Subicular Neurons Research Articles

Somatostatin and Neuropeptide Y Neurons Undergo Different Plasticity in Parahippocampal Regions in Kainic AcidYInduced Epilepsy

Parahippocampal brain areas including the subiculum, presubiculum and parasubiculum, and entorhinal cortex give rise to major input and output neurons of the hippocampus and exert increased excitability in animal models and human temporal lobe epilepsy. Using immunohistochemistry and in situ hybridization for somatostatin and neuropeptide Y, we investigated plastic morphologic and neurochemical changes in parahippocampal neurons in the kainic acid (KA) model of temporal lobe epilepsy. Although constitutively contained in similar subclasses of γ-aminobutyric acid (GABA)-ergic neurons, both neuropeptide systems undergo distinctly different changes in their expression. Somatostatin messenger RNA (mRNA) is rapidly but transiently expressed de novo in pyramidal neurons of the subiculum and entorhinal cortex 24 hours after KA. Surviving somatostatin interneurons display increased mRNA levels at late intervals (3 months) after KA and increased labeling of their terminals in the outer molecular layer of the subiculum; the labeling correlates with the number of spontaneous seizures, suggesting that the seizures may trigger somatostatin expression. In contrast, neuropeptide Y mRNA is consistently expressed in principal neurons of the proximal subiculum and the lateral entorhinal cortex and labeling for the peptide persistently increased in virtually all major excitatory pathways of the hippocampal formation. The pronounced plastic changes differentially involving both neuropeptide systems indicate marked rearrangement of parahippocampal areas, presumably aiming at endogenous seizure protection. Their receptors may be targets for anticonvulsive drug therapy.

Morphometric characteristics of the neurons of the human subiculum proper

The human subiculum is a significant part of the hippocampal formation positioned between the hippocampus proper and the entorhinal and other cortices. It plays an important role in spatial navigation, memory processing and control of the response to stress. The aim of our study was identification of the morphometric characteristics of the neurons of the human subiculum proper: the maximum length and width of cell body and total dendritic length and volume of cell body. Comparing the measured parameters of different types of subicular neurons (bipolar, multipolar, pyramidal neurons with triangular-shaped soma and neurons with oval-shaped soma), we can conclude that bipolar neurons have the lowest values of the measured parameters: the maximum length of their cell body is 14.1 ? 0.2 ?m, the maximum width is 13.9 ? 0.5 ?m, and total dendritic length is 14597 ? 3.1 ?m. The lowest volume value was observed in bipolar neurons; the polymorphic layer is 1152.99 ? 662.69 ?m3. The pyramidal neurons of the pyramidal layer have the highest value for the maximal length of the cell body (44.43 ? 7.94 ?m), maximum width (23.64 ? 1.89 ?m), total dendritic length (1830 ? 466.3 ?m) and volume (11768.65?4004.9 ?m3) These characteristics of the pyramidal neurons indicate their importance, because the axons of these neurons make up the greatest part of the fornix, along with the axons of neurons of the CA1 hippocampal field.

Target‐specific output patterns are predicted by the distribution of regular‐spiking and bursting pyramidal neurons in the subiculum

Pyramidal neurons in the subiculum project to a variety of cortical and subcortical areas in the brain to convey information processed in the hippocampus. Previous studies have shown that two groups of subicular pyramidal neurons--regular-spiking and bursting neurons--are distributed in an organized fashion along the proximal-distal axis, with more regular-spiking neurons close to CA1 (proximal) and more bursting neurons close to presubiculum (distal). Anatomically, neurons projecting to some targets are located more proximally along this axis, while others are located more distally. However, the relationship between the firing properties and the targets of subicular pyramidal neurons is not known. To study this relationship, we used in vivo injections of retrogradely transported fluorescent beads into each of nine different regions and conducted whole-cell current-clamp recordings from the bead-containing subicular neurons in acute brain slices. We found that subicular projections to each area were composed of a mixture of regular-spiking and bursting neurons. Neurons projecting to amygdala, lateral entorhinal cortex, nucleus accumbens, and medial/ventral orbitofrontal cortex were located primarily in the proximal subiculum and consisted mostly of regular-spiking neurons (∼80%). By contrast, neurons projecting to medial EC, presubiculum, retrosplenial cortex, and ventromedial hypothalamus were located primarily in the distal subiculum and consisted mostly of bursting neurons (∼80%). Neurons projecting to a thalamic nucleus were located in the middle portion of subiculum, and their probability of bursting was close to 50%. Thus, the fraction of bursting neurons projecting to each target region was consistent with the known distribution of regular-spiking and bursting neurons along the proximal-distal axis of the subiculum. Variation in the distribution of regular-spiking and bursting neurons suggests that different types of information are conveyed from the subiculum to its various targets.

