Subicular Cells Research Articles

Subicular neurons represent multiple variables of a hippocampal-dependent task by using theta rhythm.

The subiculum is positioned at a critical juncture at the interface of the hippocampus with the rest of the brain. However, the exact roles of the subiculum in most hippocampal-dependent memory tasks remain largely unknown. One obstacle to make comparisons of neural firing patterns between the subiculum and hippocampus is the broad firing fields of the subicular cells. Here, we used spiking phases in relation to theta rhythm to parse the broad firing field of a subicular neuron into multiple subfields to find the unique functional contribution of the subiculum while male rats performed a hippocampal-dependent visual scene memory task. Some of the broad firing fields of the subicular neurons were successfully divided into multiple subfields similar to those in the CA1 by using the theta phase precession cycle. The new paradigm significantly improved the detection of task-relevant information in subicular cells without affecting the information content represented by CA1 cells. Notably, we found that multiple fields of a single subicular neuron, unlike those in the CA1, carried heterogeneous task-related information such as visual context and choice response. Our findings suggest that the subicular cells integrate multiple task-related factors by using theta rhythm to associate environmental context with action.

Task-dependent mixed selectivity in the subiculum.

SummaryCA1 and subiculum (SUB) connect the hippocampus to numerous output regions. Cells in both areas have place-specific firing fields, although they are more dispersed in SUB. Weak responses to head direction and running speed have been reported in both regions. However, how such information is encoded in CA1 and SUB and the resulting impact on downstream targets are poorly understood. Here, we estimate the tuning of simultaneously recorded CA1 and SUB cells to position, head direction, and speed. Individual neurons respond conjunctively to these covariates in both regions, but the degree of mixed representation is stronger in SUB, and more so during goal-directed spatial navigation than free foraging. Each navigational variable could be decoded with higher precision, from a similar number of neurons, in SUB than CA1. The findings point to a possible contribution of mixed-selective coding in SUB to efficient transmission of hippocampal representations to widespread brain regions.

Propagation of hippocampal ripples to the neocortex by way of a subiculum-retrosplenial pathway

Bouts of high frequency activity known as sharp wave ripples (SPW-Rs) facilitate communication between the hippocampus and neocortex. However, the paths and mechanisms by which SPW-Rs broadcast their content are not well understood. Due to its anatomical positioning, the granular retrosplenial cortex (gRSC) may be a bridge for this hippocampo-cortical dialogue. Using silicon probe recordings in awake, head-fixed mice, we show the existence of SPW-R analogues in gRSC and demonstrate their coupling to hippocampal SPW-Rs. gRSC neurons reliably distinguished different subclasses of hippocampal SPW-Rs according to ensemble activity patterns in CA1. We demonstrate that this coupling is brain state-dependent, and delineate a topographically-organized anatomical pathway via VGlut2-expressing, bursty neurons in the subiculum. Optogenetic stimulation or inhibition of bursty subicular cells induced or reduced responses in superficial gRSC, respectively. These results identify a specific path and underlying mechanisms by which the hippocampus can convey neuronal content to the neocortex during SPW-Rs.

The intrinsic cell type-specific excitatory connectivity of the developing mouse subiculum is sufficient to generate synchronous epileptiform activity.

