Feed-forward and feed-back activation of the dentate gyrus in vivo during dentate spikes and sharp wave bursts

Intermittently occurring field events, dentate spikes (DS), and sharp waves (SPW) in the hippocampus reflect population synchrony of principal cells and interneurons along the entorhinal cortex-hippocampus axis. We have investigated the cellular-synaptic generation of DSs and SPWs by intracellular recording from granule cells, pyramidal cells, and interneurons in anesthetized rats. The recorded neurons were anatomically identified by intracellular injection of biocytin. Extracellular recording electrodes were placed in the hilus to record field DSs and multiple units and in the CA1 pyramidal cell layer to monitor SPW-associated fast field oscillations (ripples) and unit activity. DSs were associated with large depolarizing potentials in granule cells, but they rarely discharged action potentials. When they were depolarized slightly with intracellular current injection, bursts of action potentials occurred concurrently with extracellularly recorded DSs. Two interneurons in the hilar region were also found to discharge preferentially with DSs. In contrast, CA1 pyramidal cells, recorded extracellularly and intracellularly, were suppressed during DSs. In association with field SPWs, extracellular recordings from the CA1 pyramidal layer and the hilar region revealed synchronous bursting of these cell populations. Intracellular recordings from CA3 and CA1 pyramidal cells, granule cells, and from a single CA3 region interneuron revealed SPW-concurrent depolarizing potentials and action potentials. These findings suggest that granule cells may be discharged anterogradely by entorhinal input or retrogradely by the CA3-mossy cell feedback pathway during DSs and SPWs, respectively. Although both of these intermittent population patterns can activate granule cells, the impact of DSs and SPWs is diametrically opposite on the rest of the hippocampal circuitry. Entorhinal cortex activation of the granule cells during DSs induces a transient decrease in the hippocampal output, whereas during SPW bursts every principal cell population of the hippocampal formation may be recruited into the population event. Hippocampus 7:437–450, 1997. © 1997 Wiley-Liss, Inc.     

Intrinsic membrane properties determine hippocampal differential firing pattern in vivo in anesthetized rats

The hippocampus plays a key role in learning and memory. Previous studies suggested that the main types of principal neurons, dentate gyrus granule cells (GCs), CA3 pyramidal neurons, and CA1 pyramidal neurons, differ in their activity pattern, with sparse firing in GCs and more frequent firing in CA3 and CA1 pyramidal neurons. It has been assumed but never shown that such different activity may be caused by differential synaptic excitation. To test this hypothesis, we performed high‐resolution whole‐cell patch‐clamp recordings in anesthetized rats in vivo. In contrast to previous in vitro data, both CA3 and CA1 pyramidal neurons fired action potentials spontaneously, with a frequency of ～3–6 Hz, whereas GCs were silent. Furthermore, both CA3 and CA1 cells primarily fired in bursts. To determine the underlying mechanisms, we quantitatively assessed the frequency of spontaneous excitatory synaptic input, the passive membrane properties, and the active membrane characteristics. Surprisingly, GCs showed comparable synaptic excitation to CA3 and CA1 cells and the highest ratio of excitation versus hyperpolarizing inhibition. Thus, differential synaptic excitation is not responsible for differences in firing. Moreover, the three types of hippocampal neurons markedly differed in their passive properties. While GCs showed the most negative membrane potential, CA3 pyramidal neurons had the highest input resistance and the slowest membrane time constant. The three types of neurons also differed in the active membrane characteristics. GCs showed the highest action potential threshold, but displayed the largest gain of the input‐output curves. In conclusion, our results reveal that differential firing of the three main types of hippocampal principal neurons in vivo is not primarily caused by differences in the characteristics of the synaptic input, but by the distinct properties of synaptic integration and input‐output transformation. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Resonance properties of different neuronal populations in the immature mouse neocortex

