Subicular Complex Research Articles

New Hippocampal Circuit Organization Revealed by Viral‐genetic Tracing and Functional Circuit Mapping

The hippocampal formation plays essential roles in learning and memory, and spatial navigation. Although the general anatomy and circuit organization of hippocampal CA1 has been well‐studied, most of our understanding of hippocampal circuits comes from the conventional anatomical tracing studies which lack cell‐type specificity and quantitative measurements of connectional strengths. New advances in virology and molecular genetics complement traditional approaches and are powerful tools for mapping cell‐type‐specific circuit connectivity and function. Using monosynaptic rabies tracing, we recently discovered a non‐canonical but significant set of back‐projections comprised of both excitatory and inhibitory elements from the subiculum to CA1 in the mouse. This discovery suggests previously unconsidered functional roles for direct subicular modulation of hippocampal CA1 circuit activity. In this talk, I will first report our quantitative analysis of canonical‐ and non‐canonical inputs to excitatory neurons in dorsal hippocampal CA1. We find that comparable strength of subiculum complex and entorhinal cortex (EC) inputs to CA1, significant inputs from presubiculum and parasubiculum to CA1, and a threefold stronger input to proximal versus distal CA1 from CA3. Non‐canonical subicular complex inputs exhibit opposing topographic connectivity gradients whereby the subiculum‐CA1 input strength systematically increases but the presubiculum‐CA1 input strength decreases along the proximal‐distal axis. These results reveal a novel anatomical framework by which to determine the circuit bases for CA1 physiological representations. Further, to test the hypothesis that CA1‐projecting subiculum neurons integrate strong CA1 and local subicular inputs to exert direct feedback regulation of CA1 circuit activity, we map and compare global circuit input and output connections of CA1‐projecting and other excitatory subicular neurons using retrograde monosynaptic rabies tracing and anterograde directed herpes simplex virus (H129 strain) in intact brains, respectively. In conjunction with behavior analysis and genetically targeted neuronal activation and inactivation, in vivo GCaMP6‐based calcium imaging of CA1 neurons in freely moving animals is used to resolve how CA1‐projecting subicular neurons modulate CA1 place cell activity and how they contribute to location dependent learning and memory. Together, these studies provide new insights into this subicular‐CA1 pathway, and advance our understanding of how the subiculum interacts with CA1 to regulate hippocampal circuit activity and learning and memory behaviors.Support or Funding InformationThis research is supported by the National Institutes of Health grant (R01NS078434).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

RETRACTED ARTICLE: Solid lipid curcumin particles provide greater anti-amyloid, anti-inflammatory and neuroprotective effects than curcumin in the 5xFAD mouse model of Alzheimer’s disease

BackgroundNeuroinflammation and the presence of amyloid beta protein (Aβ) and neurofibrillary tangles are key pathologies in Alzheimer’s disease (AD). As a potent anti-amyloid and anti-inflammatory natural polyphenol, curcumin (Cur) could be potential therapies for AD. Unfortunately, poor solubility, instability in physiological fluids, and low bioavailability limit its clinical utility. Recently, different lipid modifications in the formulae of Cur have been developed that would enhance its therapeutic potential. For example, we have reported greater permeability and neuroprotection with solid lipid curcumin particles (SLCP) than with natural Cur in an in vitro model of AD. In the present study, we compared the Aβ aggregation inhibition, anti-amyloid, anti-inflammatory responses of Cur and or SLCP in both in vitro and in vivo models of AD. One-year-old 5xFAD-and age-matched wild-type mice were given intraperitoneal injections of Cur or SLCP (50 mg/kg body weight) for 2- or 5-days. Levels of Aβ aggregation, including oligomers and fibril formation, were assessed by dot blot assay, while Aβ plaque load and neuronal morphology in the pre-frontal cortex (PFC) and hippocampus were assayed by immunolabeling with Aβ-specific antibody and cresyl violet staining, respectively. In addition, neuroinflammation was assessed the immunoreactivity (IR) of activated astrocytes (GFAP) and microglia (Iba-1) in different brain areas. Finally, comparisons of solubility and permeability of Cur and SLCP were made in cultured N2a cells and in primary hippocampal neurons derived from E16 pups of 5xFAD mice.ResultsWe observed that relative to Cur, SLCP was more permeable, labeled Aβ plaques more effectively, and produced a larger decrease in Aβ plaque loads in PFC and dentate gyrus (DG) of hippocampus. Similarly, relative to Cur, SLCP produced a larger decrease of pyknotic, or tangle-like, neurons in PFC, CA1, and CA3 areas of hippocampus after 5 days of treatment. Both Cur and or SLCP significantly reduced GFAP-IR and Iba-1-IR in PFC, in the striatum as well as CA1, CA3, DG, subicular complex of hippocampus, and the entorhinal cortex in the 5xFAD mice after 5 days of treatment.ConclusionsThe use of SLCP provides more anti-amyloid, anti-inflammatory, and neuroprotective outcomes than does Cur in the 5xFAD mouse model of AD.