The activity of local excitatory circuits of the subiculum has been suggested to be involved in the initiation of pathological activity in epileptic patients and experimental animal models of temporal lobe epilepsy. We have taken advantage of multimodal techniques to classify subicular cells in distinct subclasses and have investigated their morphofunctional properties and connectivity in vitro. Our results indicate that local subicular excitatory circuits are connected in a cell type-specific fashion and that synapses are preferentially established on basal vs. apical dendrites. We show that local excitatory circuits, isolated from extrasubicular inputs and pharmacologically disinhibited, are sufficient to initiate synchronous epileptiform activity in vitro. In conclusion, this work provides a high-resolution description of local excitatory circuits of the subiculum and highlights their mechanistic involvement in the generation of pathological activity. The subiculum has been suggested to be involved in the initiation of pathological discharges in human patients and animal models of temporal lobe epilepsy. Although converging evidence has revealed the existence of functional diversity within its principal neurons, much less attention has been devoted to its intrinsic connectivity and whether its local excitatory circuits are sufficient to generate epileptiform activity. Here, we have directly addressed these two key points in mouse subicular slices. First, using multivariate techniques, we have distinguished two groups of principal cells, which we have termed type1 and type2. These subgroups roughly overlap with what were classically indicated as regular and bursting cells, and showed differences in the extension and complexity of their apical dendrites. Functional connectivity was found both between similar (homotypic) and different (heterotypic) types of cells, with a marked asymmetry within heterotypic pairs. Unitary excitatory postsynaptic potentials (uEPSPs) revealed a high degree of variability both in amplitude, failure rate, rise time and half-width. Post hoc analysis of functionally connected pairs suggested that the observed uEPSPs were mediated by few contact sites, predominantly located on the basal dendrites. When surgically isolated from extrasubicular excitatory afferents, pharmacologically disinhibited subicular slices generated hyper-synchronous discharges. Thus, we conclude that local subicular excitatory circuits, connected according to cell type-specific rules, are sufficient to promote epileptiform activity. This conclusion fits well with a previous suggestion that local subicular events, purely mediated by excitatory connections, may underlie the pre-ictal discharges that govern interictal-ictal transitions.

Transcriptomic profile of the subiculum-projecting VIP GABAergic neurons in the mouse CA1 hippocampus.

In cortical circuits, the vasoactive intestinal peptide (VIP+)-expressing GABAergic cells represent a heterogeneous but unique group of interneurons that is mainly specialized in network disinhibition. While the physiological properties and connectivity patterns have been elucidated in several types of VIP+ interneurons, little is known about the cell type-specific molecular repertoires important for selective targeting of VIP+ cell types and understanding their functions. Using patch-sequencing approach, we analyzed the transcriptomic profile of anatomically identified subiculum-projecting VIP+ GABAergic neurons that reside in the mouse hippocampal CA1 area, express muscarinic receptor 2 and coordinate the hippocampo-subicular interactions via selective innervation of interneurons in the CA1 area and of interneurons and pyramidal cells in subiculum. We explored the VIP+ cell gene expression within major gene families including ion channels, neurotransmitter receptors, neuromodulators, cell adhesion and myelination molecules. Among others, a large variety of genes involved in neuromodulatory signaling, including acetylcholine (Chrna4), norepinephrin (Adrb1), dopamine (Drd1), serotonin (Htr1d), cannabinoid (Cnr1), opioid (Oprd1, Oprl1) and neuropeptide Y (Npy1r) receptors was detected in these cells. Many genes that were enriched in other local VIP+ cell types, including the interneuron-selective interneurons and the cholecystokinin-coexpressing basket cells, were detected in VIP+ subiculum-projecting cells. In addition, the neuronatin (Nnat) and the Purkinje Cell Protein 4 (Pcp4) genes, which were detected previously in long-range projecting GABAergic neurons, were also common for the subiculum-projecting VIP+ cells. The expression of some genes was validated at the protein level, with proenkephalin being identified as an additional molecular marker of this VIP+ cell type. Together, our data indicate that the VIP+ subiculum-projecting cells share molecular identity with other VIP+ and long-range projecting GABAergic neurons, which can be important for specific function of these cells associated with their local and distant projection patterns.

