3‐Hz subthreshold oscillations of CA2 neurons In vivo

The CA2 region is unique in the hippocampus; it receives direct synaptic innervations from several hypothalamic nuclei and expresses various receptors of neuromodulators, including adenosine, vasopressin, and oxytocin. Furthermore, the CA2 region may have distinct brain functions, such as the control of instinctive and social behaviors; however, little is known about the dynamics of the subthreshold membrane potentials of CA2 neurons in vivo. We conducted whole‐cell current‐clamp recordings from CA2 pyramidal cells in urethane‐anesthetized mice and monitored the intrinsic fluctuations in their membrane potentials. The CA2 pyramidal cells emitted spontaneous action potentials at mean firing rates of ～0.8 Hz. In approximately half of the neurons, the subthreshold membrane potential oscillated at ～3 Hz. In two neurons, we obtained simultaneous recordings of local field potentials from the CA1 stratum radiatum and demonstrated that the 3‐Hz oscillations of CA2 neurons were not correlated with CA1 field potentials. In tetrodotoxin‐perfused acute hippocampal slices, the membrane potentials of CA2 pyramidal cells were not preferentially entrained to 3‐Hz sinusoidal current inputs, which suggest that intracellular 3‐Hz oscillations reflect the neuronal dynamics of the surrounding networks. © 2016 Wiley Periodicals, Inc.     

Learning‐dependent plasticity of hippocampal CA1 pyramidal neuron postburst afterhyperpolarizations and increased excitability after inhibitory avoidance learning depend upon basolateral amygdala inputs

Hippocampal pyramidal neurons in vitro exhibit transient learning‐dependent reductions in the amplitude and duration of calcium‐dependent postburst afterhyperpolarizations (AHPs), accompanied by other increases in excitability (i.e., increased firing rate, or reduced spike‐frequency accommodation) after trace eyeblink conditioning or spatial learning, with a time‐course appropriate to support consolidation of the learned tasks. Both these tasks require multiple days of training for acquisition. The hippocampus also plays a role in acquisition of single trial inhibitory avoidance learning. The current study assessed AHP plasticity in this single‐trial learning task using in vitro tissue slices prepared at varying intervals posttrial using intracellular current‐clamp recordings. Reduced AHPs and reduced accommodation were seen in ventral CA1 pyramidal neurons within 1 h posttraining, plasticity which persisted 24 h but was extinguished >72 h posttrial. There was also a reduction in ventral CA1 AHPs and accommodation 1 h following simple exposure to the IA apparatus (a novel context) but this change was extinguished by 24 h postexposure. Reductions in AHPs and accommodation were also seen in dorsal CA1 pyramidal neurons, but were delayed until 24 h posttrial and extinguished at >72 h posttrial. Finally, transient inactivation of the basolateral complex of the amygdala (with the local anesthetics lidocaine or bupivacaine) either immediately before or immediately posttrial blocked both learning and learning‐dependent changes in excitability in the hippocampus assessed 24 h posttrial. CA3 pyramidal neurons showed no reductions in AHP peak amplitude or accommodation following IA training or context exposure. © 2012 Wiley Periodicals, Inc.     

Transient effect of mossy fiber stimulation on spatial firing of CA3 neurons

Strong hippocampal mossy fiber synapses are thought to function as detonators, imposing “teaching” signals onto CA3 neurons during new memory formation. For an empirical test of this long‐standing view, we examined effects of optogenetically stimulating mossy fibers on spatial firing of CA3 neurons in freely‐moving mice. We found that spatially restricted mossy fiber stimulation drives novel place‐specific firing in some CA3 pyramidal neurons. Such neurons comprise only a minority, however, and many more CA3 neurons showed inhibited spatial firing during mossy fiber stimulation. Also, changes in spatial firing induced by mossy fiber stimulation, both activated and inhibited, reverted immediately upon stimulation termination, leaving CA3 place fields unaltered. Our results do not support the traditional view that mossy fibers impose teaching signals onto CA3 network, and show robustness of established CA3 spatial representations.     

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.     

