha interacting protein interacting protein, C terminus 1 regulates epileptogenesis by increasing the expression of metabotropic glutamate receptor 7.

AimsIt has been reported that the G‐alpha interacting protein (GAIP) interacting protein, C terminus 1 (GIPC1/GIPC) engages in vesicular trafficking, receptor transport and expression, and endocytosis. However, its role in epilepsy is unclear. Therefore, in this study, we aimed to explore the role of GIPC1 in epilepsy and its possible underlying mechanism.MethodsThe expression patterns of GIPC1 in patients with temporal lobe epilepsy (TLE) and in mice with kainic acid (KA)‐induced epilepsy were detected. Behavioral video monitoring and hippocampal local field potential (LFP) recordings were carried out to determine the role of GIPC1 in epileptogenesis after overexpression of GIPC1. Coimmunoprecipitation (Co‐IP) assay and high‐resolution immunofluorescence staining were conducted to investigate the relationship between GIPC1 and metabotropic glutamate receptor 7 (mGluR7). In addition, the expression of mGluR7 after overexpression of GIPC1 was measured, and behavioral video monitoring and LFP recordings after antagonism of mGluR7 were performed to explore the possible mechanism mediated by GIPC1.ResultsGIPC1 was downregulated in the brain tissues of patients with TLE and mice with KA‐induced epilepsy. After overexpression of GIPC1, prolonged latency period, decreased epileptic seizures and reduced seizure severity in behavioral analyses, and fewer and shorter abnormal brain discharges in LFP recordings of KA‐induced epileptic mice were observed. The result of the Co‐IP assay showed the interaction between GIPC1 and mGluR7, and the high‐resolution immunofluorescence staining also showed the colocalization of these two proteins. Additionally, along with GIPC1 overexpression, the total and cell membrane expression levels of mGluR7 were also increased. And after antagonism of mGluR7, increased epileptic seizures and aggravated seizure severity in behavioral analyses and more and longer abnormal brain discharges in LFP recordings were observed.ConclusionGIPC1 regulates epileptogenesis by interacting with mGluR7 and increasing its expression.

Sharp-Wave Ripple Frequency and Interictal Epileptic Discharges Increase in Tandem During Thermal Induction of Seizures in a Mouse Model of Genetic Epilepsy.

Dravet Syndrome (DS) is a genetic, infantile-onset epilepsy with refractory seizures and severe cognitive impairment. While network level pathophysiology is poorly understood, work in genetic mouse models of DS reveals selective reduction of inhibitory interneuron excitability, a likely mechanism of seizures and comorbidities. Consistent with the critical role of interneurons in timing and recruitment of network activity, hippocampal sharp wave ripples (SPW-R)—interneuron dependent compound brain rhythms essential for spatial learning and memory—are less frequent and ripple frequency is slower in DS mice, both likely to impair cognitive performance. Febrile seizures are characteristic of DS, reflecting a temperature-dependent shift in excitation–inhibition balance. DS interneurons are sensitive to depolarization block and may fall silent with increased excitation precipitating epileptic transformation of ripples. To determine the temperature dependence of SWP-R features and relationship of SPW-R to hippocampal interictal activity, we recorded hippocampal local field potentials in a DS mouse model and wildtype littermate controls while increasing core body temperature. In both genotypes, temperature elevation speeds ripple frequency, although DS ripples remain consistently slower. The rate of SPW-R also increases in both genotypes but subsequently falls in DS mice as interictal epileptic activity simultaneously increases preceding a thermally-evoked seizure. Epileptic events occur intermixed with SPW-R, some during SPW-R burst complexes, and transiently suppress SPW-R occurrence suggesting shared network elements. Together these data demonstrate a temperature dependence of SPW-R rate and ripple frequency and suggest a pathophysiologic mechanism by which elevated temperature transforms a normal brain rhythm into epileptic event.

Spectrum Degradation of Hippocampal LFP During Euthanasia.

The hippocampal local field potential (LFP) exhibits a strong correlation with behavior. During rest, the theta rhythm is not prominent, but during active behavior, there are strong rhythms in the theta, theta harmonics, and gamma ranges. With increasing running velocity, theta, theta harmonics and gamma increase in power and in cross-frequency coupling, suggesting that neural entrainment is a direct consequence of the total excitatory input. While it is common to study the parametric range between the LFP and its complementing power spectra between deep rest and epochs of high running velocity, it is also possible to explore how the spectra degrades as the energy is completely quenched from the system. Specifically, it is unknown whether the 1/f slope is preserved as synaptic activity becomes diminished, as low frequencies are generated by large pools of neurons while higher frequencies comprise the activity of more local neuronal populations. To test this hypothesis, we examined rat LFPs recorded from the hippocampus and entorhinal cortex during barbiturate overdose euthanasia. Within the hippocampus, the initial stage entailed a quasi-stationary LFP state with a power-law feature in the power spectral density. In the second stage, there was a successive erosion of power from high- to low-frequencies in the second stage that continued until the only dominant remaining power was <20 Hz. This stage was followed by a rapid collapse of power spectrum toward the absolute electrothermal noise background. As the collapse of activity occurred later in hippocampus compared with medial entorhinal cortex, it suggests that the ability of a neural network to maintain the 1/f slope with decreasing energy is a function of general connectivity. Broadly, these data support the energy cascade theory where there is a cascade of energy from large cortical populations into smaller loops, such as those that supports the higher frequency gamma rhythm. As energy is pulled from the system, neural entrainment at gamma frequency (and higher) decline first. The larger loops, comprising a larger population, are fault-tolerant to a point capable of maintaining their activity before a final collapse.