In vivo recordings in the immature neocortex revealed spontaneous and sensory‐driven oscillatory activity from delta (0.5–4 Hz) to gamma (30–100 Hz) frequencies. In order to investigate whether the resonance properties of distinct neuronal populations in the immature neocortex contribute to these network oscillations, we performed whole‐cell patch‐clamp recordings from visually identified neurons in tangential and coronal neocortical slices from postnatal day (P)0–P7 C57Bl/6 mice. Subthreshold resonance was analysed by sinusoidal current injection of varying frequency. All Cajal–Retzius cells showed subthreshold resonance, with an average frequency of 2.6 ± 0.1 Hz (n = 60), which was massively reduced by ZD7288, a blocker of hyperpolarization‐activated cation currents. Approximately 65.6% (n = 61) of the supragranular pyramidal neurons showed subthreshold resonance, with an average frequency of 1.4 ± 0.1 Hz (n = 40). Application of Ni²⁺ suppressed subthreshold resonance, suggesting that low‐threshold calcium currents contribute to resonance in these neurons. Approximately 63.6% (n = 77) of the layer V pyramidal neurons showed subthreshold resonance, with an average frequency of 1.4 ± 0.2 Hz (n = 49), which was abolished by ZD7288. Only 44.1% (n = 59) of the subplate neurons showed subthreshold resonance, with an average frequency of 1.3 ± 0.2 Hz (n = 26) and a small resonance strength. In summary, these results demonstrate that neurons in all investigated layers show resonance behavior, with either hyperpolarization‐activated cation or low‐threshold calcium currents contributing to the subthreshold resonance. The observed resonance frequencies are in the range of slow activity patterns observed in the immature neocortex, suggesting that subthreshold resonance may support the generation of this activity.     

Intrinsic subthreshold oscillations of the membrane potential in pyramidal neurons of the olfactory amygdala

The amygdala complex is a heterogeneous group of temporal lobe brain structures involved in the processing of biologically significant sensory stimuli and in the generation of appropriate responses to them. The amygdala has also been implicated in certain forms of emotional learning and memory. While much progress has been made in understanding neural processing in the basolateral subgroup of the amygdala, physiological studies in the cortical regions of the complex, also known as olfactory amygdala, are missing. Using a rat brain slice preparation, we conducted whole-cell recordings on pyramidal neurons of the periamygdaloid cortex and the anterior cortical nucleus, two structures receiving direct connections from the olfactory bulb. Upon depolarization by current injection through the recording electrode, a fraction of periamygdaloid cortex and most anterior cortical nucleus layer II pyramidal neurons displayed an intermittent discharge pattern, where clusters of action potentials were interspersed by periods of membrane potential subthreshold oscillations. Oscillations frequency increased with membrane potential and correlated linearly with the cluster spiking frequency. Frequency ranged from 3 to 20 Hz, considering different cells and membrane potential values (up to approximately 30 mV above resting potentials of typically approximately -70 mV). Subthreshold oscillations were preserved after pharmacological inhibition of fast excitatory and inhibitory synaptic transmission, but were abolished by application of the sodium channel blocker tetrodotoxin. We conclude that pyramidal neurons of the olfactory cortical amygdala display intrinsically generated voltage-dependent membrane potential rhythmic fluctuations in the theta-low beta range, requiring the activation of a sodium conductance.     

Activity dynamics and behavioral correlates of CA3 and CA1 hippocampal pyramidal neurons

The CA3 and CA1 pyramidal neurons are the major principal cell types of the hippocampus proper. The strongly recurrent collateral system of CA3 cells and the largely parallel‐organized CA1 neurons suggest that these regions perform distinct computations. However, a comprehensive comparison between CA1 and CA3 pyramidal cells in terms of firing properties, network dynamics, and behavioral correlations is sparse in the intact animal. We performed large‐scale recordings in the dorsal hippocampus of rats to quantify the similarities and differences between CA1 (n > 3,600) and CA3 (n > 2,200) pyramidal cells during sleep and exploration in multiple environments. CA1 and CA3 neurons differed significantly in firing rates, spike burst propensity, spike entrainment by the theta rhythm, and other aspects of spiking dynamics in a brain state‐dependent manner. A smaller proportion of CA3 than CA1 cells displayed prominent place fields, but place fields of CA3 neurons were more compact, more stable, and carried more spatial information per spike than those of CA1 pyramidal cells. Several other features of the two cell types were specific to the testing environment. CA3 neurons showed less pronounced phase precession and a weaker position versus spike‐phase relationship than CA1 cells. Our findings suggest that these distinct activity dynamics of CA1 and CA3 pyramidal cells support their distinct computational roles. © 2012 Wiley Periodicals, Inc.     