Opposing and Complementary Topographic Connectivity Gradients Revealed by Quantitative Analysis of Canonical and Noncanonical Hippocampal CA1 Inputs.

Physiological studies suggest spatial representation gradients along the CA1 proximodistal axis. To determine the underlying anatomical basis, we quantitatively mapped canonical and noncanonical inputs to excitatory neurons in dorsal hippocampal CA1 along the proximal-distal axis in mice of both sexes using monosynaptic rabies tracing. Our quantitative analyses show comparable strength of subiculum complex and entorhinal cortex (EC) inputs to CA1, significant inputs from presubiculum and parasubiculum to CA1, and a threefold stronger input to proximal versus distal CA1 from CA3. Noncanonical subicular complex inputs exhibit opposing topographic connectivity gradients whereby the subiculum-CA1 input strength systematically increases but the presubiculum-CA1 input strength decreases along the proximal-distal axis. The subiculum input strength cotracks that of the lateral EC, known to be less spatially selective than the medial EC. The functional significance of this organization is verified physiologically for subiculum-to-CA1 inputs. These results reveal a novel anatomical framework by which to determine the circuit bases for CA1 representations.

Complementary Modular Microcircuits of the Rat Medial Entorhinal Cortex.

The parahippocampal region is organized into different areas, with the medial entorhinal cortex (MEC), presubiculum and parasubiculum prominent in spatial memory. Here, we also describe a region at the extremity of the MEC and bordering the subicular complex, the medial-most part of the entorhinal cortex. While the subdivisions of hippocampus proper form more or less continuous cell sheets, the superficial layers of the parahippocampal region have a distinct modular architecture. We investigate the spatial distribution, laminar position, and putative connectivity of zinc-positive modules in layer 2 of the MEC of rats and relate them to the calbindin-positive patches previously described in the entorhinal cortex. We found that the zinc-positive modules are complementary to the previously described calbindin-positive patches. We also found that inputs from the presubiculum are directed toward the zinc-positive modules while the calbindin-positive patches received inputs from the parasubiculum. Notably, the dendrites of neurons from layers 3 and 5, positive for Purkinje Cell Protein 4 expression, overlap with the zinc modules. Our data thus indicate that these two complementary modular systems, the calbindin patches and zinc modules, are part of parallel information streams in the hippocampal formation.