Increased density of GAD65/67 immunoreactive neurons in the posterior subiculum and parahippocampal gyrus in treated patients with chronic schizophrenia

Objectives. Alterations of glutamic acid decarboxylase (GAD) play a crucial role in schizophrenic pathology. While GAD has been studied in several brain regions, its expression in the posterior hippocampus formation has not been investigated in schizophrenia. Methods. We studied the brains of 17 patients with chronic schizophrenia and 15 controls. Using the optical dissector method we counted GAD65/67 immunoreactive neurons and pyramidal cells in the posterior hippocampus, subiculum, and parahippocampal gyrus, and measured the cortical thickness in posterior subiculum and parahippocampal gyrus. Patients had received typical neuroleptics for the mean of 20.8 years. Results. In the patients we observed a significant increase of GAD immunoreactive neurons in the subiculum (left/right P = 0.004) and the parahippocampal gyrus (left P = 0.001, right P = 0.006). The hippocampus showed no or only subtle trends towards higher GAD densities. The density of pyramidal neurons and cortical thickness did not differ between the groups. A significant association between GAD density and the duration of illness was found in women with schizophrenia. Conclusions. The current data on GAD65/67 indicates a dysregulation of the GABAergic system in schizophrenia patients that may be associated with cognitive decline. However, a long term effect of neuroleptics on the GABAergic system cannot be excluded.

Disrupted Activity in the Hippocampal–Accumbens Circuit of Type III Neuregulin 1 Mutant Mice

Neuregulin 1 (Nrg1), a schizophrenia susceptibility gene, is involved in fundamental aspects of neurodevelopment. Mice lacking any one of the several isoforms of Nrg1 have a variety of schizophrenia-related phenotypes, including deficits in working memory and sensorimotor gating, loss of spines in pyramidal neurons in the ventral subiculum, loss of dendrites in cortical pyramidal cells, loss of parvalbumin-positive interneurons in the prefrontal cortex, and altered plasticity in corticolimbic synapses. Mice heterozygous for a disruption in exon 7 of the Nrg1 gene lack Type III (cysteine-rich-domain-containing) isoforms and have sensorimotor gating deficits that may involve changes in the activity of a circuit involving projections from the ventral hippocampus (vHPC) to medium spiny neurons in the nucleus accumbens (nACC). To explore the neural basis of these deficits, we examined electrophysiological activity in the nACC and vHPC of these mice. Under urethane anesthesia, bursts of spontaneous activity propagated from the vHPC to the nACC in both wild-type and mutant mice. However, these bursts were weaker in mutant nACC, with reduced local field potential amplitude and spiking activity. Single units in mutant nACC fired less frequently within the bursts, and more frequently outside of the bursts. Moreover, within-burst nACC spiking was less modulated by vHPC activity, as determined by phase-locking to the low-frequency oscillatory components of the bursts. These data suggest that the efficacy of vHPC input to the nACC is reduced in the Type III Nrg1 heterozygotes, supporting a role for Nrg1 in the functional profile of hippocampal-accumbens synapses.

Astrocytes and Epilepsy

Astrocytes form a significant constituent of seizure foci in the human brain. For a long time it was believed that astrocytes play a significant role in the causation of seizures. With the increase in our understanding of the unique biology of these cells, their precise role in seizure foci is receiving renewed attention. This article reviews the information now available on the role of astrocytes in the hippocampal seizure focus in patients with temporal lobe epilepsy with hippocampal sclerosis. Our intent is to try to integrate the available data. Astrocytes at seizure foci seem to not be a homogeneous population of cells, and in addition to typical glial fibrillary acidic protein, positive reactive astrocytes also include a population of neuron glia-2-like cells The astrocytes in sclerotic hippocampi differ from those in nonsclerotic hippocampi in their membrane physiology, having elevated Na+ channels and reduced inwardly rectifying potassium ion channels, and some having the capacity to generate action potentials. They also have reduced glutamine synthetase and increased glutamate dehydrogenase activity. The molecular interface between the astrocyte and microvasculature is also changed. The astrocytes are also associated with increased expression of many molecules normally concerned with immune and inflammatory functions. A speculative mechanism postulates that neuron glia-2-like cells may be involved in creating a high glutamate environment, whereas the function of more typical reactive astrocytes contribute to maintain high extracellular K+ levels; both factors contributing to the hyperexcitability of subicular neurons to generate epileptiform activity. The functions of the astrocyte vascular interface may be more critical to the processes involved in epileptogenesis.

