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PubMed2002

Active, phosphorylation-dependent MAP kinases, MAPK/ERK, SAPK/JNK and p38, and specific transcription factor substrates are differentially expressed following systemic administration of kainic acid to the adult rat.

Excitotoxicity is considered a major cell death inductor in neurodegeneration. Yet the mechanisms involved in cell death and cell survival following excitotoxic insults are poorly understood. Expression of active, phosphorylation-dependent mitogen-activated extracellular signal-regulated kinases (MAPK/ERKs), stress-activated c-Jun N-terminal kinases (SAPK/JNKs) and p38 kinases, as well as their putative active, phosphorylation-dependent specific transcriptional factor substrates CREB, Elk-1, ATF-2, c-Myc and c-Jun, has been examined following systemic administration of kainic acid (KA) at convulsant doses to rats. Increased phosphorylated MAPK (MAPK(P)) immunoreactivity has been found at 3 and 6 h in the vulnerable regions entorhinal cortex and CA3, in which neurons are committed to die, as well as in sensitive regions dentate gyrus and gyrus cinguli, in which neurons will survive. JNK(P) has been observed in the entorhinal cortex and dentate gyrus, and p38(P) immunoreactivity occurs in the entorhinal cortex. Strong c-Myc(P) expression parallels MAPK(P) immunoreactivity in the entorhinal cortex, CA3, dentate gyrus and gyrus cinguli, showing that enhanced c-Myc(P) expression does not preclude cell death or cell survival. Selective decrease of CREB(P) immunoreactivity in entorhinal cortex and CA3 indicates CREB(P) reduction associated with cell death. Strong c-Jun(P) immunoreactivity has been found in the entorhinal cortex, CA3 and dentate gyrus, thus suggesting that regulation of two opposing cellular programs (cell death or cell survival) of c-Jun(P) depends on c-Jun interactions with other factors. Interestingly, ATF-2(P), and to a lesser extent Elk-1(P), is selectively increased in the dentate gyrus. These results suggest ATF-2(P) involvement in cell survival of dentate gyrus granule cells. The present results demonstrate activation of specific MAPK pathways in association with either cell death or cell survival triggered by KA. Furthermore, increased Ras activation, as seen with p21 Ras activation assay, indicates a crucial role for Ras in activating MAP kinases following excitotoxic insult.

Activating Transcription Factor 2↗
PubMed1982

A disconnection analysis of hippocampal function.

A disconnection analysis determined the extent to which the fornix, hippocampus and entorhinal cortex are components of the same functional system in tasks that require working memory. Preoperatively, rats were trained to perform accurately on a radial arm maze. Then various combinations of unilateral and bilateral lesions were placed in the fornix and entorhinal cortex, either with or without a transection of the hippocampal commissures. When the lesions left intact at least one pathway through the hippocampus interconnecting the fornix and entorhinal cortex, rats performed normally. Either an uncrossed pathway (following a unilateral lesion of the fornix, transection of the hippocampal commissures, and an ipsilateral lesion of the entorhinal cortex) or a crossed pathway (following a unilateral lesion of the fornix and a contralateral lesion of the entorhinal cortex, leaving the hippocampal commissures intact) was sufficient. When the lesions produced a complete bilateral disconnection of the fornix and entorhinal cortex, rats performed poorly. The results indicate that the hippocampal system provides a functional connection between the subcortical structures associated with the fornix and the neocortical structures associated with the entorhinal cortex, and that without this connection normal processing of working memory can not occur.

Animals↗
PubMed2001

Induction of brain-derived neurotrophic factor by convulsant drugs in the rat brain: involvement of region-specific voltage-dependent calcium channels.