Cocaine- and amphetamine-regulated transcript and calcium binding proteins immunoreactivity in the subicular complex of the guinea pig

In this study we present the distribution and colocalization pattern of cocaine- and amphetamine-regulated transcript (CART) and three calcium-binding proteins: calbindin (CB), calretinin (CR) and parvalbumin (PV) in the subicular complex (SC) of the guinea pig. The subiculum (S) and presubiculum (PrS) showed higher CART-immunoreactivity (-IR) than the parasubiculum (PaS) as far as the perikarya and neuropil were concerned. CART- IR cells were mainly observed in the pyramidal layer and occasionally in the molecular layer of the S. In the PrS and PaS, single CART-IR perikarya were dispersed, however with a tendency to be found only in superficial layers. CART-IR fibers were observed throughout the entire guinea pig subicular neuropil. Double-labeling immunofluorescence showed that CART-IR perikarya, as well as fibers, did not stain positively for any of the three CaBPs. CART-IR fibers were only located near the CB-, CR-, PV-IR perikarya, whereas CART-IR fibers occasionally intersected fibers containing one of the three CaBPs. The distribution pattern of CART was more similar to that of CB and CR than to that of PV. In the PrS, the CART, CB and CR immunoreactivity showed a laminar distribution pattern. In the case of the PV, this distribution pattern in the PrS was much less prominent than that of CART, CB and CR. We conclude that a heterogeneous distribution of the CART and CaBPs in the guinea pig SC is in keeping with findings from other mammals, however species specific differences have been observed.

Developmental Profile, Morphology, and Synaptic Connectivity of Cajal-Retzius Cells in the Postnatal Mouse Hippocampus.

Cajal–Retzius (CR) cells are early generated neurons, involved in the assembly of developing neocortical and hippocampal circuits. However, their roles in networks of the postnatal brain remain poorly understood. In order to get insights into these latter functions, we have studied their morphological and synaptic properties in the postnatal hippocampus of the CXCR4-EGFP mouse, where CR cells are easily identifiable. Our data indicate that CR cells are nonuniformly distributed along different subfields of the hippocampal formation, and that their postnatal decline is regulated in a region-specific manner. In fact, CR cells persist in distinct areas of fully mature animals. Subclasses of CR cells project and target either local (molecular layers) or distant regions [subicular complex and entorhinal cortex (EC)] of the hippocampal formation, but have similar firing patterns. Lastly, CR cells are biased toward targeting dendritic shafts compared with spines, and produce large-amplitude glutamatergic unitary postsynaptic potentials on γ-aminobutyric acid (GABA) containing interneurons. Taken together, our results suggest that CR cells are involved in a novel excitatory loop of the postnatal hippocampal formation, which potentially contributes to shaping the flow of information between the hippocampus, parahippocampal regions and entorhinal cortex, and to the low seizure threshold of these brain areas.

Altered functional connectivity networks of hippocampal subregions in remitted late-onset depression: a longitudinal resting-state study

The regional specificity of hippocampal abnormalities in late-life depression (LLD) has been demonstrated in previous studies. In this study, we sought to examine the functional connectivity (FC) patterns of hippocampal subregions in remitted late-onset depression (rLOD), a special subtype of LLD. Fourteen rLOD patients and 18 healthy controls underwent clinical and cognitive evaluations as well as resting-state functional magnetic resonance imaging scans at baseline and at ∼21 months of follow-up. Each hippocampus was divided into three parts, the cornu ammonis (CA), the dentate gyrus, and the subicular complex, and then six seed-based hippocampal subregional networks were established. Longitudinal changes of the six networks over time were directly compared between the rLOD and control groups. From baseline to follow-up, the rLOD group showed a greater decline in connectivity of the left CA to the bilateral posterior cingulate cortex/precuneus (PCC/PCUN), but showed increased connectivity of the right hippocampal subregional networks with the frontal cortex (bilateral medial prefrontal cortex/anterior cingulate cortex and supplementary motor area). Further correlative analyses revealed that the longitudinal changes in FC between the left CA and PCC/PCUN were positively correlated with longitudinal changes in the Symbol Digit Modalities Test (r = 0.624, P = 0.017) and the Digit Span Test (r = 0.545, P = 0.044) scores in the rLOD group. These results may provide insights into the neurobiological mechanism underlying the cognitive dysfunction in rLOD patients.

Anatomy of the hippocampal formation.