Propagation of Hippocampal Ripples to the Neocortex by Way of a Subiculum-Retrospleanial Pathway

Bouts of high frequency activity known as sharp wave ripples (SPW-Rs) facilitate communication between the hippocampus and neocortex. However, the paths and mechanisms by which SPW-Rs broadcast their content are not well understood. Due to its anatomical positioning, the granular retrosplenial cortex (gRSC) may be a bridge for this hippocampo-cortical dialogue. Using silicon probe recordings in awake, head-fixed mice, we show the existence of SPW-R analogues in gRSC and investigate their coupling to hippocampal SPW-Rs. Ensemble activity across regions was congruent across ripples, as neurons in gRSC reliably distinguished the spike content of different types of SPW-Rs. We demonstrate that this coupling is brain-state-dependent, and delineate a topographically-organized anatomical pathway via VGlut2-expressing, bursty neurons in the subiculum. Optogenetic stimulation or inhibition of bursty subicular cells induced or reduced responses in superficial gRSC, respectively. These results identify a specific path and underlying mechanisms by which the hippocampus can convey neuronal content during SPW-Rs to the neocortex.

Region- and Cell Type-Specific Facilitation of Synaptic Function at Destination Synapses Induced by Oligodendrocyte Depolarization.

The axonal conduction of action potentials affects the absolute time it takes to transmit nerve impulses as well as temporal summation at destination synapses. At the physiological level, oligodendrocyte depolarization facilitates axonal conduction along myelinated fibers in the hippocampus; however, the functional significance of this facilitation is largely unknown. In this study, we examined the physiology of the facilitation of axonal conduction by investigating the changes in synaptic responses at destination synapses using male and female mice in which channelrhodopsin-2 expression was restricted to oligodendrocytes. The subiculum, one of the projection areas of the examined axons at the alveus of the hippocampus, is divided into three regions (proximal, mid, and distal) and contains two types of principal neurons: regular firing and bursting pyramidal cells. We found a significant increase in excitatory synaptic responses following optogenetic oligodendrocyte depolarization in bursting neurons at two of the three regions, but not in regular firing neurons at any region. The long-term potentiation (LTP) induced by theta burst stimulation at the synapses showing a significant increase was also enhanced after oligodendrocyte depolarization. Conversely, the reduction of oligodendrocyte depolarization during theta burst stimulation, which was achieved by photostimulation of archaerhodopsin-T expressed selectively on oligodendrocytes, reduced the magnitude of LTP. These results show that oligodendrocyte depolarization contributes to the fine control of synaptic activity between the axons they myelinate and targets subicular cells in a region- and cell type-specific manner, and suggest that oligodendrocyte depolarization during conditioning of stimuli is involved in the induction of LTP.SIGNIFICANCE STATEMENT All activity in the nervous system depends on the propagation of action potentials. Changes in the axonal conduction of action potentials influence the timing of synaptic transmission and information processing in neural circuits. At the physiological level, oligodendrocyte depolarization facilitates axonal conduction along myelinated fibers. In this study, we investigated the functional significance of the facilitation of axonal conduction induced by physiological oligodendrocyte depolarization. Using optogenetics and electrophysiological recordings, we demonstrated that oligodendrocyte depolarization in mice expressing channelrhodopsin-2 on oligodendrocytes increased excitatory synaptic responses and enhanced the induction of long-term potentiation at destination synapses in a region- and cell type-specific manner. This facilitation may have a hitherto unappreciated influence on the transfer of information between regions in the nervous system.

Burst Firing and Spatial Coding in Subicular Principal Cells.