Convergence of associational and commissural pathways on CA1 pyramidal cells of the rat hippocampus

The interaction of the commissural and associational systems to the CA1 region of the hippocampus was studied by recording extracellular field potentials and single unit activity in anesthetized rats. Associational fibers were activated by stimulating the stratum oriens of the CA1 region contralateral to recording: this stimulation activated the Schaffer collaterals by antidromically firing the pyramidal cells of the CA3 region on the side of recording. Commissural fibers were stimulated where they emerge from CA3 region. Both pathways excited both the basal and apical dendrites of the CA1 pyramidal cells. Commissural activation in stratum oriens was more efficient than associational path stimulation, while the opposite was seen in stratum radiatum. Responses elicited by associational path activation had their peak negativity 100–150 μm deeper in stratum radiatum than commissurally evoked responses. Both pathways were able to discharge pyramidal neurons. Both homonymous and heteronymous double pulse stimulation showed response facilitation. Simultaneous activation of both pathways induced a greater amplitude population spike than predicted by algebraic summation of the independent responses. Over 80% of the responsive CA1 cells could be fired by either pathway. These results show a considerable convergence of the commissural and associational pathways on CA1 pyramidal cells, although their predominant locus of excitation might be different.     

Hippocampal place cell dysfunction and the effects of muscarinic M1 receptor agonism in a rat model of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disease that disproportionately impacts memory and the hippocampus. However, it is unclear how AD pathology influences the activity of surviving neurons in the hippocampus to contribute to the memory symptoms in AD. One well‐understood connection between spatial memory and neuronal activity in healthy brains is the activity of place cells, neurons in the hippocampus that fire preferentially in a specific location of a given environment (the place field of the place cell). In the present study, place cells were recorded from the hippocampus in a recently‐developed rat model of AD (Tg‐F344 AD) at an age (12–20 months) at which the AD rats showed marked spatial memory deficits. Place cells in the CA2 and CA3 pyramidal regions of the hippocampus in AD rats showed sharply reduced spatial fidelity relative to wild‐type (WT) rats. In contrast, spiking activity of place cells recorded in region CA1 in AD rats showed good spatial fidelity that was similar to CA1 place cells in WT rats. Oral administration of the M₁ muscarinic acetylcholine receptor agonist VU0364572 impacted place cell firing rates in CA1 and CA2/3 hippocampal regions, but did not improve the spatial fidelity of CA2/3 hippocampal place cells in AD rats. The results indicated that, to the extent the spatial memory impairment in AD rats was attributable to hippocampal dysfunction, the memory impairment was more attributable to dysfunction in hippocampal regions CA2 and CA3 rather than CA1.     

The influence of objects on place field expression and size in distal hippocampal CA1

The perirhinal and lateral entorhinal cortices send prominent projections to the portion of the hippocampal CA1 subfield closest to the subiculum, but relatively little is known regarding the contributions of these cortical areas to hippocampal activity patterns. The anatomical connections of the lateral entorhinal and perirhinal cortices, as well as lesion data, suggest that these brain regions may contribute to the perception of complex stimuli such as objects. The current experiments investigated the degree to which three‐dimensional objects affect place field size and activity within the distal region (closest to the subiculum) of CA1. The activity of CA1 pyramidal cells was monitored as rats traversed a circular track that contained no objects in some conditions and three‐dimensional objects in other conditions. In the area of CA1 that receives direct lateral entorhinal input, three factors differentiated the objects‐on‐track conditions from the no‐object conditions: more pyramidal cells expressed place fields when objects were present, adding or removing objects from the environment led to partial remapping in CA1, and the size of place fields decreased when objects were present. In addition, a proportion of place fields remapped under conditions in which the object locations were shuffled, which suggests that at least some of the CA1 neurons' firing patterns were sensitive to a particular object in a particular location. Together, these data suggest that the activity characteristics of neurons in the areas of CA1 receiving direct input from the perirhinal and lateral entorhinal cortices are modulated by non‐spatial sensory input such as three‐dimensional objects. © 2011 Wiley‐Liss, Inc.     