The hippocampus is one of several brain regions that together comprise the hippocampal formation. The hippocampal formation is a prominent C-shaped structure bulging in the floor of the temporal horn of the lateral ventricle. The hippocampus proper consists of three major subfields (CA1-CA3). The other regions that together comprise the hippocampal formation consist of the dentate gyrus, the subicular complex, and the entorhinal cortex. Based on its extrinsic connectivity, the hippocampal formation receives a vast amount of highly processed multimodal sensory information that is funneled into the hippocampal formation mainly by the entorhinal cortex. The entorhinal cortex is connected to associational neocortical areas in a reciprocal manner. Extensive hippocampal integration of sensory information is established by a largely unidirectional chain of intrinsic hippocampal projections. Our current knowledge on hippocampal connectivity and function is largely based on studies of rodents and monkeys. It still remains to be determined to which extent such neuroanatomical data of experimental animals is applicable to the human hippocampal formation.

Comparative anatomy of the prosubiculum, subiculum, presubiculum, postsubiculum, and parasubiculum in human, monkey, and rodent

The subicular complex, including the prosubiculum (ProS), subiculum (Sub), presubiculum, postsubiculum (PoS), and parasubiculum (PaS), plays important roles in the medial temporal memory system and is heavily involved in many neurological diseases such as Alzheimer's disease and epilepsy. In the literature, the ProS (in primate) and PoS (in rodent) are inconstantly identified, making data comparison difficult across species. This review is an attempt to discuss equivalencies and extent of the five subicular components in human, monkey, and rodent based on available information on their cytoarchitecture, chemoarchitecture, molecular signature, and neural connectivity. All five subicular cortices exist in human, monkey, and rodent. In human and monkey, the ProS and Sub extend into the uncal region anteriorly, and the PoS and PaS reach the cingulate isthmus posteriorly. In rodent, most of the typical subicular cortices are located in the dorsal and caudal portions of the hippocampal formation, and the modified version of the ventral ProS and Sub corresponds to the modified description of the uncal ProS and Sub in monkey and human. An interesting triangular region in rodent located at the juncture of the PoS, PaS, retrosplenial cortex, and visual cortex appears to be the equivalent of the monkey area prostriata. Major connections of the five subicular cortices are also summarized based on unified criteria discussed in this review, with distinct connections revealed between the ProS and the Sub.

Multisynaptic Inputs from the Medial Temporal Lobe to V4 in Macaques

Retrograde transsynaptic transport of rabies virus was employed to undertake the top-down projections from the medial temporal lobe (MTL) to visual area V4 of the occipitotemporal visual pathway in Japanese monkeys (Macaca fuscata). On day 3 after rabies injections into V4, neuronal labeling was observed prominently in the temporal lobe areas that have direct connections with V4, including area TF of the parahippocampal cortex. Furthermore, conspicuous neuron labeling appeared disynaptically in area TH of the parahippocampal cortex, and areas 35 and 36 of the perirhinal cortex. The labeled neurons were located predominantly in deep layers. On day 4 after the rabies injections, labeled neurons were found in the hippocampal formation, along with massive labeling in the parahippocampal and perirhinal cortices. In the hippocampal formation, the densest neuron labeling was seen in layer 5 of the entorhinal cortex, and a small but certain number of neurons were labeled in other regions, such as the subicular complex and CA1 and CA3 of the hippocampus proper. The present results indicate that V4 receives major input from the hippocampus proper via the entorhinal cortex, as well as “short-cut” pathways that bypass the entorhinal cortex. These multisynaptic pathways may define an anatomical basis for hippocampal-cortical interactions involving lower visual areas. The multisynaptic input from the MTL to V4 is likely to provide mnemonic information about object recognition that is accomplished through the occipitotemporal pathway.