Computational model of carbachol-induced delta, theta, and gamma oscillations in the hippocampus.

Field potential recordings from the rat hippocampus in vivo contain distinct frequency bands of activity, including delta (0.5-2 Hz), theta (4-12 Hz), and gamma (30-80 Hz), that are correlated with the behavioral state of the animal. The cholinergic agonist carbachol (CCH) induces oscillations in the delta (CCH-delta), theta (CCH-theta), and gamma (CCH-gamma) frequency ranges in the hippocampal slice preparation, eliciting asynchronous CCH-theta, synchronous CCH-delta, and synchronous CCH-theta with increasing CCH concentration (Fellous and Seinowski, Hippocampus 2000;1 0:187-197). In a network model of area CA3, the time scale for CCH-delta corresponded to the decay constant of the gating variable of the calcium-dependent potassium (K-AHP) current, that of CCH-theta to an intrinsic subthreshold membrane potential oscillation of the pyramidal cells, and that of CCH-gamma to the decay constant of GABAergic inhibitory synaptic potentials onto the pyramidal cells. In model simulations, the known physiological effects of carbachol on the muscarinic and K-AHP currents, and on the strengths of excitatory postsynaptic potentials, reproduced transitions from asynchronous CCH-theta to CCH-delta and from CCH-delta to synchronous CCH-theta. The simulations also exhibited the interspersed CCH-gamma/CCH-delta and CCH-gamma/CCH-theta that were observed in experiments. The model, in addition, predicted an oscillatory state with all three frequency bands present, which has not yet been observed experimentally.     

Synchronization of GABAergic interneuronal networks during seizure-like activity in the rat horizontal hippocampal slice

We studied the contribution of GABAergic (gamma-aminobutyric acid) neurotransmission to epileptiform activity using the horizontal hippocampal rat brain slice. Seizure-like (ictal) activity was evoked in the CA1 area by applying high-frequency trains (80 Hz for 2 s) to the Schaffer collaterals. Whole-cell recordings from stratum oriens-alveus interneurons revealed burst firing with superimposed high-frequency spiking which was synchronous with field events and pyramidal cell firing during ictal activity. On the other hand, interictal interneuronal bursts were synchronous with large-amplitude inhibitory postsynaptic potentials (IPSPs) in pyramidal cells. Excitatory and inhibitory postsynaptic potentials were simultaneously received by pyramidal neurons during the ictal afterdischarge, and were synchronous with interneuronal bursting and field potential ictal events. The GABAA receptor antagonist bicuculline greatly reduced the duration of the ictal activity in the CA1 layer, and evoked rhythmic interictal synchronous bursting of interneurons and pyramidal cells. With intact GABAergic transmission, interictal field potential events were synchronous with large amplitude IPSPs (9.8 +/- 2.4 mV) in CA1 pyramidal cells, and with interneuronal bursting. Simultaneous dual recordings revealed synchronous IPSPs received by widely separated pyramidal neurons during ictal and interictal periods, indicative of widespread interneuronal firing synchrony throughout the hippocampus. CA3 pyramidal neurons fired in synchrony with interictal field potential events recorded in the CA1 layer, and glutamate receptor antagonists abolished interictal interneuronal firing and synchronous large amplitude IPSPs received by CA1 pyramidal cells. These observations provide evidence that the interneuronal network may be entrained in hyperexcitable states by GABAergic and glutamatergic mechanisms.     