A high level of hippocampal brain-derived neurotrophic factor (BDNF) in normally aged as compared with young rats suggests that it is important to maintain a considerable level of hippocampal BDNF during aging in order to keep normal hippocampal functions. To elucidate possible mechanisms of endogenous BDNF increase, changes in levels of BDNF were studied in the rat brain following systemic administration of various convulsant agents; excitotoxic glutamate agonists, NMDA, kainic acid and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA); GABA receptor antagonists, picrotoxin, pentylenetetrazole (PTZ) and lindane (gamma-hexachlorocyclohexane); and L-type voltage-dependent calcium channel agonist, BAY-K 8644. Kainic acid and AMPA, but not NMDA, caused remarkable increases in BDNF protein in the rat hippocampus and entorhinal cortex. Picrotoxin, PTZ and lindane stimulated BDNF production in the entorhinal cortex and also in the hippocampus of rats showing very severe convulsions. On the other hand, BAY-K 8644 treatment increased BDNF levels in the neocortex and entorhinal cortex. Maximal levels of BDNF protein were observed at 12--24 h, 8--16 h and 6 h following administration of kainic acid, PTZ and BAY-K 8644, respectively. Kainic acid stimulated BDNF synthesis in presynaptic hippocampal granule neurons, but not in postsynaptic neurons with its receptors, while PTZ and BAY-K 8644 produced the same effects in postsynaptic neurons in the entorhinal cortex (in granule neurons in the hippocampus) and in the whole cortex, respectively. Nifedipine inhibited almost completely BAY-K 8644, but not PTZ, effects. omega-Conotoxin GVIA and DCG-IV partially blocked kainic acid-induced enhancement of BDNF, indicating involvement of L-type and N-type voltage-dependent calcium channels, respectively. In addition, BDNF levels in the hippocampus of mice deficient in D-myo-inositol-1,4,5-triphosphate receptor gene were scarcely different from those in the same region of controls, suggesting little involvement of intracellular calcium increase through this receptor. BAY-K 8644, but not kainic acid or PTZ, stimulated the phosphorylation of cyclic AMP responsive element binding protein. Our results indicate convulsant-dependent stimulation of BDNF production and involvement of region-specific voltage-dependent calcium channels.

Animals↗
PubMed1997

Hyperexcitability in combined entorhinal/hippocampal slices of adult rat after exposure to brain-derived neurotrophic factor.

Effects of brain-derived neurotrophic factor (BDNF) in area CA3, the dentate gyrus, and medial entorhinal cortex were examined electrophysiologically by bath application of BDNF in slices containing the hippocampus and entorhinal cortex. Bath application of 25-100 ng/ml BDNF for 30-90 min increased responses to single afferent stimuli in selective pathways in the majority of slices. In area CA3, responses to mossy fiber stimulation increased in 73% of slices and entorhinal cortex responses to white matter stimulation increased in 64% of slices. After exposure to BDNF, these areas also demonstrated evidence of hyperexcitability, because responses to repetitive stimulation (1-Hz paired pulses for several s) produced multiple population spikes in response to mossy fiber stimulation in CA3 or multiple field potentials in response to white matter stimulation in the entorhinal cortex. Repetitive field potentials persisted after repetitive stimulation ended and usually were followed by spreading depression. Enhancement of responses to single stimuli and hyperexcitability were never evoked in untreated slices or after bath application of boiled BDNF or cytochrome C. The tyrosine kinase antagonist K252a (2 microM) blocked the effects of BDNF. In area CA3, both the potentiation of responses to single stimuli and hyperexcitability showed afferent specificity, because responses to mossy fiber stimulation were affected but responses to fimbria or Schaffer collateral stimulation were not. In addition, regional specificity was demonstrated in that the dentate gyrus was much less affected. The effects of BDNF in area CA3 were similar to those produced by bath application of low doses of kainic acid, which is thought to modulate glutamate release from mossy fiber terminals by a presynaptic action. These results suggest that BDNF has acute effects on excitability in different areas of the hippocampal-entorhinal circuit. These effects appear to be greatest in areas that are highly immunoreactive for BDNF, such as the mossy fibers and the entorhinal cortex. Although the present experiments do not elucidate mechanism(s) definitively, the afferent specificity, similarity to the effects of kainic acid, and block by K252a are consistent with previous hypotheses that BDNF affects acute excitability by a presynaptic action on trkB receptors that modulate excitatory amino acid transmission. However, we cannot rule out actions on inhibitory synapses or postsynaptic processes.

Afferent Pathways↗
PubMed2005

Progression in temporal lobe epilepsy: differential atrophy in mesial temporal structures.