IC‐P‐096: Altered functional brain network in cognitively normal elderly with genetic high risk for Alzheimer's disease: Graph‐theoretical analysis of brain glucose metabolism

carriers had lower volumes at bilateral presubiculum, left hippocampus & left subiculum. Among controls none of the hippocampal subfields were differing between ApoE4 carrier status. Conclusions: Study validates previous observations of hippocampal atrophy including the sub-regions in AD. There is a modest association between ApoE4 carrier status and alterations in white-matter microstructural integrity at medial temporal and hippocampus. ApoE4 associated changes are more pronounced in AD with atrophy of subicular complex, which is the main information router from hippocampus to subcortical structures.

Selective disconnection of the hippocampal formation projections to the mammillary bodies produces only mild deficits on spatial memory tasks: Implications for fornix function

It is now clear that the integrity of the fornix is important for normal mnemonic function. The fornix, however, is a major white matter tract, carrying numerous hippocampal formation afferents and efferents, and it is not known which specific components support memory processes. Established theories of extended hippocampal function emphasize the sequential pathway from the hippocampal formation (i.e., subicular complex) to the mammillary bodies and, thence, to the anterior thalamus, as pathology in each of these structures is implicated in anterograde amnesia in humans and spatial memory deficits in rats. The specific importance of the hippocampal formation projections that just innervate the mammillary bodies has, however, never been tested. This study isolated these specific projections in the rat by selectively cutting the descending component of the postcommissural fornix. Two successive, cohorts of rats with these tract lesions were tested on working memory tasks in the water-maze, T-maze, and radial-arm maze. Disconnecting the descending postcommissural fornix had only a mild effect or sometimes no apparent effect on the performance of these spatial memory tasks, even though tracing experiments confirmed the loss of hippocampal formation-mammillary projections. One implication is that the spatial deficits found in rats following standard fornix lesions are only partly attributable to the loss of projections from the hippocampal formation to the mammillary bodies. Perhaps more surprising, the behavioral impact of cutting the descending postcommissural fornix in rats appeared appreciably less than the effect of either mammillary body or mammillothalamic tract lesions. The present experiments show that the mammillary bodies can still effectively support spatial memory in the absence of their dense subicular complex inputs, so revealing the importance of the other afferents for sustaining mammillary body function. This new evidence for independent functions shows that the mammillary bodies are more than just a hippocampal relay.

Intact Performance on Feature-Ambiguous Discriminations in Rats with Lesions of the Perirhinal Cortex

We developed a behavioral paradigm for the rat that made it possible to separate the evaluation of memory functions from the evaluation of perceptual functions. Animals were given extensive training on an automated two-choice discrimination task and then maintained their memory performance at a high level while interpolated probe trials tested visual perceptual ability. The probe trials systematically varied the degree of feature ambiguity between the stimuli, such that perceptual functions could be tested across 14 different levels of difficulty. As feature ambiguity increased, performance declined in an orderly, monotonic manner (from 87% correct to chance, 50% correct). Bilateral lesions of the perirhinal cortex fully spared the capacity to make feature-ambiguous discriminations and the performance of lesioned and intact animals was indistinguishable at every difficulty level. In contrast, the perirhinal lesions did impair recognition memory. The findings suggest that the perirhinal cortex is important for memory and not for perceptual functions.