High-frequency synaptic input contributes to seizure initiation in the low-[Mg2+] model of epilepsy

High-frequency field potential activity between 50 and 400 Hz occurs throughout seizure-like events recorded from the CA3 region of juvenile rat hippocampal slices under low-[Mg(2+)] condition. Another (400-800 Hz) component occurred mainly during preictal paroxysmal spiking and the onsets of seizure-like events (97%) and less frequently during tonic and clonic phases (38% and 70%, respectively). Short epochs of oscillations in this range were associated with fast negative field potential deflections at the start of field potential transients. Voltage-clamp recordings from putative CA3 pyramidal cells showed the occurrence of synaptic inputs in the same frequency range at the onset of seizure-like events and the beginning of preictal or clonic paroxysmal spikes, while the frequency of action potentials never reached that range. The amplitude of fast negative field potential deflection, the rise time of membrane potential or voltage-clamp current changes and the mean phase coherence were consistent with an increase of synchronization towards the onset of a seizure-like event. Their parallel changes indicate the involvement of both synaptic and nonsynaptic mechanisms in the synchronization of neuronal activity and the development of seizure-like events in the low-[Mg(2+)] model of epilepsy.     

Inhibiting cholesterol degradation induces neuronal sclerosis and epileptic activity in mouse hippocampus

Elevations in neuronal cholesterol have been associated with several degenerative diseases. An enhanced excitability and synchronous firing in surviving neurons are among the sequels of neuronal death in these diseases and also in some epileptic syndromes. Here, we attempted to increase neuronal cholesterol levels, using a short hairpin RNA to suppress expression of the enzyme cytochrome P450 family 46, subfamily A, polypeptide 1 gene (CYP46A1). This protein hydroxylates cholesterol and so facilitates transmembrane extrusion. A short hairpin RNA CYP46A1construction coupled to the adeno‐associated virus type 5 was injected focally and unilaterally into mouse hippocampus. It was selectively expressed first in neurons of the cornu ammonis (hippocampus) (CA)3a region. Cytoplasmic and membrane cholesterol increased, and the neuronal soma volume increased and then decreased before pyramidal cells died. As CA3a pyramidal cells died, interictal electroencephalographic (EEG) events occurred during exploration and non‐rapid eye movement sleep. With time, neuronal death spread to involve pyramidal cells and interneurons of the CA1 region. CA1 neuronal death was correlated with a delayed local expression of phosphorylated tau. Astrocytes were activated throughout the hippocampus and microglial activation was specific to regions of neuronal death. CA1 neuronal death was correlated with distinct aberrant EEG activity. During exploratory behaviour and rapid eye movement sleep, EEG oscillations at 7–10 Hz (theta) could accelerate to 14–21 Hz (beta) waves. They were accompanied by low‐amplitude, high‐frequency oscillations of peak power at ~300 Hz and a range of 250–350 Hz. Although episodes of EEG acceleration were not correlated with changes in exploratory behaviour, they were followed in some animals by structured seizure‐like discharges. These data strengthen links between increased cholesterol, neuronal sclerosis and epileptic behaviour.     

Intrinsic subthreshold oscillations extend the influence of inhibitory synaptic inputs on cortical pyramidal neurons

Fast inhibitory synaptic inputs, which cause conductance changes that typically last for 10–100 ms, participate in the generation and maintenance of cortical rhythms. We show here that these fast events can have influences that outlast the duration of the synaptic potentials by interacting with subthreshold membrane potential oscillations. Inhibitory postsynaptic potentials (IPSPs) in cortical neurons in vitro shifted the oscillatory phase for several seconds. The phase shift caused by two IPSPs or two current pulses summed non‐linearly. Cholinergic neuromodulation increased the power of the oscillations and decreased the magnitude of the phase shifts. These results show that the intrinsic conductances of cortical pyramidal neurons can carry information about inhibitory inputs and can extend the integration window for synaptic input.     