OBJECTIVE: To determine the relationship between hippocampal, amygdalar, and entorhinal cortex atrophy and duration of epilepsy, presence of secondary generalized seizures, and prolonged childhood febrile convulsions in patients with pharmacologically intractable temporal lobe epilepsy (TLE). METHODS: Volumetric MRI of the hippocampus, amygdala, and entorhinal cortex were performed in 86 consecutive patients with TLE and 44 age- and sex-matched healthy control subjects. Linear regression analysis was used to explore the relation between the volumetric measurements and the clinical parameters. RESULTS: In simple regressions, duration of epilepsy but not age at seizure onset was related to hippocampal (r2 = 0.19, p < 0.001), entorhinal cortex (r2 = 0.11, p = 0.002), and amygdalar (r2 = 0.15, p < 0.001) atrophy ipsilateral to the seizure focus. Prediction of the regression function to time of onset of recurrent seizures (time = 0) resulted in a y intercept of < 0 for the hippocampus and the entorhinal cortex but was not different from 0 for the amygdala. Patients with a positive history of febrile convulsions had smaller hippocampal volumes ipsilateral to the seizure (p < 0.001). No relationship was found between febrile convulsions and entorhinal cortex and amygdalar volumes or between secondary generalization of seizures and any mesial temporal volume. CONCLUSION: Progressive volume loss in the mesial temporal lobe in relation to duration of epilepsy is not limited to the hippocampus but affects the entorhinal cortex and the amygdala.

Adolescent↗
PubMed1996

Multiple-unit recordings during slow field-potential shifts in low-[Ca2+]0 solutions in rat hippocampal and cortical slices.

Multiple-unit and field-potential recordings in low-[Ca2+]0 solutions were used to study epileptiform bursts generated in hippocampal region CA1 and medial entorhinal cortex, a cortical region that is not as densely packed or highly laminated as the hippocampus. As expected in CA1, multiple-unit activity appeared as large spikes that corresponded one-to-one with population spikes in the field-potential recordings. During the negative field-potential shifts that lacked large population spikes, the multiple-unit recordings showed an increase in baseline activity. Initiation of the negative field-potential shift always coincided with increased multiple-unit activity. Slices displaying a post-burst positive overshoot showed a corresponding decrease in multiple-unit activity. In addition to the large ictal-like events in CA1, small-amplitude field-potential shifts were also observed, these events were associated with increases in baseline spike activity in the multiple-unit recording. These small-amplitude field-potential shifts appeared to precede the occurrence of the ictal-like events, but they decreased in frequency during low-[Ca2+]0 exposure. Recordings in normal artificial cerebrospinal fluid (nominally 1.3 mM [Ca2+]0) showed rhythmic, multiple-unit bursts of action potentials and corresponding negative small-amplitude field-potential shifts in the medial entorhinal cortex of immature rats (two-to three-weeks old), but not of adult rats. Rhythmic, spontaneous bursts of activity in low-[Ca2+]0 solution were found in both immature and adult medial entorhinal cortex, and were similar in amplitude to the small field-potential events generated in CA1. The probability of burst generation was higher in the immature than the adult medial entorhinal cortex, and the bursts in the immature cortex had more robust multiple-unit activity and an increased burst frequency compared with adult. These results indicate that the medial entorhinal cortex can also generate spontaneous synchronous bursts of activity in low-[Ca2+]0 solutions, and they suggest that the increased susceptibility of medial entorhinal cortex from immature versus adult rats to generate intense bursts of electrical activity does not require active chemical synaptic transmission. The various forms of epileptiform activity in low-[Ca2+]0 solutions probably arise from different contributions of electrical and ionic mechanisms of synchronization in these neuronal populations. The data suggest the hypothesis that ionic mechanisms (i.e. changes in [K+]0) may synchronize neurons in cortical regions (e.g. entorhinal cortex) that are not as densely packed and highly laminated as the hippocampus and dentate gyrus. The data also support the hypothesis that these mechanisms contribute significantly to the increased seizure susceptibility of the immature brain.

Animals↗
PubMed2003

Effects of taurine and glycine on epileptiform activity induced by removal of Mg2+ in combined rat entorhinal cortex-hippocampal slices.