Cholinotrophic basal forebrain system alterations in 3xTg-AD transgenic mice

The cholinotrophic system, which is dependent upon nerve growth factor and its receptors for survival, is selectively vulnerable in Alzheimer's disease (AD). But, virtually nothing is known about how this deficit develops in relation to the hallmark lesions of this disease, amyloid plaques and tau containing neurofibrillary tangles. The vast majority of transgenic models of AD used to evaluate the effect of beta amyloid (Aβ) deposition upon the cholinotrophic system over-express the amyloid precursor protein (APP). However, nothing is known about how this system is affected in triple transgenic (3xTg)-AD mice, an AD animal model displaying Aβ plaque- and tangle-like pathology in the cortex and hippocampus, which receive extensive cholinergic innervation. We performed a detailed morphological and biochemical characterization of the cholinotrophic system in young (2–4 months), middle-aged (13–15 months) and old (18–20 months) 3xTg-AD mice. Cholinergic neuritic swellings increased in number and size with age, and were more conspicuous in the hippocampal–subicular complex in aged female than in 3xTg-AD male mice. Stereological analysis revealed a reduction in choline acetyltransferase (ChAT) positive cells in the medial septum/vertical limb of the diagonal band of Broca in aged 3xTg-AD mice. ChAT enzyme activity levels decreased significantly in the hippocampus of middle-aged 3xTg-AD mice compared to age-matched non-transgenic (or wild type) mice. ProNGF protein levels increased in the cortex of aged 3xTg-AD mice, whereas TrkA protein levels were reduced in a gender-dependent manner in aged mutant mice. In contrast, p75 NTR protein cortical levels were stable but increased in the hippocampus of aged 3xTg-AD mice. These data demonstrate that cholinotrophic alterations in 3xTg-AD mice are age- and gender-dependent and more pronounced in the hippocampus, a structure more severely affected by Aβ plaque pathology.

Morphology of neurons of human subiculum proper

Subiculum proper is an archicortical structure of the subicular complex and presents the place of origin of great majority of axons of the whole hippocampal formation. In contrast to the hippocampus which has been intensively studied, the data about human subiculum proper are quite scarce. The aim of our study was to identify morphological characteristics of neurons of the human subiculum proper. The study was performed on 10 brains of both genders by using Golgi impregnation and Nissl staining. The subiculum has three layers: molecular, pyramidal and polymorphic layer. The dominant cell type in the pyramidal layer was the pyramidal neurons, which had pyramidal shaped soma, multiple basal dendrites and one apical dendrite. The nonpyramidal cells were scattered among the pyramidal cells of the pyramidal layer. The nonpyramidal cells were classified on: multipolar, bipolar and neurons with triangular-shaped soma. The neurons of the molecular layer of the human subiculum were divided into groups: bipolar and multipolar neurons. The most numerous cells of the polymorphic layer were bipolar and multipolar neurons.

The limbic system

Byline: V. RajMohan, E. Mohandas hypothalamus, anterior thalamic nucleus, cingulate gyrus, hippocampus and their interconnections, constitute a harmonious mechanism which may elaborate functions of central emotion as well as participate in emotional expression. James Papez, 1937 The consists of phylogenetically old lobe and other subcortical structures and their connections. Although not empirically proven, is a functional concept which may be employed to explain various brain functions.[sup] [1] History Paul Pierre Broca in 1878 spoke of ' le grand lobe limbique' or great lobe and applied term (from Latin limbus for border) to curved rim of cortex which incudes cingulate and parahippocampal gyri. However, its putative role in emotion was elaborated by American physician, James Papez in 1937 in seminal paper titled 'A proposed mechanism of emotion'. This anatomical model is referred to as Papez circuit.[sup] [2] Yakovlev in 1948 proposed Yakovlev's circuit in control of emotion involving orbitofrontal, insular and anterior temporal lobe cortex, amygdala and dorsomedial nucleus of thalamus.[sup] [3] In 1952, Paul D. MacLean coined term limbic system to describe Broca's lobe and related subcortical nuclei as collective neural substrate for emotion.[sup] [1] MacLean was also instrumental in proposing and defining concept of brain. MacLean's evolutionary Triune brain theory proposed that human brain was in reality three brains in one: R-complex (reptilian complex), and neocortex.[sup] [4] The concept of has since been further expanded and developed by Nauta, Heimer and others. Components of Limbic System There is no universal agreement on total list of structures, which comprise system. The brain regions that constitute are: *Limbic cortex i. Cingulate ii. Parahippocampal *Hippocampal formation i. The dentate ii. Hippocampus iii. Subicular Complex *Amygdala *Septal area *Hypothalamus These structures form a complex network for controlling emotion.[sup] [5] Limbic lobe The lobe situated at inferomedial aspect of the[sup] cerebral hemispheres, consists of two concentric gyri surrounding[sup] corpus callosum. Broca proposed that larger outer gyrus[sup] be named[sup] gyrus and smaller inner one the intralimbic gyrus.[sup] The (limbic lobe) consists of the[sup] isthmus of cingulate gyrus, parahippocampal (both of which are continuous via a bundle of white matter called cingulum) and subcallosal area.[sup] [6] The cingulate (Latin = Belt ridge) dorsal to corpus callosum is heavily interconnected with association areas of cerebral cortex. The parahippocampal in medial temporal lobe contains several distinct regions, most important being entorhinal cortex (ERC). The ERC funnels highly processed cortical information to hippocampal formation and serves as its major output pathway.[sup] [5] The hippocampal formation Hippocampal formation in temporal lobe has three distinct zones: *The dentate *The hippocampus proper *The subiculum Embryologically, hippocampal formation is an extension of medial edge of temporal lobe. The entire hippocampal formation has a length of about 5 cm from its anterior end at amygdala to its tapering posterior end near splenium of corpus callosum.[sup] [5] Dentate The dentate is composed of three layers: an outer acellular molecular layer, a granular middle layer and an inner polymorphic layer. …