The subiculum is the major output structure of the hippocampal formation and is involved in learning and memory as well as in spatial navigation. Little is known about how neuronal diversity contributes to function in the subiculum. Previously, in vitro studies have identified distinct bursting patterns in the subiculum. Here, we asked how burst firing is related to spatial coding in vivo. Using juxtacellular recordings in freely moving male rats, we studied the bursting behavior of 102 subicular principal neurons and distinguished two populations: sparsely bursting (∼80%) and dominantly bursting neurons (∼20%). These bursting behaviors were not linked to anatomy: both cell types were found all along the proximodistal and radial axes of the subiculum and all identified cells were pyramidal neurons. However, the distinct burst firing patterns were related to functional differences: the activity of sparsely bursting cells showed a stronger spatial modulation than the activity of dominantly bursting neurons. In addition, all cells classified as boundary cells were sparsely bursting cells. In most sparsely bursting cells, bursts defined sharper firing fields and carried more spatial information than isolated spikes. We conclude that burst firing is functionally relevant to subicular spatially tuned neurons, possibly by serving as a mechanism to transmit spatial information to downstream structures.SIGNIFICANCE STATEMENT The subiculum is the major output structure of the hippocampal formation and is involved in spatial navigation. In vitro, subicular cells can be distinguished by their ability to initiate bursts as brief sequences of spikes fired at high frequencies. Little is known about the relationship between cellular diversity and spatial coding in the subiculum. We performed high-resolution juxtacellular recordings in freely moving rats and found that bursting behavior predicts functional differences between subicular neurons. Specifically, sparsely bursting cells have lower firing rates and carry more spatial information than dominantly bursting cells. Additionally, bursts fired by sparsely bursting cells encoded spatial information better than isolated spikes, indicating that bursts act as a unit of information dedicated to spatial coding.

Cell-Type-Specific Changes in Intrinsic Excitability in the Subiculum following Learning and Exposure to Novel Environmental Contexts.

The subiculum is the main target of the hippocampal region CA1 and is the principle output region of the hippocampus. The subiculum is critical to learning and memory, although it has been relatively understudied. There are two functional types of principle neurons within the subiculum: regular spiking (RS) and burst spiking (BS) neurons. To determine whether these cell types are differentially modified by learning-related experience, we performed whole-cell patch clamp recordings from male mouse brain slices following contextual fear conditioning (FC) and memory retrieval relative to a number of control behavioral paradigms. RS cells, but not BS cells, displayed a greater degree of experience-related plasticity in intrinsic excitability measures [afterhyperpolarization (AHP), input resistance (Rinput), current required to elicit a spike], with fear conditioned animals having generally more excitable RS cells compared to naïve controls. Furthermore, we found that the relative proportion of RS to BS neurons is modified by the type of exposure, with the lowest proportion of BS subicular cells occurring in animals that underwent contextual FC followed by a retrieval test. These studies indicate that pyramidal neurons in the subiculum undergo experience- and learning-related plasticity in intrinsic properties in a cell-type-specific manner. As BS and RS cells are thought to convey distinct types of information, this plasticity may be particularly important in encoding, consolidating, and recalling spatial information by modulating information flow from the hippocampus to cortical regions.

Routes to, from and within the subiculum.

The subiculum is one of the major output areas of the hippocampus and has extensive projections to extrahippocampal targets. It is likely to play a pivotal role in the distribution of outgoing information from the hippocampus. The hippocampus, including the subiculum, is important for the formation, consolidation and retrieval of memory. These functions require a network that is flexible enough to encode incoming information and also allows for reliable distribution, storage and integration into previously encoded memories. Finally, relevant information has to be retrieved in a context-specific manner to allow for an appropriate behavioral response. The subiculum as a gateway between the hippocampus and cortex might serve to integrate and process information from the hippocampus proper and its other inputs before conveying it to more permanent storage locations. This review summarizes how the subiculum is embedded into upstream and downstream circuits, describes what is known about the local network topology and discusses cellular and functional properties of subicular cells subtypes. Lastly, it describes how these properties might help to separate information into parallel output streams and distribute it to its multiple target areas.

Effects of a reduced efficacy of the KCC2 co-transporter in temporal lobe epilepsy: single neuron and network study