Stochastic resonance in the hippocampal CA3–CA1 model: a possible memory recall mechanism

Stochastic resonance (SR) in a hippocampal network model was investigated. The hippocampal model consists of two layers, CA3 and CA1. Pyramidal cells in CA3 are connected to pyramidal cells in CA1 through Schaffer collateral synapses. The CA3 network causes spontaneous irregular activity (broadband spectrum peaking at around 3 Hz), while the CA1 network does not. The activity of CA3 causes membrane potential fluctuations in CA1 pyramidal cells. The CA1 network also receives a subthreshold signal (2.5 or 50 Hz) through the perforant path (PP). The subthreshold PP signals can fire CA1 pyramidal cells in cooperation with the membrane potential fluctuations that work as noise. The firing of the CA1 network shows typical features of SR. When the frequency of the PP signal is in the gamma range (50 Hz), SR that takes place in the present model shows distinctive features. 50 Hz firing of CA1 pyramidal cells is modulated by the membrane potential fluctuations, resulting in bursts. Such burst firing in the CA1 network, which resembles the firing patterns observed in the real hippocampal CA1, improves performance of subthreshold signal detection in CA1. Moreover, memory embedded at Schaffer collateral synapses can be recalled by means of SR. When Schaffer collateral synapses in subregions of CA1 are augmented three-fold as a memory pattern, pyramidal cells in the subregions respond to the subthreshold PP signal due to SR, while pyramidal cells in the rest of CA1 do not fire.     

A model of gamma-frequency network oscillations induced in the rat CA3 region by carbachol in vitro

Carbachol (> 20 microM) and kainate (100 nM) induce, in the in vitro CA3 region, synchronized neuronal population oscillations at approximately 40 Hz having distinctive features: (i) the oscillations persist for hours; (ii) interneurons in kainate fire at 5-20 Hz and their firing is tightly locked to field potential maxima (recorded in s. radiatum); (iii) in contrast, pyramidal cells, in both carbachol and kainate, fire at frequencies as low as 2 Hz, and their firing is less tightly locked to field potentials; (iv) the oscillations require GABAA receptors, AMPA receptors and gap junctions. Using a network of 3072 pyramidal cells and 384 interneurons (each multicompartmental and containing a segment of unmyelinated axon), we employed computer simulations to examine conditions under which network oscillations might occur with the experimentally determined properties. We found that such network oscillations could be generated, robustly, when gap junctions were located between pyramidal cell axons, as suggested to occur based on studies of spontaneous high-frequency (> 100 Hz) network oscillations in the in vitro hippocampus. In the model, pyramidal cell somatic firing was not essential for the oscillations. Critical components of the model are (i) the plexus of pyramidal cell axons, randomly and sparsely interconnected by gap junctions; (ii) glutamate synapses onto interneurons; (iii) synaptic inhibition between interneurons and onto pyramidal cell axons and somata; (iv) a sufficiently high rate of spontaneous action potentials generated in pyramidal cell axons. This model explains the dependence of network oscillations on GABA(A) and AMPA receptors, as well as on gap junctions. Besides the existence of axon-axon gap junctions, the model predicts that many of the pyramidal cell action potentials, during sustained gamma oscillations, are initiated in axons.     

Subthreshold delta‐frequency resonance in thalamic reticular neurons

The thalamic reticular nucleus (nRt) is an assembly of GABAergic projection neurons that participate in the generation of brain rhythms during synchronous sleep and absence epilepsy. NRt cells receive inhibitory and excitatory synaptic inputs, and are endowed with an intricate set of intrinsic conductances. However, little is known about how intrinsic and synaptic properties interact to generate rhythmic discharges in these neurons. In order to better understand this interaction, I studied the subthreshold responses of nRt cells to time‐varying inputs. Patch‐clamp recordings were performed in acute slices of rat thalamus (postnatal days 12–21). Sinusoidal current waveforms of linearly changing frequencies were injected into the soma, and the resulting voltage oscillations were recorded. At the resting membrane potential, the impedance profile showed a characteristic resonance at 1.7 Hz. The relative strength of the resonance was 1.2, and increased with membrane hyperpolarization. Small suprathreshold current injections led to preferred spike generation at the resonance frequency. Bath application of ZD7288 or Cs⁺, inhibitors of the hyperpolarization‐activated cation current (I_h), transformed the resonance into low‐pass behaviour, whereas the T‐channel blockers mibefradil and Ni²⁺ decreased the strength of the resonance. It is concluded that nRt cells have an I_h‐mediated intrinsic frequency preference in the subthreshold voltage range that favours action potential generation in the delta‐frequency band.     