Distinct classes of pyramidal cells exhibit mutually exclusive firing patterns in hippocampal area CA3b

It is thought that CA3 pyramidal neurons communicate mainly through bursts of spikes rather than so-called trains of regular firing action potentials. Reports of both burst firing and nonburst firing CA3 cells suggest that they may fire with more than one output pattern. With the use of whole-cell recording methods we studied the firing properties of rat hippocampal pyramidal neurons in vitro within the CA3b subregion and found three distinct types of firing patterns. Approximately 37% of cells were regular firing where spikes generated by minimal current injection (rheobase) were elicited with a short latency and with stronger current intensities trains of spikes exhibited spike frequency adaptation (SFA). Another 46% of neurons exhibited a delayed onset at rheobase with a weakly-adapting firing pattern upon stronger stimulation. The remaining 17% of cells showed a burst-firing pattern, though only elicited in response to strong current injection and spontaneous bursts were never observed. Control experiments indicated that the distinct firing patterns were not due to our particular slicing methods or recording techniques. Finally, computer modeling was used to identify how relative differences in K+ conductances, specifically K(C), K(M), and K(D), between cells contribute to the different characteristics of the three types of firing patterns observed experimentally.     

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.     

Neonatal seizures induced persistent changes in intrinsic properties of CA1 rat hippocampal cells

We investigated the effects of repeated early-life seizures induced by flurothyl inhalation on intrinsic membrane properties of hippocampal pyramidal neurons from young rats (postnatal day 15-20). Intracellular recordings of CA1 and CA3 pyramidal neurons from flurothyl-treated and control rats revealed no significant differences in resting membrane potential, input resistance, membrane time constant, and action potential characteristics. In CA1 pyramidal cells from flurothyl-treated rats, the spike frequency adaptation and afterhyperpolarizing potential following a spike train were markedly reduced when compared with controls. In contrast, no significant alterations in the firing properties of CA3 pyramidal neurons were found. It is concluded that neonatal seizures lead to persistent changes in intrinsic membrane properties of CA1 pyramidal neurons. These alterations are consistent with an increase in neuronal excitability and may contribute to the behavioral deficit and epileptogenic predisposition observed in rats that experienced repeated neonatal seizures.     

Schaffer-specific local field potentials reflect discrete excitatory events at gamma frequency that may fire postsynaptic hippocampal CA1 units

Information processing and exchange between brain nuclei are made through spike series sent by individual neurons in highly irregular temporal patterns. Synchronization in cell assemblies, proposed as a network language for internal neural representations, still has little experimental support. We use a novel technique to extract pathway-specific local field potentials (LFPs) in the hippocampus to explore the ongoing temporal structure of a single presynaptic input, the CA3 Schaffer pathway, and its contribution to the spontaneous output of CA1 units in anesthetized rat. We found that Schaffer-specific LFPs are composed of a regular succession of pulse-like excitatory packages initiated by spontaneous clustered firing of CA3 pyramidal cells to which individual units contribute variably. A fraction of these packages readily induce firing of CA1 pyramidal cells and interneurons, the so-called Schaffer-driven spikes, revealing the presynaptic origin in the output code of single CA1 units. The output of 70% of CA1 pyramidal neurons contains up to 10% of such spikes. Our results suggest a hierarchical internal operation of the CA3 region based on sequential oscillatory activation of pyramidal cell assemblies whose activity partly gets in the output code at the next station. We conclude that CA1 output may directly reflect the activity of specific ensembles of CA3 neurons. Thus, the fine temporal structure of pathway-specific LFPs, as an accurate readout of the activity of a presynaptic population, is useful in searching for hidden presynaptic code in irregular spikes series of individual neurons and assemblies.     

Suppression by topiramate of epileptiform burst discharges in hippocampal CA3 neurons of spontaneously epileptic rat in vitro