Epilepsy is one of the most common neurological disorders. Seizures in about 40% of patients with temporal lobe epilepsies are pharmaco-resistant [1]. In surgically removed hippocampal tissue from these patients, the KCC2 cotransporter is absent or non-functional in about 20 % of subicular pyramidal cells [2]. KCC2 normally assures the maintenance of low intra-neuronal chloride levels [3] and also regulates potassium levels [4]. Chloride concentration changes in the remaining pyramidal cells due to intensive GABAergic input during seizures could reverse the effects of GABA currents from inhibitory to excitatory [5,6]. Such changes may shift a pyramidal cell into a periodic bursting regime associated with ictal discharges. Using a detailed biophysical model of a single cell incorporating these mechanisms of ionic homeostasis and a neural network model, we show that decreasing the activity of KCC2 pump leads to repetitive seizure-like firing in the pathologic network due to increased extracellular potassium and intracellular chloride (Fig. ​(Fig.1).1). This model provides insights into how a dysregulation of pyramidal cell chloride homeostasis due to reduced levels of the KCC2 cotransporter may lead to seizures in the epileptic human subiculum. Figure 1 A raster plot of pyramidal cell population firing; B raster plot of interneuron firing; C spatial distribution of extracellular potassium; D intracellular chloride distribution.

Hippocampal disconnection in early Alzheimer's disease: a 7 tesla MRI study.

In patients with Alzheimer's disease (AD), atrophy of the entorhinal cortex (ERC) and hippocampal formation may induce degeneration of connecting white matter tracts. We examined the association of hippocampal subfield and ERC atrophy at 7 tesla MRI with fornix and parahippocampal cingulum (PHC) microstructure in patients with early AD. Twenty-five patients with amnestic mild cognitive impairment (aMCI) (n = 15) or early AD (n = 10) and 17 controls underwent 3 tesla diffusion MRI to obtain fractional anisotropy (FA) of the fornix and PHC and 7 tesla MRI to obtain ERC and hippocampal subfield volumes. Linear regression analyses were performed, adjusted for age, gender, and intracranial volume. Fornix FA was significantly lower and subiculum, cornu ammonis (CA) 1, and dentate gyrus &CA4 volume were significantly smaller in patients with MCI or AD as compared to controls. In patients with MCI or AD, fornix FA was positively associated with subiculum volume (β = 0.53, 95% CI 0.10; 0.96), but not with ERC/other subfield volumes. PHC FA was not associated with ERC/subfield volumes. These findings indicate that in early AD subiculum atrophy is associated with lower FA of the fornix, which primarily consists of axons originating in the subiculum. This suggests that degeneration of subicular cell bodies and their axons are related processes in early AD.

Hippocampus and epilepsy: Findings from human tissues

Surgical removal of the epileptogenic zone provides an effective therapy for several focal epileptic syndromes. This surgery offers the opportunity to study pathological activity in living human tissue for pharmacoresistant partial epilepsy syndromes including temporal lobe epilepsies with hippocampal sclerosis, cortical dysplasias, epilepsies associated with tumors and developmental malformations. Slices of tissue from patients with these syndromes retain functional neuronal networks and may generate epileptic activities. The properties of cells in this tissue may not be greatly changed, but excitatory synaptic transmission is often enhanced and GABAergic inhibition is preserved. Typically epileptic activity is not generated spontaneously by the neocortex, whether dysplastic or not, but can be induced by convulsants. The initiation of ictal discharges in the neocortex depends on both GABAergic signaling and increased extracellular potassium. In contrast, a spontaneous interictal-like activity is generated by tissues from patients with temporal lobe epilepsies associated with hippocampal sclerosis. This activity is initiated, not in the hippocampus but in the subiculum, an output region, which projects to the entorhinal cortex. Interictal events seem to be triggered by GABAergic cells, which paradoxically excite about 20% of subicular pyramidal cells while simultaneously inhibiting the majority. Interictal discharges thus depend on both GABAergic and glutamatergic signaling. The depolarizing effects of GABA depend on a pathological elevation in levels of chloride in some subicular cells, similar to those of developmentally immature cells. Such defect is caused by a perturbed expression of the cotransporters regulating intracellular chloride concentration, the importer NKCC1 and the extruder KCC2. Blockade of NKCC1 actions by the diuretic bumetanide restores intracellular chloride and thus hyperpolarizing GABAergic actions and consequently suppressing interictal activity.

