Estradiol enhances the formation of dendritic spines and excitatory synapses in hippocampal neurons in vitro and in vivo, but the underlying mechanisms are not fully understood. Kalirin-7 (Kal7), the major isoform of Kalirin in the adult hippocampus, is a Rho GDP/GTP exchange factor localized to postsynaptic densities. In the hippocampus, both Kal7 and estrogen receptor α (ERα) are highly expressed in a subset of interneurons. Over-expression of Kal7 caused an increase in spine density and size in hippocampal neurons. To determine whether Kalirin might play a role in the effects of estradiol on spine formation, Kal7 expression was examined in the hippocampus of ovariectomized rats. Estradiol replacement increased Kal7 staining in both CA1 pyramidal neurons and interneurons in ovariectomized rats. Estradiol treatment of cultured hippocampal neurons increased Kal7 levels at the postsynaptic side of excitatory synapses and increased the number of excitatory synapses along the dendrites of pyramidal neurons. These increases were mediated via ERα because a selective ERα agonist, but not a selective ERβ agonist, caused a similar increase in both Kal7 levels and excitatory synapse number in cultured hippocampal neurons. When Kal7 expression was reduced using a Kal7-specific shRNA, the density of excitatory synapses was reduced and estradiol was no longer able to increase synapse formation. Expression of exogenous Kal7 in hippocampal interneurons resulted in decreased levels of GAD65 staining. Inhibition of GABAergic transmission with bicuculline produced a robust increase in Kal7 expression. These studies suggest Kal7 plays a key role in the mechanisms of estradiol-mediated synaptic plasticity.

Recently, expression of glutamate decarboxylase-67 (GAD67), a key enzyme of GABA synthesis, was detected in the otherwise glutamatergic mossy fibers of the rat hippocampus. Synthesis of the enzyme was markedly enhanced after experimentally induced status epilepticus. Here, we investigated the expression of GAD67 protein and mRNA in 44 hippocampal specimens from patients with mesial temporal lobe epilepsy (TLE) using double immunofluorescence histochemistry, immunoblotting, and in situ hybridization. Both in specimens with (n = 37) and without (n = 7) hippocampal sclerosis, GAD67 was highly coexpressed with dynorphin in terminal areas of mossy fibers, including the dentate hilus and the stratum lucidum of sector CA3. In the cases with Ammon's horn sclerosis, also the inner molecular layer of the dentate gyrus contained strong staining for GAD67 immunoreactivity, indicating labeling of mossy fiber terminals that specifically sprout into this area. Double immunofluorescence revealed the colocalization of GAD67 immunoreactivity with the mossy fiber marker dynorphin. The extent of colabeling correlated with the number of seizures experienced by the patients. Furthermore, GAD67 mRNA was found in granule cells of the dentate gyrus. Levels, both of GAD67 mRNA and of GAD67 immunoreactivity were similar in sclerotic and nonsclerotic specimens and appeared to be increased compared to post mortem controls. Provided that the strong expression of GAD67 results in synthesis of GABA in hippocampal mossy fibers this may represent a self-protecting mechanism in TLE. In addition GAD67 expression also may result in conversion of excessive intracellular glutamate to nontoxic GABA within mossy fiber terminals.

The hippocampus receives two streams of information, spatial and nonspatial, via major afferent inputs from the medial (MEC) and lateral entorhinal cortexes (LEC). The MEC and LEC projections in the temporoammonic pathway are topographically organized along the transverse-axis of area CA1. The potential for functional segregation of area CA1, however, remains relatively unexplored. Here, we demonstrated differential novelty-induced c-Fos expression along the transverse-axis of area CA1 corresponding to topographic projections of MEC and LEC inputs. We found that, while novel place exposure induced a uniform c-Fos expression along the transverse-axis of area CA1, novel object exposure primarily activated the distal half of CA1 neurons. In hippocampal slices, we observed distinct presynaptic properties between LEC and MEC terminals, and application of either DA or NE produced a largely selective influence on one set of inputs (LEC). Finally, we demonstrated that differential c-Fos expression along the transverse axis of area CA1 was largely abolished by an antagonist of neuromodulatory receptors, clozapine. Our results suggest that neuromodulators can control topographic TA projections allowing the hippocampus to differentially encode new information along the transverse axis of area CA1.