VEGFR2 (KDR/Flk1) Signaling Mediates Axon Growth in Response to Semaphorin 3E in the Developing Brain

Common factors are thought to control vascular and neuronal patterning. Here we report an in vivo requirement for the vascular endothelial growth factor receptor type 2 (VEGFR2) in axon tract formation in the mouse brain. We show that VEGFR2 is expressed by neurons of the subiculum and mediates axonal elongation in response to the semaphorin (Sema) family molecule, Sema3E. We further show that VEGFR2 associates with the PlexinD1/Neuropilin-1 (Nrp1) receptor complex for Sema3E and becomes tyrosine-phosphorylated upon Sema3E stimulation. In subicular neurons, Sema3E triggers VEGFR2-dependent activation of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway that is required for the increase in axonal growth. These results implicate VEGFR2 in axonal wiring through a mechanism dependent on Sema3E and independent of vascular endothelial growth factor (VEGF) ligands. This mechanism provides an explanation as to how a semaphorin can activate an axon growth promoting response in developing neurons.

Morpho‐Physiologic Characteristics of Dorsal Subicular Network in Mice after Pilocarpine‐Induced Status Epilepticus

The goal of this study was to examine the morpho-physiologic changes in the dorsal subiculum network in the mouse model of temporal lobe epilepsy using extracellular recording, juxtacellular and immunofluorescence double labeling, and anterograde tracing methods. A significant loss of total dorsal subicular neurons, particularly calbindin, parvalbumin (PV) and immunopositive interneurons, was found at 2 months after pilocarpine-induced status epilepticus (SE). However, the sprouting of axons from lateral entorhinal cortex (LEnt) was observed to contact with surviving subicular neurons. These neurons had two predominant discharge patterns: bursting and fast irregular discharges. The bursting neurons were mainly pyramidal cells, and their dendritic spine density and bursting discharge rates were increased significantly in SE mice compared with the control group. Fast irregular discharge neurons were PV-immunopositive interneurons and had less dendritic spines in SE mice when compared with the control mice. When LEnt was stimulated, bursting and fast irregular discharge neurons had much shorter latency and stronger excitatory response in SE mice compared with the control group. Our results illustrate that morpho-physiologic changes in the dorsal subiculum could be part of a multilevel pathologic network that occurs simultaneously in many brain areas to contribute to the generation of epileptiform activity.

Estimation of variance components of local stereological volume estimators: a pilot study

Local stereological techniques can be used for particle volume estimation based on information collected on a section plane through a reference point of the particle. We present methods for variability estimation of the local stereological volume estimators. This variability arises during the stereological estimation procedure and in the particle population. Both of these components can be estimated separately from planar sections. Our aim is to give a preliminary analysis of the possibility to include the particle structure interaction into the estimation procedure. For this reason, not only the section profiles, but also their locations, have to be recorded. The methods are applied for the sectional data obtained from neurons in the hippocampal brain region subiculum of four 3-month-old male Wistar rats. The proposed procedure enables one to obtain information about particle volume distribution.

Adenosine A 1 receptors presynaptically modulate excitatory synaptic input onto subiculum neurons

Adenosine is an endogenous neuromodulator previously shown to suppress synaptic transmission and membrane excitability in the CNS. In this study we have determined the actions of adenosine on excitatory synaptic transmission in the subiculum, the main output area for the hippocampus. Adenosine (10 μM) reversibly inhibited excitatory post synaptic currents (EPSCs) recorded from subiculum neurons. These actions were mimicked by the A 1 receptor-specific agonist, N 6-cyclopentyl-adenosine (CPA, 10 nM) and blocked by the A 1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 500 nM), but were unaffected by the A 2A antagonist ZM 241385 (50 nM). In membrane excitability experiments, bath application of adenosine and CPA reversibly inhibited action potentials (AP) in subiculum neurons that were evoked by stimulation of the pyramidal cell layer of the CA1, but not by depolarizing current injection steps in subiculum neurons, suggesting a presynaptic mechanism of action. In support, adenosine and CPA application reduced mEPSC frequency without modulating mEPSC amplitude. These studies suggest that modulation of subiculum neuron excitability by adenosine is mediated via presynaptic A 1 receptors.