PURPOSE: The imbalance between neuronal inhibition and excitation contributes to epileptogenesis. Inhibition in the central nervous system (CNS) is mediated by gamma-aminobutyric acid (GABA) and glycine. Recent studies indicate the expression of glycine receptor (GlyR) in hippocampus and neocortex. However, the function of GlyR in these regions is not clarified completely. The aim of this study was to investigate whether the GlyR agonists glycine and taurine promote an anticonvulsive effect. METHODS: We induced epileptiform discharges by reducing extracellular Mg2+ concentration in combined rat entorhinal cortex-hippocampal slices (400 micro m). Epileptiform discharges were detected by using extracellular recording techniques. RESULTS: Seizure-like events were suppressed by taurine, exhibiting a half-maximal inhibitory effect (IC50) of 0.9 mM. Suppression of late recurrent discharges in the medial entorhinal cortex and recurrent short discharges in the hippocampus was obtained at an IC50 value of 1.6 and 2.1 mM, respectively. Strychnine at concentrations <1 micro M abolished these effects. Likewise glycine, after an initial proconvulsant effect, suppressed epileptiform discharges. CONCLUSIONS: These findings show that GlyR agonists, in particular taurine, could serve as potential anticonvulsants and suggest an important role of GlyR in cortical function and dysfunction.

Action Potentials↗
PubMed1999

Primary motor cortex involvement in Alzheimer disease.

In Alzheimer disease (AD) the involvement of entorhinal cortex, hippocampus, and associative cortical areas is well established. Regarding the involvement of the primary motor cortex the reported data are contradictory. In order to determine whether the primary motor cortex is involved in AD, the brains of 29 autopsy cases were studied, including, 17 cases with severe cortical AD-type changes with definite diagnoses of AD, 7 age-matched cases with discrete to moderate cortical AD-type changes, and 5 control cases without any AD-type cortical changes. Morphometric analysis of the cortical surface occupied by senile plaques (SPs) on beta-amyloid-immunostained sections and quantitative analysis of neurofibrillary tangles (NFTs) on Gallyas-stained sections was performed in 5 different cortical areas including the primary motor cortex. The percentage of cortical surface occupied by SPs was similar in all cortical areas, without significant difference and corresponded to 16.7% in entorhinal cortex, 21.3% in frontal associative, 16% in parietal associative, and 15.8% in primary motor cortex. The number of NFTs in the entorhinal cortex was significantly higher (41 per 0.4 mm2), compared with those in other cortical areas (20.5 in frontal, 17.9 in parietal and 11.5 in the primary motor cortex). Our findings indicate that the primary motor cortex is significantly involved in AD and suggest the appearance of motor dysfunction in late and terminal stages of the disease.

Adult↗
PubMed1997

Alterations in glutamate receptor 2/3 subunits and amyloid precursor protein expression during the course of Alzheimer's disease and Lewy body variant.

Alterations in the processing and patterns of trophic and/or toxic factors might lead to the increased neuronal vulnerability in the entorhinal cortex in Alzheimer's disease (AD) and Lewy body variant (LBV). Therefore, patterns and levels of amyloid precursor protein (APP) and glutamate receptor (gluR) expression in the entorhinal cortex and hippocampus in relation to disease severity were investigated. Sections from the hippocampus and entorhinal cortex were single and double immunolabeled for APP, gluR2/3, and N-methyl-D-aspartate receptor (NMDA-R). Within the hippocampus and entorhinal cortex, image analysis revealed progressively decreased APP and gluR2/3 levels during the course of AD and LBV, whereas levels of NMDA-R were unaltered. Furthermore, the present study showed a positive correlation and close co-localization of APP and gluR2/3 immunoreactivity in neurons, suggesting a possible interaction between these two factors. In conclusion, these data imply that alterations in neuronal APP and gluR2/3 expression in the entorhinal cortex lead to increased susceptibility to neurodegeneration and might be markers of vulnerability.

Alzheimer Disease↗
PubMed1992

Ketamine blocks the induction of LTP at the lateral entorhinal cortex-dentate gyrus synapses.

In many regions NMDA receptor activation is required for the synaptic induction of long-term potentiation (LTP). This role for NMDA receptors is controversial at the synapses formed between the cells of the lateral entorhinal cortex (LEC) and the dentate gyrus (DG). Using anesthetized rats, the present study shows that ketamine reversibly blocks the induction of LTP at the LEC-DG synapses, thus favoring a role for NMDA receptors in the induction of LTP there. Ketamine also reversibly blocks the induction of the small translaminar depression of the medial EC response or of the LEC response by conditioning the other system while the test system is inactive.