A range of ionic currents have been suggested to be involved in distinct aspects of epileptogenesis. Based on pharmacological and genetic studies, potassium currents have been implicated, in particular the transient A-type potassium current (K(A)). Epileptogenic activity comprises a rich repertoire of characteristics, one of which is synchronized activity of principal cells as revealed by occurrences of for instance fast ripples. Synchronized activity of this kind is particularly efficient in driving target cells into spiking. In the recipient cell, this synchronized input generates large brief compound excitatory postsynaptic potentials (EPSPs). The fast activation and inactivation of K(A) lead us to hypothesize a potential role in suppression of such EPSPs. In this work, using computational modeling, we have studied the activation of K(A) by synaptic inputs of different levels of synchronicity. We find that K(A) participates particularly in suppressing inputs of high synchronicity. We also show that the selective suppression stems from the current's ability to become activated by potentials with high slopes. We further show that K(A) suppresses input mimicking the activity of a fast ripple. Finally, we show that the degree of selectivity of K(A) can be modified by changes to its kinetic parameters, changes of the type that are produced by the modulatory action of KChIPs and DPPs. We suggest that the wealth of modulators affecting K(A) might be explained by a need to control cellular excitability in general and suppression of responses to synchronicity in particular. Wealso suggest that compounds changing K(A)-kinetics may be used to pharmacologically improve epileptic status.

Impaired gating by hippocampal dentate granule cells may promote the development of limbic epilepsy by facilitating seizure spread through the hippocampal trisynaptic circuit. The second synapse in this circuit, the dentate granule cell≫CA3 pyramidal cell connection, may be of particular importance because pathological changes occurring within the dentate likely exert their principal effect on downstream CA3 pyramids. Here, we utilized GFP-expressing mice and immunolabeling for the zinc transporter ZnT-3 to reveal the pre- and postsynaptic components of granule cell≫CA3 pyramidal cell synapses following pilocarpine-epileptogenesis. Confocal analyses of these terminals revealed that while granule cell presynaptic giant boutons increased in size and complexity 1 month after status epilepticus, individual thorns making up the postsynaptic thorny excrescences of the CA3 pyramidal cells were reduced in number. This reduction, however, was transient, and 3 months after status, thorn density recovered. This recovery was accompanied by a significant change in the distribution of thorns along pyramidal cells dendrites. While thorns in control animals tended to be tightly clustered, thorns in epileptic animals were more evenly distributed. Computational modeling of thorn distributions predicted an increase in the number of boutons required to cover equivalent numbers of thorns in epileptic vs. control mice. Confirming this prediction, ZnT-3 labeling of presynaptic giant boutons apposed to GFP-expressing thorns revealed a near doubling in bouton density, while the number of individual thorns per bouton was reduced by half. Together, these data provide clear evidence of novel plastic changes occurring within the epileptic hippocampus.

Functional magnetic resonance imaging (fMRI) was employed to examine the effects of a study task manipulation on pre-stimulus activity in the hippocampus predictive of later successful recollection. Eighteen young participants were scanned while making either animacy or syllable judgments on visually presented study words. Cues presented before each word denoted which judgment should be made. Following the study phase, a surprise recognition memory test was administered in which each test item had to be endorsed as "Remembered," "Known," or "New." As expected, "deep" animacy judgments led to better memory for study items than did "shallow" syllable judgments. In both study tasks, pre-stimulus subsequent recollection effects were evident in the interval between the cue and the study item in bilateral anterior hippocampus. However, the direction of the effects differed according to the study task: whereas pre-stimulus hippocampal activity on animacy trials was greater for later recollected items than items judged old on the basis of familiarity (replicating prior findings), these effects reversed for syllable trials. We propose that the direction of pre-stimulus hippocampal subsequent memory effects depends on whether an optimal pre-stimulus task set facilitates study processing that is conducive or unconducive to the formation of contextually rich episodic memories.