Topiramate, a novel antiepileptic drug, inhibits the seizures of spontaneously epileptic rat (SER), a double mutant (zi/zi, tm/tm) which exhibits both tonic convulsion and absence-like seizures from the age of 8-weeks. Hippocampal CA3 pyramidal neurons in SER show a long-lasting depolarization shift with accompanying repetitive firing when a single electrostimulation is delivered to the mossy fibers in vitro. The effects of topiramate on the excitability of CA3 pyramidal neurons in SER were examined to elucidate the mechanism underlying the antiepileptic action. Intracellular recordings were performed in 23 hippocampal slice preparations of 16 SER aged 8–17 weeks. Topiramate (10–100 μM) dose-dependently inhibited the depolarizing shifts with repetitive firing induced by mossy fiber stimulation without affecting the first spike and resting membrane potentials in hippocampal CA3 neurons of SER. Higher dose of topiramate (100 μM) sometimes inhibited the first spike, and decreased excitatory postsynaptic potentials in the SER CA3 neurons. However, topiramate up to 100 μM did not affect the single action potential elicited by the stimulation in the hippocampal CA3 neurons of age-matched Wistar rat devoid of the seizure. Application of topiramate (100 μM) did not significantly affect the firing induced by depolarizing pulse applied in the CA3 neurons of the SER. In addition, topiramate (100 μM) had no effects on the Ca²⁺ spike induced by intracellularly applied depolarizing pulse in the presence of tetrodotoxin and tetraethylammonium. In contrast, a dose-dependent inhibition of depolarization and repetitive firing induced by bath application of glutamate in CA3 pyramidal neurons was obtained with topiramate (10–100 μM). Furthermore, topiramate (100 μM) decreased the number of miniature postsynaptic potential of CA3 pyramidal neurons of SER. In patch clamp whole cell recording using acutely dissociated hippocampal CA3 neurons from SER aged 8-weeks and age-matched normal Wistar rats, there were no remarkable effects on voltage dependent Ca²⁺ current with topiramate up to 300 μM in either animal; the current was completely blocked by Cd²⁺ at a concentration of 1 mM. These findings suggest that topiramate inhibits release of glutamate from the nerve terminals and/or abnormal firing of the CA3 pyramidal neurons of SER by mainly blocking glutamate receptors in the neurons.     

Somatosensory stimulation suppresses the excitability of pyramidal cells in the hippocampal CA1 region in rats

The hippocampal region of the brain is important for encoding environment inputs and memory formation. However, the underlying mechanisms are unclear. To investigate the behavior of indi-vidual neurons in response to somatosensory inputs in the hippocampal CA1 region, we recorded and analyzed changes in local ifeld potentials and the ifring rates of individual pyramidal cells and interneurons during tail clamping in urethane-anesthetized rats. We also explored the mechanisms underlying the neuronal responses. Somatosensory stimulation, in the form of tail clamping, chan-ged local ifeld potentials into theta rhythm-dominated waveforms, decreased the spike ifring of py-ramidal cells, and increased interneuron ifring. In addition, somatosensory stimulation attenuated orthodromic-evoked population spikes. These results suggest that somatosensory stimulation sup-presses the excitability of pyramidal cells in the hippocampal CA1 region. Increased inhibition by local interneurons might underlie this effect. These ifndings provide insight into the mechanisms of signal processing in the hippocampus and suggest that sensory stimulation might have thera-peutic potential for brain disorders associated with neuronal hyperexcitability.     

Frequency-Dependent Synaptic Dynamics Differentially Tune CA1 and CA2 Pyramidal Neuron Responses to Cortical Input

Entorhinal cortex neurons make monosynaptic connections onto distal apical dendrites of CA1 and CA2 pyramidal neurons through the perforant path (PP) projection. Previous studies show that differences in dendritic properties and synaptic input density enable the PP inputs to produce a much stronger excitation of CA2 compared with CA1 pyramidal neurons. Here, using mice of both sexes, we report that the difference in PP efficacy varies substantially as a function of presynaptic firing rate. Although a single PP stimulus evokes a 5- to 6-fold greater EPSP in CA2 compared with CA1, a brief high-frequency train of PP stimuli evokes a strongly facilitating postsynaptic response in CA1, with relatively little change in CA2. Furthermore, we demonstrate that blockade of NMDARs significantly reduces strong temporal summation in CA1 but has little impact on that in CA2. As a result of the differences in the frequency- and NMDAR-dependent temporal summation, naturalistic patterns of presynaptic activity evoke CA1 and CA2 responses with distinct dynamics, differentially tuning CA1 and CA2 responses to bursts of presynaptic firing versus single presynaptic spikes, respectively.SIGNIFICANCE STATEMENT Recent studies have demonstrated that abundant entorhinal cortical innervation and efficient dendritic propagation enable hippocampal CA2 pyramidal neurons to produce robust excitation evoked by single cortical stimuli, compared with CA1. Here we uncovered, unexpectedly, that the difference in efficacy of cortical excitation varies substantially as a function of presynaptic firing rate. A burst of stimuli evokes a strongly facilitating response in CA1, but not in CA2. As a result, the postsynaptic response of CA1 and CA2 to presynaptic naturalistic firing displays contrasting temporal dynamics, which depends on the activation of NMDARs. Thus, whereas CA2 responds to single stimuli, CA1 is selectively recruited by bursts of cortical input.     