Aucubin prevents loss of hippocampal neurons and regulates antioxidative activity in diabetic encephalopathy rats

In this study, the neuroprotection of aucubin and its mechanism were evaluated in the rat model of diabetic encephalopathy. Diabetes mellitus (DM) rats were stratified by cognitive capability (CC), and assigned to four treatment groups for aucubin treatment (doses of 0, 1, 5 or 10 mg/kg aucubin), with a further two groups of non-DM rats ranked by CC as controls for aucubin (doses of 0 or 5 mg/kg aucubin). Neuroprotection was estimated by the indexes of behavior and histology. Behavioral testing was performed in a Y-maze. The surviving neurons in CA1-CA4 and subiculum (SC) of the hippocampus were counted under a microscope. In addition, the apoptotic neurons in the CA1 of the hippocampus were also examined by using TUNEL staining. In order to clarify the mechanism of aucubin's neuroprotection, the activities of endogenous antioxidants and nitric oxide synthase (NOS) together with the content of lipid peroxide in the hippocampus were assayed. The results proved that aucubin significantly reduced the content of lipid peroxide, regulated the activities of antioxidant enzymatic and decreased the activity of NOS. All these effects indicated that aucubin was a potential neuroprotective agent and its neuroprotective effects were achieved, at least in part, by promoting endogenous antioxidant enzymatic activities.

Apoptosis in subicular neurons: A comparison between suicide and Addison's disease.

Background:Stress and depression shows possible links to neuronal death in hippocampus. Subiculum plays a prominent role in limbic stress integration and direct effect of corticosteroids on subicular neurons needs to be defined to assess its subsequent impact on hippocampal plasticity.Aim:This study was intended to assess apoptosis in subicular neurons of a young depressed suicide victim, where presumably stress induced excess of corticosteroids and a case of young Addison's disease with low level of corticosteroids.Materials and Method:Both bilateral adrenal glands (Addison's) and subiculum (both cases) were initially stained with hematoxylin and eosin; subicular neurons of both cases were examined for the degree of apoptosis using ‘ApopTag Kit’. Apoptotic cell counts were expressed as average number of labeled cells/mm2 and the results were analysed statistically using a non-parametric Mann–Whitney U test.Result:Apoptotic neurons were detected in the subicular region of both suicide and Addison victims, and it is statistically significant in both right and left between the cases (P < 0.05). In suicide victim, the neuronal apoptosis is considerably significant between the two hemispheres (P < 0.05), in contrast to Addison disease where the number of neuronal cell death between right and left was statistically insignificant (P > 0.05).Conclusion:The present study confirms the vulnerability of the subicular neurons to apoptosis, possibly due to corticosteroids in both ends of spectrum.

Subicular and CA1 hippocampal projections to the accessory olfactory bulb

The hippocampal formation is anatomically and functionally related to the olfactory structures especially in rodents. The entorhinal cortex (EC) receives afferent projections from the main olfactory bulb; this constitutes an olfactory pathway to the hippocampus. In addition to the olfactory system, most mammals possess an accessory olfactory (or vomeronasal) system. The relationships between the hippocampal formation and the vomeronasal system are virtually unexplored. Recently, a centrifugal projection from CA1 to the accessory olfactory bulb has been identified using anterograde tracers. In the study reported herein, experiments using anterograde tracers confirm this projection, and injections of retrograde tracers show the distribution and morphology of a population of CA1 and ventral subicular neurons projecting to the accessory olfactory bulb of rats. These results extend previous descriptions of hippocampal projections to the accessory olfactory bulb by including the ventral subiculum and characterizing the morphology, neurochemistry (double labeling with somatostatin), and distribution of such neurons. These data suggest feedback hippocampal control of chemosensory stimuli in the accessory olfactory bulb. Whether this projection processes spatial information on conspecifics or is involved in learning and memory processes associated with chemical stimuli remains to be elucidated.