In hippocampal area CA1 of rats, the frequency of gamma activity has been shown to increase with running speed (Ahmed and Mehta, 2012). This finding suggests that different gamma frequencies simply allow for different timings of transitions across cell assemblies at varying running speeds, rather than serving unique functions. However, accumulating evidence supports the conclusion that slow (∼25-55 Hz) and fast (∼60-100 Hz) gamma are distinct network states with different functions. If slow and fast gamma constitute distinct network states, then it is possible that slow and fast gamma frequencies are differentially affected by running speed. In this study, we tested this hypothesis and found that slow and fast gamma frequencies change differently as a function of running speed in hippocampal areas CA1 and CA3, and in the superficial layers of the medial entorhinal cortex (MEC). Fast gamma frequencies increased with increasing running speed in all three areas. Slow gamma frequencies changed significantly less across different speeds. Furthermore, at high running speeds, CA3 firing rates were low, and MEC firing rates were high, suggesting that CA1 transitions from CA3 inputs to MEC inputs as running speed increases. These results support the hypothesis that slow and fast gamma reflect functionally distinct states in the hippocampal network, with fast gamma driven by MEC at high running speeds and slow gamma driven by CA3 at low running speeds.

Although hippocampus unequivocally supports explicit/declarative memory, fewer findings have demonstrated its role in implicit expressions of memory. We tested for hippocampal contributions to an implicit expression of configural/relational memory for complex scenes using eye-movement tracking during functional magnetic resonance imaging (fMRI) scanning. Participants studied scenes and were later tested using scenes that resembled study scenes in their overall feature configuration but comprised different elements. These configurally similar scenes were used to limit explicit memory, and were intermixed with new scenes that did not resemble studied scenes. Scene configuration memory was expressed through eye movements reflecting exploration overlap (EO), which is the viewing of the same scene locations at both study and test. EO reliably discriminated similar study-test scene pairs from study-new scene pairs, was reliably greater for similarity-based recognition hits than for misses, and correlated with hippocampal fMRI activity. In contrast, subjects could not reliably discriminate similar from new scenes by overt judgments, although ratings of familiarity were slightly higher for similar than new scenes. Hippocampal fMRI correlates of this weak explicit memory were distinct from EO-related activity. These findings collectively suggest that EO was an implicit expression of scene configuration memory associated with hippocampal activity. Visual exploration can therefore reflect implicit hippocampal-related memory processing that can be observed in eye-movement behavior during naturalistic scene viewing.

Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder, affecting over 35 million people worldwide. Pathologically, AD is characterized by the progressive accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles within the brain. Together, these pathologies lead to marked neuronal and synaptic loss and corresponding impairments in cognition. Current treatments, and recent clinical trials, have failed to modify the clinical course of AD; thus, the development of novel and innovative therapies is urgently needed. Over the last decade, the potential use of stem cells to treat cognitive impairment has received growing attention. Specifically, neural stem cell transplantation as a treatment for AD offers a novel approach with tremendous therapeutic potential. We previously reported that intrahippocampal transplantation of murine neural stem cells (mNSCs) can enhance synaptogenesis and improve cognition in 3xTg-AD mice and the CaM/Tet-DT(A) model of hippocampal neuronal loss. These promising findings prompted us to examine a human neural stem cell population, HuCNS-SC, which has already been clinically tested for other neurodegenerative disorders. In this study, we provide the first evidence that transplantation of research grade HuCNS-SCs can improve cognition in two complementary models of neurodegeneration. We also demonstrate that HuCNS-SC cells can migrate and differentiate into immature neurons and glia and significantly increase synaptic and growth-associated markers in both 3xTg-AD and CaM/Tet-DTA mice. Interestingly, improvements in aged 3xTg-AD mice were not associated with altered Aβ or tau pathology. Rather, our findings suggest that human NSC transplantation improves cognition by enhancing endogenous synaptogenesis. Taken together, our data provide the first preclinical evidence that human NSC transplantation could be a safe and effective therapeutic approach for treating AD.

The hippocampus is a brain area characterized by its high plasticity, observed at all levels of organization: molecular, synaptic, and cellular, the latter referring to the capacity of neural precursors within the hippocampus to give rise to new neurons throughout life. Recent findings suggest that promoter methylation is a plastic process subjected to regulation, and this plasticity seems to be particularly important for hippocampal neurogenesis. We have detected the enzyme GNMT (a liver metabolic enzyme) in the hippocampus. GNMT regulates intracellular levels of SAMe, which is a universal methyl donor implied in almost all methylation reactions and, thus, of prime importance for DNA methylation. In addition, we show that deficiency of this enzyme in mice (Gnmt-/-) results in high SAMe levels within the hippocampus, reduced neurogenic capacity, and spatial learning and memory impairment. In vitro, SAMe inhibited neural precursor cell division in a concentration-dependent manner, but only when proliferation signals were triggered by bFGF. Indeed, SAMe inhibited the bFGF-stimulated MAP kinase signaling cascade, resulting in decreased cyclin E expression. These results suggest that alterations in the concentration of SAMe impair neurogenesis and contribute to cognitive decline.