Theta phase precession in hippocampal neuronal populations and the compression of temporal sequences

O'Keefe and Recce [1993] Hippocampus 3:317–330 described an interaction between the hippocampal theta rhythm and the spatial firing of pyramidal cells in the CA1 region of the rat hippocampus: they found that a cell's spike activity advances to earlier phases of the theta cycle as the rat passes through the cell's place field. The present study makes use of large-scale parallel recordings to clarify and extend this finding in several ways: 1) Most CA1 pyramidal cells show maximal activity at the same phase of the theta cycle. Although individual units exhibit deeper modulation, the depth of modulation of CA1 population activity is about 50%. The peak firing of inhibitory interneurons in CA1 occurs about 60° in advance of the peak firing of pyramidal cells, but different interneurons vary widely in their peak phases. 2) The first spikes, as the rat enters a pyramidal cell's place field, come 90°–120° after the phase of maximal pyramidal cell population activity, near the phase where inhibition is least. 3) The phase advance is typically an accelerating, rather than linear, function of position within the place field. 4) These phenomena occur both on linear tracks and in two-dimensional environments where locomotion is not constrained to specific paths. 5) In two-dimensional environments, place-related firing is more spatially specific during the early part of the theta cycle than during the late part. This is also true, to a lesser extent, on a linear track. Thus, spatial selectivity waxes and wanes over the theta cycle. 6) Granule cells of the fascia dentata are also modulated by theta. The depth of modulation for the granule cell population approaches 100%, and the peak activity of the granule cell population comes about 90° earlier in the theta cycle than the peak firing of CA1 pyramidal cells. 7) Granule cells, like pyramidal cells, show robust phase precession. 8) Cross-correlation analysis shows that portions of the temporal sequence of CA1 pyramidal cell place fields are replicated repeatedly within individual theta cycles, in highly compressed form. The compression ratio can be as much as 10:1. These findings indicate that phase precession is a very robust effect, distributed across the entire hippocampal population, and that it is likely to be inherited from the fascia dentata or an earlier stage in the hippocampal circuit, rather than generated intrinsically within CA1. It is hypothesized that the compression of temporal sequences of place fields within individual theta cycles permits the use of long-term potentiation for learning of sequential structure, thereby giving a temporal dimension to hippocampal memory traces. © 1996 Wiley-Liss, Inc.     

Influence of local objects on hippocampal representations: Landmark vectors and memory

The hippocampus is thought to represent nonspatial information in the context of spatial information. An animal can derive both spatial information as well as nonspatial information from the objects (landmarks) it encounters as it moves around in an environment. In this article, correlates of both object‐derived spatial as well as nonspatial information in the hippocampus of rats foraging in the presence of objects are demonstrated. A new form of CA1 place cells, called landmark‐vector cells, that encode spatial locations as a vector relationship to local landmarks is described. Such landmark vector relationships can be dynamically encoded. Of the 26 CA1 neurons that developed new fields in the course of a day's recording sessions, in eight cases, the new fields were located at a similar distance and direction from a landmark as the initial field was located relative to a different landmark. In addition, object‐location memory in the hippocampus is also described. When objects were removed from an environment or moved to new locations, a small number of neurons in CA1 and CA3 increased firing at the locations where the objects used to be. In some neurons, this increase occurred only in one location, indicating object + place conjunctive memory; in other neurons, the increase in firing was seen at multiple locations where an object used to be. Taken together, these results demonstrate that the spatially restricted firing of hippocampal neurons encode multiple types of information regarding the relationship between an animal's location and the location of objects in its environment. © 2013 Wiley Periodicals, Inc.     