Changes to open field surfaces typically used to elicit hippocampal remapping elicit graded exploratory responses

Studies show that changes in environmental context alter the spatial firing patterns (‘remapping’) and increase immediate early gene activation in hippocampal but not subicular neurons. However, such studies rarely report co-occurring behavioural responses. We examined the behavioural effects of habituating rats to a walled open field, and then of changing the environmental context by altering wall patterns and floor colour. These kinds of cue change are known to elicit spatial remapping in hippocampal regions, but not the subiculum. Relative to controls (no cue alterations), alteration of wall patterns elicited significant increases in exploratory locomotion through the open field, while combined alterations of floor colour and wall patterns elicited an even higher increase in exploratory locomotion. In addition, combined alterations (floor colour and wall patterns) significantly increased rearing frequency, and significantly decreased the time the rats spent immobile. These findings are relevant to how changes in environmental context affect neuronal responses in the hippocampal formation, and may aid in the development of novelty-response tasks where novelty resides in open field surfaces.

Activity-dependent volume transmission by transgene NPY attenuates glutamate release and LTP in the subiculum

Neuropeptide Y (NPY) gene transduction of the brain using viral vectors in epileptogenic regions can effectively suppress seizures in animals, and is being considered as a promising alternative treatment strategy for epilepsy. Therefore, it is fundamental to understand the detailed mechanisms governing the release and action of transgene NPY in neuronal circuitries. Using whole-cell recordings from subicular neurons, we show that in animals transduced by recombinant adeno-associated viral (rAAV) vector carrying the NPY gene, transgene NPY is released during high-frequency activation of CA1-subicular synapses. Released transgene NPY attenuates excitatory synaptic transmission not only in activated, but also in neighboring, non-activated synapses. Such broad action of transgene NPY may prevent recruitment of excitatory synapses in epileptic activity and could play a key role in limiting the spread and generalization of seizures.

Spatiotemporal analyses of interactions between entorhinal and CA1 projections to the subiculum in rat brain slices

The subiculum and the entorhinal cortex (EC) are important structures in processing and transmitting information between the neocortex and the hippocampus. The subiculum potentially receives information from the EC through two routes. In addition to a direct projection from EC to the subiculum, there is an indirect polysynaptic connection. The latter uses a number of possible pathways, which all converge onto the final projection from the hippocampal field CA1 to the subiculum. In this series of experiments we investigated to what extent activity in both pathways influences population activity of subicular neurons. We used voltage sensitive dyes in combined hippocampal-EC slices of the rat to measure the spatio-temporal activity patterns. To activate the two inputs to the subiculum, stimulation electrodes were placed in the stratum oriens/alveus of CA1 and in layer III of the medial EC. The response patterns evoked in the subiculum after electrical stimulation of each of these input pathways separately were compared with the response patterns after simultaneous stimulation of both areas (medial EC + CA1). A comparison of the computed added responses of the two individual stimulations with the measured responses after simultaneous stimulation suggests that both inputs are linearly added in the subiculum with very little nonlinear interactions. This strongly suggests that in the subiculum interaction at a single cell level of the direct and the indirect pathways from the EC is an unlikely scenario.

Different levels of Ih determine distinct temporal integration in bursting and regular-spiking neurons in rat subiculum.

Pyramidal neurons in the subiculum typically display either bursting or regular-spiking behaviour. Although this classification into two neuronal classes is well described, it is unknown how these two classes of neurons contribute to the integration of input to the subiculum. Here, we report that bursting neurons possess a hyperpolarization-activated cation current (I(h)) that is two-fold larger (conductance, 5.3 +/- 0.5 nS) than in regular-spiking neurons (2.2 +/- 0.6 nS), whereas I(h) exhibits similar voltage-dependent and kinetic properties in both classes of neurons. Bursting and regular-spiking neurons display similar morphology. The difference in I(h) between the two classes of neurons is not responsible for the distinct firing patterns, as neither pharmacological blockade of I(h) nor enhancement of I(h) using a dynamic clamp affects the qualitative firing patterns. Instead, the difference in I(h) between bursting and regular-spiking neurons determines the temporal integration of evoked synaptic input from the CA1 area. In response to stimulation at 50 Hz, bursting neurons, with a large I(h), show approximately 50% less temporal summation than regular-spiking neurons. The amount of temporal summation in both neuronal classes is equal after pharmacological blockade of I(h). A computer simulation model of a subicular neuron with the properties of either a bursting or a regular-spiking neuron confirmed the pivotal role of I(h) in temporal integration of synaptic input. These data suggest that in the subicular network, bursting neurons are better suited to discriminate the content of high-frequency input, such as that occurring during gamma oscillations, than regular-spiking neurons.