Emotional arousal, mediated by the amygdala, is known to modulate episodic memories stored by the hippocampus, a region involved in pattern separation (the process by which similar representations are independently stored). While emotional modulation and pattern separation have been examined independently, this study attempts to link the two areas of research to propose an alternative account for how emotion modulates episodic memory. We used an emotional discrimination task designed to tax pattern separation of emotional information by concurrently varying emotional valence and similarity of stimuli. To examine emotional modulation of memory at the level of hippocampal subfields, we used high-resolution fMRI (1.5 mm isotropic) of the medial temporal lobe. Consistent with prior reports, we observed engagement of the hippocampal dentate gyrus (DG) and CA3 during accurate discrimination of highly similar items (behavioral correlate of pattern separation). Furthermore, we observed an emotional modulation of this signal (negative > neutral) specific to trials on which participants accurately discriminated similar emotional items. The amygdala was also modulated by emotion, regardless of the accuracy of discrimination. Additionally, we found aberrant amygdala-hippocampal network activity in a sample of adults with depressive symptoms. In this sample, amygdala activation was enhanced and DG/CA3 activation was diminished during emotional discrimination compared to those without depressive symptoms. Depressive symptom severity was also negatively correlated with DG/CA3 activity. This study suggests a novel mechanistic account for how emotional information is processed by hippocampal subfields as well as how this network may be altered in mood disorders.

The proximal and distal segments of CA1 are thought to perform distinct computations. Neurons in proximal CA1 are reciprocally connected with the medial entorhinal cortex (MEC) and exhibit precise spatial firing. In contrast, cells in distal CA1 communicate with the lateral entorhinal cortex (LEC), exhibit more diffuse spatial firing and are affected by the presence of objects in the environment. To determine if these segments make unique contributions to memory retrieval, we examined cellular activity along the proximodistal axis of CA1 using transgenic reporter mice. Neurons tagged during context learning in proximal CA1 were more likely to be reactivated during testing than those in distal CA1. This was true following context fear conditioning and after exposure to a novel environment. Reactivation was also higher in brain regions connected to proximal CA1 (MEC, distal CA3) than those connected to the distal segment (LEC, proximal CA3). To examine contributions to memory retrieval, we performed neurotoxic lesions of proximal or distal CA1 after training. Lesions of the proximal segment significantly impaired memory retrieval while damage to distal CA1 had no effect. These data suggest that context memories are retrieved by a hippocampal microcircuit that involves the proximal but not distal segment of CA1. © 2016 Wiley Periodicals, Inc.

Episodic memory is characterized by remembering events as unique combinations of features. Even when some features of events overlap, we are later often able to discriminate among them. Here we ask whether hippocampally mediated reactivation of an earlier event when a similar one occurs supports subsequent memory that two similar but not identical events occurred (mnemonic discrimination). In two experiments, participants viewed objects (Experiment 1) or scenes (Experiment 2) during functional MRI (fMRI). After scanning, participants had to remember whether repeated items had been identical or similar. In Experiment 2, representational similarity between the 1st and 2nd presentation predicted participants' ability to remember that the presentations were different, suggesting that the first item was reactivated while viewing the second. A similar but weaker result was found in Experiment 1 that did not survive correction for multiple comparisons. Furthermore, both experiments yielded evidence that the hippocampus was involved in reactivation; hippocampal pattern similarity (and, in Experiment 2, hippocampal activity during the 2nd presentation) correlated with pattern similarity in several regions of visual cortex. These results provide the first fMRI evidence that hippocampally mediated reactivation contributes to the later memory that two similar, but different events occurred. © 2016 Wiley Periodicals, Inc.