Behavior‐driven arc expression is reduced in all ventral hippocampal subfields compared to CA1, CA3, and dentate gyrus in rat dorsal hippocampus

Anatomical connectivity and lesion studies reveal distinct functional heterogeneity along the dorsal–ventral axis of the hippocampus. The immediate early gene Arc is known to be involved in neural plasticity and memory and can be used as a marker for cell activity that occurs, for example, when hippocampal place cells fire. We report here, that Arc is expressed in a greater proportion of cells in dorsal CA1, CA3, and dentate gyrus (DG), following spatial behavioral experiences compared to ventral hippocampal subregions (dorsal CA1 = 33%; ventral CA1 = 13%; dorsal CA3 = 23%; ventral CA3 = 8%; and dorsal DG = 2.5%; ventral DG = 1.2%). The technique used here to obtain estimates of numbers of behavior‐driven cells across the dorsal–ventral axis, however, corresponds quite well with samples from available single unit recording studies. Several explanations for the two‐ to‐threefold reduction in spatial behavior‐driven cell activity in the ventral hippocampus can be offered. These include anatomical connectivity differences, differential gain of the self‐motion signals that appear to alter the scale of place fields and the proportion of active cells, and possibly variations in the neuronal responses to non‐spatial information within the hippocampus along its dorso‐ventral axis.     

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.     

Disrupted‐in‐schizophrenia 1 overexpression disrupts hippocampal coding and oscillatory synchronization

Aberrant proteostasis of protein aggregation may lead to behavior disorders including chronic mental illnesses (CMI). Furthermore, the neuronal activity alterations that underlie CMI are not well understood. We recorded the local field potential and single‐unit activity of the hippocampal CA1 region in vivo in rats transgenically overexpressing the Disrupted‐in‐Schizophrenia 1 (DISC1) gene (tgDISC1), modeling sporadic CMI. These tgDISC1 rats have previously been shown to exhibit DISC1 protein aggregation, disturbances in the dopaminergic system and attention‐related deficits. Recordings were performed during exploration of familiar and novel open field environments and during sleep, allowing investigation of neuronal abnormalities in unconstrained behavior. Compared to controls, tgDISC1 place cells exhibited smaller place fields and decreased speed‐modulation of their firing rates, demonstrating altered spatial coding and deficits in encoding location‐independent sensory inputs. Oscillation analyses showed that tgDISC1 pyramidal neurons had higher theta phase locking strength during novelty, limiting their phase coding ability. However, their mean theta phases were more variable at the population level, reducing oscillatory network synchronization. Finally, tgDISC1 pyramidal neurons showed a lack of novelty‐induced shift in their preferred theta and gamma firing phases, indicating deficits in coding of novel environments with oscillatory firing. By combining single cell and neuronal population analyses, we link DISC1 protein pathology with abnormal hippocampal neural coding and network synchrony, and thereby gain a more comprehensive understanding of CMI mechanisms.     

Short‐term plasticity regulates the excitation/inhibition ratio and the temporal window for spike integration in CA1 pyramidal cells

Many neurodevelopmental and neuropsychiatric disorders involve an imbalance between excitation and inhibition caused by synaptic alterations. The proper excitation/inhibition (E/I) balance is especially critical in CA1 pyramidal cells, because they control hippocampal output. Activation of Schaffer collateral axons causes direct excitation of CA1 pyramidal cells, quickly followed by disynaptic feedforward inhibition, stemming from synaptically induced firing of GABAergic interneurons. Both excitatory and inhibitory synapses are modulated by short‐term plasticity, potentially causing dynamic tuning of the E/I ratio. However, the effects of short‐term plasticity on the E/I ratio in CA1 pyramidal cells are not yet known. To determine this, we recorded disynaptic inhibitory postsynaptic currents and the E/I ratio in CA1 pyramidal cells in acute hippocampal slices from juvenile mice. We found that, whereas inhibitory synapses had paired‐pulse depression, disynaptic inhibition instead had paired‐pulse facilitation (≤ 200‐ms intervals), caused by increased recruitment of feedforward interneurons. Although enhanced disynaptic inhibition helped to constrain paired‐pulse facilitation of excitation, the E/I ratio was still larger on the second pulse, increasing pyramidal cell spiking. Surprisingly, this occurred without compromising the precision of spike timing. The E/I balance regulates the temporal spike integration window from multiple inputs; here, we showed that paired‐pulse stimulation can broaden the spike integration window. Together, our findings show that the combined effects of short‐term plasticity of disynaptic inhibition and monosynaptic excitation alter the E/I balance in CA1 pyramidal cells, leading to dynamic modulation of spike probability and the spike integration window. Short‐term plasticity is therefore an important mechanism for modulating signal processing of hippocampal output.