Animals↗
PubMed1996

Imaging the induction and spread of seizure activity in the isolated brain of the guinea pig: the roles of GABA and glutamate receptors.

1. The induction and spread of seizure activity was studied using imaging and electrophysiological techniques in the isolated whole brain of the guinea pig. We examined the role of GABA and glutamate receptor subtypes in controlling the spread of seizure activity across the olfactory cortex from a focus in the entorhinal cortex. Seizure spread was monitored by video imaging of intrinsic optical signals (reflectance changes) combined with multiple extracellular recordings. Both the unilateral and bilateral spread of seizure activity was monitored in different experiments. 2. Electrical stimulation of the lateral entorhinal cortex (10-15 V, 5 Hz, 5-10 s) evoked seizure activity that originated in the entorhinal cortex/hippocampus and later spread preferentially toward the posteromedial cortical amygdaloid nucleus ipsilaterally and bilaterally. The pattern of seizure spread in a given brain was highly reproducible. 3. The influence of gamma-aminobutyric acid (GABA) receptors on the spread of seizure activity was monitored at higher resolution on one side of the brain. Perfusion of a low concentration of the GABAA antagonist bicuculline methiodide (20 microM) resulted in spontaneous seizures that spread to the posteromedial cortical amygdaloid nucleus more rapidly than electrically evoked seizures [spread times: 5.5 +/- 3.7 s vs. 15.5 +/- 2.7 s, respectively (means +/- SE)]. Seizure spread was also more extensive in the presence of bicuculline involving the posterior perirhinal cortex and larger areas over the medial amygdala. Higher concentrations of bicuculline (100 microM) resulted in even more widespread propagation of spontaneous seizure activity throughout the olfactory cortex as well as to the perirhinal, insular, and occipital cortices. This concentration of bicuculline also further reduced the time required for seizure activity to spread from the entorhinal cortex to the posteromedial cortical amygdaloid nucleus (spread time = 2.3 +/- 1.7 s). The GABAB antagonist, CGP 35348 (200 microM), in contrast, had no significant effect of seizure induction or propagation. 4. The role of glutamate receptor subtypes in seizure propagation was studied by examining the bilateral spread of seizures. Perfusion of the kainate/alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (K/A) receptor antagonist (6-cyano-7-nitroquinoxaline-2,3-dione, CNQX, 20 microM) completely and reversibly suppressed stimulus-evoked seizure activity as detected electrophysiologically and optically. CNQX also reduced the magnitudes of field potentials recorded in the isolated brain in a reversible manner by an average of 70.8 +/- 2.21% of control. The N-methyl-D-aspartate (NMDA) receptor antagonist dibenzocyclohepteneimine (MK-801) did not significantly alter the magnitudes or shapes of field potentials recorded in the isolated brain nor did it significantly alter seizure activity measured optically or electrophysiologically. 5. Perfusion of the metabotropic glutamate receptor agonist [trans-1-amino-(IS,3R)-cyclopentanedicarboxylic acid (trans-ACPD), 150 microM] completely and reversibly suppressed stimulus-evoked seizure activity as detected electrophysiologically and optically. The magnitudes of field potentials recorded in the isolated brain also were reduced by trans-ACPD an average of 75.4 +/- 5.39% of control values. 6. These results demonstrate that GABAA-mediated transmission is functionally present and may play an important role in epileptic tissue in limiting the spread of seizure activity from the entorhinal cortex to the posteromedial cortical amygdaloid nucleus and in creating functional pathways or preferential routes of seizure spread. GABAB-mediated postsynaptic inhibition played no significant role in the induction or spread of seizure activity in this study. K/A receptors but not NMDA receptors are necessary for the induction and subsequent spread of seizure activity originating in the entorhinal cortex/hippocampus.

Animals↗
PubMed2005

Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs.