Depolarizing, GABA-mediated synaptic responses and their possible role in epileptiform events; Simulation studies

Synaptic transmission controlled by the release of the inhibitory neurotransmitter GABA is generally considered to be the mechanism by which glutamate-mediated excitation is kept under control in the human hippocampus and neocortex. Until recently, epilepsy was thought of as a simple imbalance of neuronal excitation and inhibition. This theory of epileptogenesis has been challenged by the finding that GABA does not always inhibit neuronal activity. Although in adult brain GABA usually induces hyperpolarization of cell membranes, in juvenile brain GABA is depolarizing, bringing the neuronal membrane closer to firing threshold, often enabling action potentials to be triggered. Somewhat surprisingly, GABA-mediated synaptic responses in adult brain tissue can sometimes be excitatory, too. Cohen et al. [I. Cohen, V. Navarro, S. Clemenceau, M. Baulac, R. Miles, On the origin of interictal activity in human temporal lobe epilepsy in vitro, Science 298 (2002) 1418–1421] discovered a subpopulation of excitatory projection cells that exhibited depolarizing GABA responses in slices from epileptic adult subiculum. While most subicular pyramidal cells displayed hyperpolarized behavior in response to GABA, some actually fired bursts of action potentials, in synchrony with the interneurons; the GABA released by the interneurons was only depolarizing for this subset of excitatory cells. These results suggest that it is the interaction between excitatory projection cells depolarized by GABA and interneurons that initiates epileptiform events, at least in subiculum. Interneurons usually seem to provide an inhibitory shield around excitatory neurons. However, when connected to projection cells responding ‘abnormally’ to GABA with depolarization, they may promote paroxysmal synchronizations. A summary of some recent theories and results is presented on possible causes and effects of depolarizing, GABA-mediated synaptic responses in the cerebrum. Special attention is focused on the hippocampal/parahippocampal formation, especially the subicular complex. The subiculum seems to be of particular interest because of its strategic output location to neocortex, and because of the spontaneous, interictal-like activity observed almost exclusively there in slices from patients suffering mesial temporal lobe epilepsy. Simulation results follow, starting from a commonly known GENESIS computer model of a small part of CA3. This ‘CA3’ was re-modeled to more closely resemble a small, ‘subiculum-like’ structure, with a complement of fast-spiking interneurons and three types of projection cells: ‘strong-bursting’, ‘weak-bursting’, and ‘regular-spiking’. Parametric studies of the effects of increasing E GABA A , the GABA reversal potential of certain GABA A receptors, simulate the sometimes excitatory impact of GABAergic signaling. The effects of GABA B receptor impairment in this setting are also briefly considered. Results presented here reinforce experimental evidence that the subiculum has “the right stuff” to play a significant role in epileptiform events.