The Entorhinal Cortex Entrains Fast CA1 Hippocampal Oscillations in the Anaesthetized Guinea-pig: Role of the Monosynaptic Component of the Perforant Path

Entorhinal inputs reach the hippocampal CA1 field through a trisynaptic circuit involving dentate granule cells and CA3 pyramidal neurons, as well as through a monosynaptic path ending on the distal apical dendrites of CA1 pyramidal cells. The influence of monosynaptic entorhinal inputs onto CA1 operations is poorly understood. In this study, we characterized the involvement of the monosynaptic pathway in the generation of the fast CA1 oscillation bursts (30–60 Hz) that occur in the dorsal hippocampus of anaesthetized guinea-pigs after partial cortex removal. Using multiple-site extracellular and intracellular recording, we found that in this particular preparation, devoid of theta rhythm, fast oscillations are temporally coherent over a large portion of the CA1 region along the hippocampal septotemporal axis. Current source density analysis revealed that fast CA1 oscillations involve two dipoles reflecting synchronous synaptic activities in the stratum lacunosum-moleculare of the hippocampus proper and in the stratum moleculare of the dentate gyrus. These layers constitute the two major termination zones of entorhinal afferents, suggesting that the entorhinal cortex entrains fast CA1 oscillations. This hypothesis was corroborated by the concomitant occurrence of fast oscillation bursts in the entorhinal cortex and CA1 region. Furthermore, fast CA1 oscillations were abolished by lidocaine or tetrodotoxin injections in the entorhinal cortex. Finally, acute interruption of the hippocampal trisynaptic loop did not affect the stratum lacunosum-moleculare dipole recorded extracellularly, but also intracellularly, as high-frequency postsynaptic potentials in CA1 pyramidal cells. These results indicate that the monosynaptic pathway is involved in the genesis of fast CA1 oscillations.     

Tetanic stimulation of schaffer collaterals induces rhythmic bursts via NMDA receptor activation in rat CA1 pyramidal neurons

Exploring the principles that regulate rhythmic membrane potential (Vm) oscillations and bursts in hippocampal CA1 pyramidal neurons is essential to understanding the theta rhythm (theta). Recordings were performed in vitro in hippocampal slices from young rats, and a group of the recorded CA1 pyramidal cells were dye-filled with carboxifluorescein and immunolabeled for the R1 subunit of the NMDA receptor. Tetanic stimulation of Schaffer collaterals (SCs) and iontophoresis of glutamate evoked rhythmic Vm oscillations and bursts (approximately 10 mV, approximately 7 Hz, 2-5 spikes per burst) in cells (31%) placed close to the midline ("medial cells"). Rhythmic bursts remained under picrotoxin (10 microM) and Vm oscillations persisted with tetrodotoxin (1.5 microM), but bursts were blocked by AP5 (25 microM) and Mg2+-free solutions. Depolarization and AMPA never induced rhythmic bursts. The rest of the neurons (69%), recorded closer to the CA3 region ("lateral cells"), discharged rhythmically single repetitive spikes under SC stimulation and glutamate in control conditions, but fired rhythmic bursts under similar stimulation, both when NMDA was applied and when non-NMDA receptors were blocked with CNQX (20 microM). Medial cells exhibited a larger NMDA current component and a higher NMDAR1 density at the apical dendritic shafts than lateral cells, suggesting that these differences underlie the dissimilar responses of both cell groups. We conclude that the "theta-like" rhythmic oscillations and bursts induced by glutamate and SC stimulation relied on the activation of NMDA receptors at the apical dendrites of medial cells. These results suggest a role of CA3 pyramidal neurons in the generation of CA1 theta via the activation of NMDA receptors of CA1 pyramidal neurons.     