Topographic distribution of cortical projection cells in the rat subiculum

The topographic distribution of subicular pyramidal cells, which give rise to projections to the entorhinal cortex, presubiculum, parasubiculum, and the retrosplenial granular cortex, was investigated in the rat using retrograde labeling with wheat germ agglutinin-horseradish peroxidase. Using two-dimensional unfolded maps of the entire hippocampal and parahippocampal fields, we found that the cells originating the projections to the above cortical areas were consistently observed throughout the entire septotemporal extent of the subiculum. In the transverse plane, most of the cortical projection cells were vertically located in the middle region of the subicular pyramidal cell layer. The cells giving rise to the projections to the lateral entorhinal cortex were predominantly located in the most proximal (near CA1), superficial region. Few cortical projection cells were located in the deepest (adjacent to the angular bundle) region. The distribution of cortical projection cells showed an oblique tri-laminar pattern, which was similar to the previously reported laminal pattern of subcortical projection cells in the subiculum. These results suggest that cortical projection cells in middle and superficial regions of the subiculum may correspond to layer V of the isocortex and cells in the deepest region corresponding to layer VI.

Anatomical substrates for direct interactions between hippocampus, medial prefrontal cortex, and the thalamic nucleus reuniens.

The reuniens nucleus in the midline thalamus projects to the medial prefrontal cortex (mPFC) and the hippocampus, and has been suggested to modulate interactions between these regions, such as spindle-ripple correlations during sleep and theta band coherence during exploratory behavior. Feedback from the hippocampus to the nucleus reuniens has received less attention but has the potential to influence thalamocortical networks as a function of hippocampal activation. We used the retrograde tracer cholera toxin B conjugated to two fluorophores to study thalamic projections to the dorsal and ventral hippocampus and to the prelimbic and infralimbic subregions of mPFC. We also examined the feedback connections from the hippocampus to reuniens. The goal was to evaluate the anatomical basis for direct coordination between reuniens, mPFC, and hippocampus by looking for double-labeled cells in reuniens and hippocampus. In confirmation of previous reports, the nucleus reuniens was the origin of most thalamic afferents to the dorsal hippocampus, whereas both reuniens and the lateral dorsal nucleus projected to ventral hippocampus. Feedback from hippocampus to reuniens originated primarily in the dorsal and ventral subiculum. Thalamic cells with collaterals to mPFC and hippocampus were found in reuniens, across its anteroposterior axis, and represented, on average, about 8% of the labeled cells in reuniens. Hippocampal cells with collaterals to mPFC and reuniens were less common (~1% of the labeled subicular cells), and located in the molecular layer of the subiculum. The results indicate that a subset of reuniens cells can directly coordinate activity in mPFC and hippocampus. Cells with collaterals in the hippocampus-reuniens-mPFC network may be important for the systems consolidation of memory traces and for theta synchronization during exploratory behavior.

Beta-adrenergic receptor activation induces long-lasting potentiation in burst-spiking but not regular-spiking cells at CA1-subiculum synapses

The hippocampus plays a central role in memory formation in the mammalian brain. The subiculum is the principal target of CA1 pyramidal cells and thus serves as the major relay station for the outgoing hippocampal information. Pyramidal cells in the subiculum have been classified as burst-spiking (BS) and regular-spiking (RS) cells. In this study we demonstrate that application of the β-adrenergic agonist isoproterenol (2 μM) induces a chemical form of long-term potentiation (LTP) of responses to alvear stimulation in (BS) but not in (RS) cells. This effect is prevented by the β-adrenergic receptor antagonist propranolol (2 μM). The isoproterenol-induced LTP in (BS) cells does not depend on postsynaptic Ca2+-signaling, as 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA) does not prevent its induction. Furthermore, paired-pulse facilitation (PPF) and coefficient of variation (CV) analysis indicate the site of the LTP expression to be presynaptic. Our findings show that activation of β-adrenergic receptors (β-ARs) at CA1-subiculum synapses induces a cell-type-specific form of chemical LTP in subicular (BS) cells that may allow a target-specific trafficking of hippocampal output.