Mk801-induced caspase-3 in the postnatal brain: Inverse relationship with calcium binding proteins

Age-dependent, neuronal apoptosis following N-methyl- d-aspartate receptor blockade has been linked to loss of calcium. To further explore this relationship, we examined expression of activated caspase-3, as well as the calcium binding proteins, calbindin-D 28K, calretinin and parvalbumin, following injection of vehicle or the N-methyl- d-aspartate receptor blocker, MK801, in postnatal day 7 or 21 rats. At postnatal day 7, MK801-induced activated caspase-3 expression was most frequently found in mutually exclusive cell populations to those expressing any of the three calcium binding proteins. For example, in the somatosensory cortex, most immunoreactivity for activated caspase-3 was found in layers IV/V, layered between areas of high calbindin or calretinin expression. Further, in the caudate putamen, activated caspase-3 rarely invaded zones of intense calbindin immunoreactivity. Suggesting expression patterns of these proteins were inversely related, these same brain regions no longer displayed MK801-induced activated caspase-3 at postnatal day 21, but instead robustly expressed calcium binding proteins. This later surge in expression was especially true for parvalbumin in regions such as the somatosensory and retrosplenial cortex, as well as the subicular complex. Calbindin-D 28K was also found to increase in the same regions though not as impressively as parvalbumin. Thus, developmental regulation of calcium binding protein expression may be a critical factor in age-dependent sensitivity to agents that disrupt calcium homeostasis in maturing neurons, providing a possible mechanistic explanation for age-dependent MK801 toxicity.

Lesión de las cortezas extrahipocampales del lóbulo temporal medial: descripción de un caso

The cortex of medial temporal lobe is a group of different allocortical fields which included the hippocampal formation (dentate gyrus, hippocampus proper, and subicular complex) and extrahippocampal cortices (entorhinal, perirhinal, and parahippocampal). It is widely accepted that both of them play an important role in memory process. In humans, several reports indicates that damage to the hippocampus alone would lead to a clinically significant amnesia; when the injuries are more extensive others cognitive disorders, as those related to visual sphere, make worse the clinic picture, and some of these cases were reported as associative visual agnosias. Nevertheless, although evidence from animal studies points to the importance of the extrahippocampal medial temporal lobe cortices in order to recognise visual stimuli, such involvement has not been demonstrated in humans.A 44 year-old male who consulted us because they had lost about of '80% of his vision' after a stroke. Ophthalmological examination was entirely within normal limits, but neuropsychological test put in evidence difficulties in the visuo-verbal naming, discrimination of superposed images, recognition of faces and, mainly, in the test of immediate and deferred visual memory. Anterograde memory impairment was also revealed. Magnetic resonance imaging showed a lesion of left entorhinal, perirhinal and parahippocampal cortices.We suggest, in relation to anatomical evidences, that isolation of hippocampus is responsible for symptomatollogy of our patient.

Changes in immediate early gene expression in the rat brain after unilateral lesions of the hippocampus

Activity of the immediate early genes c- fos and zif268 was compared across hemispheres in rats with unilateral, excitotoxic lesions of the hippocampus (dentate gyrus and CA fields 1–4). Counts of the protein products of these genes were made shortly after rats performed a test of spatial working memory in the radial-arm maze, a task that is sensitive to bilateral lesions of the hippocampus. Unilateral hippocampal lesions produced evidence of widespread hypoactivity. Significant reductions in immediate early gene counts were observed within all three anterior thalamic nuclei, as well as the entorhinal, perirhinal, and postrhinal cortices, and much of the subicular complex. In contrast, no observable changes were detected in the anterior cingulate, infralimbic or prelimbic cortices, as well as several amygdala nuclei, even though many of these regions receive projections from the subiculum. Instead, the immediate early gene changes were closely linked to sites that are thought to be required for successful task performance, with both immediate early genes giving similar patterns of results. The findings support the notion that the anterior thalamic nuclei, hippocampus, and parahippocampal cortices form the key components of an interdependent neuronal network involved in spatial mnemonic processing.