Atorvastatin enhances kainate‐induced gamma oscillations in rat hippocampal slices

Atorvastatin has been shown to affect cognitive functions in rodents and humans. However, the underlying mechanism is not fully understood. Because hippocampal gamma oscillations (γ, 20–80 Hz) are associated with cognitive functions, we studied the effect of atorvastatin on persistent kainate‐induced γ oscillation in the CA3 area of rat hippocampal slices. The involvement of NMDA receptors and multiple kinases was tested before and after administration of atorvastatin. Whole‐cell current‐clamp and voltage‐clamp recordings were made from CA3 pyramidal neurons and interneurons before and after atorvastatin application. Atorvastatin increased γ power by ~ 50% in a concentration‐dependent manner, without affecting dominant frequency. Whereas atorvastatin did not affect intrinsic properties of both pyramidal neurons and interneurons, it increased the firing frequency of interneurons but not that of pyramidal neurons. Furthermore, whereas atorvastatin did not affect synaptic current amplitude, it increased the frequency of spontaneous inhibitory post‐synaptic currents, but did not affect the frequency of spontaneous excitatory post‐synaptic currents. The atorvastatin‐induced enhancement of γ oscillations was prevented by pretreatment with the PKA inhibitor H89, the ERK inhibitor U0126, or the PI3K inhibitor wortmanin, but not by the NMDA receptor antagonist D‐AP5. Taken together, these results demonstrate that atorvastatin enhanced the kainate‐induced γ oscillation by increasing interneuron excitability, with an involvement of multiple intracellular kinase pathways. Our study suggests that the classical cholesterol‐lowering agent atorvastatin may improve cognitive functions compromised in disease, via the enhancement of hippocampal γ oscillations.     

GABAergic interneurons targeting dendrites of pyramidal cells in the CA1 area of the hippocampus

The dendrites of pyramidal cells are active compartments capable of independent computations, input/output transformation and synaptic plasticity. Pyramidal cells in the CA1 area of the hippocampus receive 92% of their GABAergic input onto dendrites. How does this GABAergic input participate in dendritic computations of pyramidal cells? One key to understanding their contribution to dendritic computation lies in the timing of GABAergic input in relation to excitatory transmission, back‐propagating action potentials, Ca²⁺ spikes and subthreshold membrane dynamics. The issue is further complicated by the fact that dendritic GABAergic inputs originate from numerous distinct sources operating with different molecular machineries and innervating different subcellular domains of pyramidal cell dendrites. The GABAergic input from distinct sources is likely to contribute differentially to dendritic computations. In this review, I describe four groups of GABAergic interneuron according to their expression of parvalbumin, cholecystokinin, axonal arborization density and long‐range projections. These four interneuron groups contain at least 12 distinct cell types, which innervate mainly or exclusively the dendrites of CA1 pyramidal cells. Furthermore, I summarize the different spike timing of distinct interneuron types during gamma, theta and ripple oscillations in vivo, and I discuss some of the open questions on how GABAergic input modulates dendritic operations in CA1 pyramidal cells.     

The CAN‐In network: A biologically inspired model for self‐sustained theta oscillations and memory maintenance in the hippocampus

During working memory tasks, the hippocampus exhibits synchronous theta‐band activity, which is thought to be correlated with the short‐term memory maintenance of salient stimuli. Recent studies indicate that the hippocampus contains the necessary circuitry allowing it to generate and sustain theta oscillations without the need of extrinsic drive. However, the cellular and network mechanisms supporting synchronous rhythmic activity are far from being fully understood. Based on electrophysiological recordings from hippocampal pyramidal CA1 cells, we present a possible mechanism for the maintenance of such rhythmic theta‐band activity in the isolated hippocampus. Our model network, based on the Hodgkin‐Huxley formalism, comprising pyramidal neurons equipped with calcium‐activated nonspecific cationic (CAN) ion channels, is able to generate and sustain synchronized theta oscillations (4–12 Hz), following a transient stimulation. The synchronous network activity is maintained by an intrinsic CAN current (I_CAN), in the absence of constant external input. When connecting the pyramidal‐CAN network to fast‐spiking inhibitory interneurons, the dynamics of the model reveal that feedback inhibition improves the robustness of fast theta oscillations, by tightening the synchronization of the pyramidal CAN neurons. The frequency and power of the theta oscillations are both modulated by the intensity of the I_CAN, which allows for a wide range of oscillation rates within the theta band. This biologically plausible mechanism for the maintenance of synchronous theta oscillations in the hippocampus aims at extending the traditional models of septum‐driven hippocampal rhythmic activity. © 2017 Wiley Periodicals, Inc.     