Long-range glutamatergic and GABAergic projections participate in temporal coordination of neuronal activity in distributed cortical areas. In the hippocampus, GABAergic neurons project to the medial septum and retrohippocampal areas. Many GABAergic projection cells express somatostatin (SOM+) and, together with locally terminating SOM+ bistratified and O-LM cells, contribute to dendritic inhibition of pyramidal cells. We tested the hypothesis that diversity in SOM+ cells reflects temporal specialization during behavior using extracellular single cell recording and juxtacellular neurobiotin-labeling in freely moving rats. We have demonstrated that rare GABAergic projection neurons discharge rhythmically and are remarkably diverse. During sharp wave-ripples, most projection cells, including a novel SOM+ GABAergic back-projecting cell, increased their activity similar to bistratified cells, but unlike O-LM cells. During movement, most projection cells discharged along the descending slope of theta cycles, but some fired at the trough jointly with bistratified and O-LM cells. The specialization of hippocampal SOM+ projection neurons complements the action of local interneurons in differentially phasing inputs from the CA3 area to CA1 pyramidal cell dendrites during sleep and wakefulness. Our observations suggest that GABAergic projection cells mediate the behavior- and network state-dependent binding of neuronal assemblies amongst functionally-related brain regions by transmitting local rhythmic entrainment of neurons in CA1 to neuronal populations in other areas. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.

TRPV (transient receptor potential, vanilloid) channels are a family of nonselective cation channels that are activated by a wide variety of chemical and physical stimuli. TRPV1 channels are highly expressed in sensory neurons in the peripheral nervous system. However, a number of studies have also reported TRPV channels in the brain, though their functions are less well understood. In the hippocampus, the TRPV1 channel is a novel mediator of long-term depression (LTD) at excitatory synapses on interneurons. Here we tested the role of other TRPV channels in hippocampal synaptic plasticity, using hippocampal slices from Trpv1, Trpv3 and Trpv4 knockout (KO) mice. LTD at excitatory synapses on s. radiatum hippocampal interneurons was attenuated in slices from Trpv3 KO mice (as well as in Trpv1 KO mice as previously reported), but not in slices from Trpv4 KO mice. A previous study found that in hippocampal area CA1, slices from Trpv1 KO mice have reduced tetanus-induced long-term potentiation (LTP) following high-frequency stimulation; here we confirmed this and found a similar reduction in Trpv3 KO mice. We hypothesized that the loss of LTD at the excitatory synapses on local inhibitory interneurons caused the attenuated LTP in the mutants. Consistent with this idea, blocking GABAergic inhibition rescued LTP in slices from Trpv1 KO and Trpv3 KO mice. Our findings suggest a novel role for TRPV3 channels in synaptic plasticity and provide a possible mechanism by which TRPV1 and TRPV3 channels modulate hippocampal output.

In the hippocampus, signaling through G protein-coupled receptors is modulated by Regulators of G protein signaling (Rgs) proteins, which act to stimulate the rate of GTP hydrolysis, and consequently, G protein inactivation. The R7-Rgs subfamily selectively deactivates the G(i/o)-class of Gα subunits that mediate the action of several GPCRs. Here, we used co-immunoprecipitation, electrophysiology and immunoelectron microscopy techniques to investigate the formation of macromolecular complexes and spatial relationship of Rgs7/Gβ5 complexes and its prototypical signaling partners, the GABAB receptor and Girk channel. Co-expression of recombinant GABAB receptors and Girk channels in combination with co-immunoprecipitation experiments established that the Rgs7/Gβ5 forms complexes with GABAB receptors or Girk channels. Using electrophysiological experiments, we found that GABAB -Girk current deactivation kinetics was markedly faster in cells coexpressing Rgs7/Gβ5. At the electron microscopic level, immunolabeling for Rgs7 and Gβ5 proteins was found primarily in the dendritic layers of the hippocampus and showed similar distribution patterns. Immunoreactivity was mostly localized along the extrasynaptic plasma membrane of dendritic shafts and spines of pyramidal cells and, to a lesser extent, to that of presynaptic terminals. Quantitative analysis of immunogold particles for Rgs7 and Gβ5 revealed an enrichment of the two proteins around excitatory synapses on dendritic spines, virtually identical to that of Girk2 and GABAB1 . These data support the existence of macromolecular complexes composed of GABAB receptor-G protein-Rgs7-Girk channels in which Rgs7 and Gβ5 proteins may preferentialy modulate GABAB receptor signaling through the deactivation of Girk channels on dendritic spines. In contrast, Rgs7 and Girk2 were associated but mainly segregated from GABAB1 in dendritic shafts, where Rgs7/Gβ5 signaling complexes might modulate Girk-dependent signaling via a different metabotropic receptor(s).