Parallel but separate inputs from limbic cortices to the mammillary bodies and anterior thalamic nuclei in the rat.

The proposal that separate populations of subicular cells provide the direct hippocampal projections to the mammillary bodies and anterior thalamic nuclei was tested by placing two different fluorescent tracers in these two sites. In spite of varying the injection locations within the mammillary bodies and within the three principal anterior thalamic nuclei and the lateral dorsal thalamic nucleus, the overall pattern of results remained consistent. Neurons projecting to the thalamus were localized to the deepest cell populations within the subiculum while neurons projecting to the mammillary bodies consisted of more superficially placed pyramidal cells within the subiculum. Even when these two cell populations become more intermingled, e.g., in parts of the intermediate subiculum, almost no individual cells were found to project to both diencephalic targets. In adjacent limbic areas, i.e., the retrosplenial cortex, postsubiculum, and entorhinal cortex, populations of cells that project to the anterior thalamic nuclei and mammillary bodies were completely segregated. This segregated pattern included afferents to those nuclei comprising the head-direction system. The sole exception was a handful of double-labeled cells, mainly confined to the ventral subiculum, that were only found after pairs of injections in the anteromedial thalamic nucleus and mammillary bodies. The projections to the anterior thalamic nuclei also had a septal-temporal gradient with relatively fewer cells projecting from the ventral (temporal) subiculum. These limbic projections to the mammillary bodies and anterior thalamus comprise a circuit that is vital for memory, within which the two major components could convey parallel, independent information.

Environmental novelty elicits a later theta phase of firing in CA1 but not subiculum.

The mechanism supporting the role of the hippocampal formation in novelty detection remains controversial. A comparator function has been variously ascribed to CA1 or subiculum, whereas the theta rhythm has been suggested to separate neural firing into encoding and retrieval phases. We investigated theta phase of firing in principal cells in subiculum and CA1 as rats foraged in familiar and novel environments. We found that the preferred theta phase of firing in CA1, but not subiculum, was shifted to a later phase of the theta cycle during environmental novelty. Furthermore, the amount of phase shift elicited by environmental change correlated with the extent of place cell remapping in CA1. Our results support a relationship between theta phase and novelty-induced plasticity in CA1.

Light stress effects on Subicular and CA1 place cells and its implications in a MWM test in young wistar rats

Light stress effects on Subicular and CA1 place cells and its implications in a MWM test in young wistar rats

Muscarinic acetylcholine receptors and voltage-gated calcium channels contribute to bidirectional synaptic plasticity at CA1-subiculum synapses

Hippocampal output is mediated via the subiculum, which is the principal target of CA1 pyramidal cells, and which sends projections to a variety of cortical and subcortical regions. Pyramidal cells in the subiculum display two different firing modes and are classified as being burst-spiking or regular-spiking. In a previous study, we found that low-frequency stimulation induces an NMDA receptor-dependent long-term depression (LTD) in burst-spiking cells and a metabotropic glutamate receptor-dependent long-term potentiation (LTP) in regular-spiking cells [P. Fidzinski, O. Shor, J. Behr, Target-cell-specific bidirectional synaptic plasticity at hippocampal output synapses, Eur. J. Neurosci., 27 (2008) 1111–1118]. Here, we present evidence that this bidirectional plasticity relies upon the co-activation of muscarinic acetylcholine receptors, as scopolamine blocks synaptic plasticity in both cell types. In addition, we demonstrate that the L-type calcium channel inhibitor nifedipine converts LTD to LTP in burst-spiking cells and LTP to LTD in regular-spiking cells, indicating that the polarity of synaptic plasticity is modulated by voltage-gated calcium channels. Bidirectional synaptic plasticity in subicular cells therefore appears to be governed by a complex signaling system, involving cell-specific recruitment of ligand and voltage-gated ion channels as well as metabotropic receptors. This complex regulation might be necessary for fine-tuning of synaptic efficacy at hippocampal output synapses.