Temporal coupling between subicular and hippocampal neurons underlies retention of trial-specific events

The subiculum receives the majority of efferent outflow of neural information from the CA1 region of the hippocampus. As such it occupies a strategic position in which to integrate, transfer and resolve activity from the hippocampus relating to memory and performance. We have previously demonstrated that each structure has complementary ensemble firing patterns that together allow information to be represented continuously over the time course of a trial in a delayed-non-match-to-sample (DNMS) task. Here, we extend this analysis to show the precise manner in which specific neurons in both structures are coupled temporally across the delay interval on a single trial. Neurons in both structures encode position-specific information related to the sample lever press, but only subicular neurons continue to fire during the early portion of the subsequent variable delay interval. However, cross-correlation analysis of multiple spike trains showed that as the delay increased in duration other subicular neurons were temporally coupled to the subicular neurons that fired in the initial part of the delay. This latter population of subicular neurons showed strong cross-correlated firing with other initially activated subicular neurons until midway through the delay (<15 s), but on longer delay intervals were coupled to a specific type of hippocampal neuron whose firing was critical for correct performance. Subicular neurons, therefore, play a critical role in bringing the hippocampus “back online” when trial delays exceed the minimum duration thus allowing both structures to cooperatively bridge relevant information across longer time intervals than would not otherwise be possible.

Constraints on hippocampal processing imposed by the connectivity between CA1, subiculum and subicular targets

A long-held fundamental function of the rat hippocampus is to provide a spatial map of the environment. The principal hippocampal output region for spatial information is area CA1 and the major target of CA1 is the subiculum. Thus, one possible role of the subiculum is to receive, process and transmit information regarding location to areas outside the hippocampus. Anatomical experiments in the rat have shown that the projections from CA1 to subiculum exist in a series of ‘nested loops’. Thus, each part of CA1 does not connect with each part of the subiculum. In turn, the majority of subicular principal neurons at the end of these loops have only one axonal projection target. The identity of these target areas depends on the location of the projecting cell within the subiculum, that is, neurons in different loops (and different septo-temporal levels of the subiculum) project to different sites. Principal neurons in subiculum and CA1 are not highly interconnected, suggesting that spatial information within any one of the nested loops is not shared amongst the others. This anatomical arrangement suggests that spatial information from any one part of CA1 is sent only to the sub-population of subicular principal cells within the same loop. In turn, this sub-population of subicular cells projects information to only a subset of the total range of subicular target areas. Thus, these subicular targets receive spatial information from only a subset of those in CA1. One conclusion from this is that for subicular targets to receive spatial information from the whole environment, area CA1 must have multiple spatial maps, one for each major projection (nested loop) to the subiculum.

Subiculum network excitability is increased in a rodent model of temporal lobe epilepsy

In this study, we used in vitro electrophysiology along with immunohistochemistry and molecular techniques to study the subiculum--a limbic structure that gates the information flow from and to the hippocampus--in pilocarpine-treated epileptic rats. Comparative data were obtained from age-matched nonepileptic controls (NEC). Subicular neurons in hippocampal-entorhinal cortex (EC) slices of epileptic rats were: (i) hyperexcitable when activated by CA1 or EC inputs; and (ii) generated spontaneous postsynaptic potentials at higher frequencies than NEC cells. Analysis of pharmacologically isolated, GABA(A) receptor-mediated inhibitory postsynaptic potentials revealed more positive reversal potentials in epileptic tissue (-67.8 +/- 6.3 mV, n = 16 vs. -74.8 +/- 3.6 mV in NEC, n = 13; P < 0.001) combined with a reduction in peak conductance (17.6 +/- 11.3 nS vs. 41.1 +/- 26.7 nS in NEC; P < 0.003). These electrophysiological data correlated in the epileptic subiculum with (i) reduced levels of mRNA expression and immunoreactivity of the neuron-specific potassium-chloride cotransporter 2; (ii) decreased number of parvalbumin-positive cells; and (iii) increased synaptophysin (a putative marker of sprouting) immunoreactivity. These findings identify an increase in network excitability within the subiculum of pilocarpine-treated, epileptic rats and point at a reduction in inhibition as an underlying mechanism.