Long‐term high‐intensity sound stimulation inhibits h current (Ih) in CA1 pyramidal neurons

Afferent neurotransmission to hippocampal pyramidal cells can lead to long‐term changes to their intrinsic membrane properties and affect many ion currents. One of the most plastic neuronal currents is the hyperpolarization‐activated cationic current (I_h), which changes in CA1 pyramidal cells in response to many types of physiological and pathological processes, including auditory stimulation. Recently, we demonstrated that long‐term potentiation (LTP) in rat hippocampal Schaffer‐CA1 synapses is depressed by high‐intensity sound stimulation. Here, we investigated whether a long‐term high‐intensity sound stimulation could affect intrinsic membrane properties of rat CA1 pyramidal neurons. Our results showed that I_h is depressed by long‐term high‐intensity sound exposure (1 min of 110 dB sound, applied two times per day for 10 days). This resulted in a decreased resting membrane potential, increased membrane input resistance and time constant, and decreased action potential threshold. In addition, CA1 pyramidal neurons from sound‐exposed animals fired more action potentials than neurons from control animals; however, this effect was not caused by a decreased I_h. On the other hand, a single episode (1 min) of 110 dB sound stimulation which also inhibits hippocampal LTP did not affect I_h and firing in pyramidal neurons, suggesting that effects on I_h are long‐term responses to high‐intensity sound exposure. Our results show that prolonged exposure to high‐intensity sound affects intrinsic membrane properties of hippocampal pyramidal neurons, mainly by decreasing the amplitude of I_h.     

Hippocampal and Entorhinal Cortex High-Frequency Oscillations (100–500 Hz) in Human Epileptic Brain and in Kainic Acid-Treated Rats with Chronic Seizures

Summary: Purpose: Properties of oscillations with frequencies >100 Hz were studied in kainic acid (KA)-treated rats and compared with those recorded in normal and kindled rats as well as in patients with epilepsy to determine differences associated with epilepsy. Methods: Prolonged in vivo wideband recordings of electrical activity were made in hippocampus and entorhinal cortex (EC) of (a) normal rats, (b) kindled rats, (c) rats having chronic recurrent spontaneous seizures after intrahippocampal KA injections, and (d) patients with epilepsy undergoing depth electrode evaluation in preparation for surgical treatment. Results: Intermittent oscillatory activity ranging from 100 to 200 Hz in frequency and 50–150 ms in duration was recorded in CA1 and EC of all three animal groups, and in epileptic human hippocampus and EC. This activity had the same characteristics in all groups, resembled previously observed “ripples” described by Buzsáki et al., and appeared to represent field potentials of inhibitory postsynaptic potentials (IPSPs) on principal cells. Unexpectedly, higher frequency intermittent oscillatory activity ranging from 200 to 500 Hz and 10–100 ms in duration was encountered only in KA-treated rats and patients with epilepsy. These oscillations, termed fast ripples (FRs), were found only adjacent to the epileptogenic lesion in hippocampus, EC, and dentate gyrus, and appeared to represent field potential population spikes. Their local origin was indicated by correspondence with the negative phase of burst discharges of putative pyramidal cells. Conclusions: The persistence of normal-appearing ripples in epileptic brain support the view that inhibitory processes are preserved. FRs appear to be field potentials reflecting hypersynchronous bursting of excitatory neurons and provide an opportunity to study the role of this pathophysiologic phenomenon in epilepsy and seizure initiation. Furthermore, if FR activity is unique to brain areas capable of generating spontaneous seizures, its identification could be a powerful functional indicator of the epileptic region in patients evaluated for surgical treatment.