Recent neurophysiological and functional neuroimaging studies suggest that the memory decline found with normal aging is not solely due to regional disruptions in the hippocampus, but also is brought about by alterations in the functional coupling between the hippocampus and long-distance neocortical regions. However, the anatomical basis for this functional "dyscoupling" has not been fully revealed. In this study, we applied a multimodal magnetic resonance imaging technique to noninvasively examine the large-scale anatomical and functional hippocampal network of a group of middle aged rhesus monkeys. Using diffusion spectrum imaging, we have found that monkeys with lower memory performance had weaker structural white matter connections between the hippocampus and neocortical association areas. Resting state functional imaging revealed somewhat of an opposite result. Monkeys with low memory performance displayed elevated coupling strengths in the network between the hippocampus and the neocortical areas. Taken together with recent findings, this contradictory pattern may be the result of either underlying physiological burden or abnormal neuronal decoupling due to the structural alterations, which induce a neuronal compensation mechanism for the structural loss or interference on task related neuronal activation, respectively.

Sprouty (Spry) proteins play a key role as negative feedback inhibitors of the Ras/Raf/MAPK/ERK pathway downstream of various receptor tyrosine kinases. Among the four Sprouty isoforms, Spry2 and Spry4 are expressed in the hippocampus. In this study, possible effects of Spry2 and Spry4 hypomorphism on neurodegeneration and seizure thresholds in a mouse model of epileptogenesis was analyzed. The Spry2/4 hypomorphs exhibited stronger ERK activation which was limited to the CA3 pyramidal cell layer and to the hilar region. The seizure threshold of Spry2/4(+/-) mice was significantly reduced at naive state but no difference to wildtype mice was observed 1 month following KA treatment. Histomorphological analysis revealed that dentate granule cell dispersion (GCD) was diminished in Spry2/4(+/-) mice in the subchronic phase after KA injection. Neuronal degeneration was reduced in CA1 and CA3 principal neuron layers as well as in scattered neurons of the contralateral CA1 and hilar regions. Moreover, Spry2/4 reduction resulted in enhanced survival of somatostatin and neuropeptide Y expressing interneurons. GFAP staining intensity and number of reactive astrocytes markedly increased in lesioned areas of Spry2/4(+/-) mice as compared with wildtype mice. Taken together, although the seizure threshold is reduced in naive Spry2/4(+/-) mice, neurodegeneration and GCD is mitigated following KA induced hippocampal lesions, identifying Spry proteins as possible pharmacological targets in brain injuries resulting in neurodegeneration. The present data are consistent with the established functions of the ERK pathway in astrocyte proliferation as well as protection from neuronal cell death and suggest a novel role of Spry proteins in the migration of differentiated neurons.

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.

Episodic memory involves remembering the details that characterize a prior experience. Successful memory recovery has been associated with the reinstatement of brain activity patterns in a number of sensory regions across the cortex. However, how the hippocampus and surrounding medial temporal lobe (MTL) cortex contribute to this process is less clear. Models of episodic memory posit that hippocampal pattern reinstatement, also referred to as pattern completion, may mediate cortical reinstatement during retrieval. Empirical evidence of this process, however, remains elusive. Here, we use high-resolution fMRI and encoding-retrieval multi-voxel pattern similarity analyses to demonstrate for the first time that the hippocampus, particularly right hippocampal subfield CA1, shows evidence of reinstating individual episodic memories. Furthermore, reinstatement in perirhinal cortex (PrC) is also evident. Critically, we identify distinct factors that may mediate the cortical reinstatement in PrC. First, we find that encoding activation in PrC is related to later reinstatement in this region, consistent with the theory that encoding strength in the regions that process the memoranda is important for later reinstatement. Conversely, retrieval activation in right CA1 was correlated with reinstatement in PrC, consistent with models of pattern completion. This dissociation is discussed in the context of the flow of information into and out of the hippocampus during encoding and retrieval, respectively. © 2016 Wiley Periodicals, Inc.