Suicide is a major public health problem but the neurobiological factors of risk are poorly understood. Recent studies have mentioned changes in the serotoninergic system and in neuronal plasticity, as well. The present investigation was undertaken to examine whether there is an abnormality in brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) proteins in suicide victims. The effect of diagnosis and drug treatments on the neurotrophins was also assessed. Thirty suicide victims (11 F/19 M) and twenty-four (10 F/14 M) drug-free non-suicide subjects, devoid of psychiatric or neurological disease, were examined. Antemortem diagnoses and toxicological analyses had been performed. The ventral prefrontal cortex (PFC), the hippocampus, and the entorhinal cortex were selected. BDNF and NT-3 levels were assayed either with the Western blot or with the ELISA method. Results indicated a significant decrease in BDNF and NT-3 levels in the hippocampus and PFC (only BDNF) but not in the entorhinal cortex, of suicide victims who were drug-free compared with non-suicide controls. The decrease was observed in all suicide victims, regardless of diagnosis. In drug-treated suicide victims, neurotrophin levels were not significantly different from non-suicide controls. This study supports a role of BDNF and NT-3 neurotrophin, in the pathophysiology of suicidal behavior. Anatomically, this role may implicate the hippocampus and the PFC but not the entorhinal cortex. The absence of change in BDNF and NT-3 levels of drug-treated suicide victims suggests that both neurotrophins are mediators of psychotropic drugs. A better understanding of the neurobiology of suicide could help detect populations at risk.

Adult↗
PubMed2002

Masking synchronous GABA-mediated potentials controls limbic seizures.

PURPOSE: We determined how CA3-driven interictal discharges block ictal activity generated in the entorhinal cortex during bath application of 4-aminopyridine (4AP, 50 microM). METHODS: Field potential and [K+]o recordings were obtained from mouse combined hippocampus-entorhinal cortex slices maintained in vitro. RESULTS: 4AP induced N-methyl-d-aspartate (NMDA) receptor-dependent ictal discharges that originated in the entorhinal cortex, disappeared over time, but were reestablished by cutting the Schaffer collateral (n = 20) or by depressing CA3 network excitability with local application of glutamatergic receptor antagonists (n = 5). In addition, two types of interictal activity occurred throughout the experiment. The first type was CA3 driven and was abolished by a non-NMDA glutamatergic receptor antagonist. The second type was largely contributed by gamma-aminobutyric acid type A (GABAA) receptor-mediated conductances and persisted during blockade of glutamatergic transmission. The absence of CA3-driven interictal discharges in the entorhinal cortex after Schaffer collateral cut facilitated the GABA-mediated interictal potentials that corresponded to large [K+]o elevations and played a role in ictal discharge initiation. Accordingly, ictal discharges along with GABA-mediated interictal potentials disappeared during GABAA-receptor blockade (n = 7) or activation of mu-opioid receptors that inhibit GABA release (n = 4). CONCLUSIONS: Our findings suggest that CA3-driven interictal events restrain ictal discharge generation in the entorhinal cortex by modulating the size of interictal GABA-mediated potentials that lead to large [K+]o elevations capable of initiating ictal discharges in this structure.

4-Aminopyridine↗
PubMed1999

Responses of heat shock proteins hsp27, alphaB-crystallin, and hsp70 in rat brain after kainic acid-induced seizure activity.

We determined the changes in the levels of the mammalian small heat shock protein of 25-28 kDa (hsp27) and the hsp alphaB-crystallin in various regions of rat brain after kainic acid-induced seizure activity by means of specific immunoassays. The levels of hsp27 in the hippocampus and entorhinal cortex were markedly increased and reached a maximum (1.5-2 microg/mg of protein) 2-4 days after the seizure. The levels of hsp27 in these regions were considerably high even 10 days after the seizure. A marked increase in levels of mRNA for hsp27 was also observed in the hippocampus of rats 1-2 days after the seizure. A severalfold increase in the levels of alphaB-crystallin was observed in the hippocampus and entorhinal cortex of rats 2 days after the seizure. However, the maximum levels were <50 ng/mg of protein. The levels of protein sulfhydryl group and glutathione were significantly reduced in the hippocampus of rats at 24 h after the seizure, which might have enhanced the expressions of hsp27 and alphaB-crystallin. The expression of inducible mammalian hsp of 70 kDa (hsp70) was also enhanced in the hippocampus of rats after the seizure, as detected by western and northern blotting analyses. Immunohistochemically, an intensive staining of hsp27 was observed in both glial cells and neurons in the hippocampus, piriform cortex, and entorhinal cortex of rats with kainic acid-induced seizure. However, in the cerebellum, where the receptors for kainic acid are also rich, hsp27 was barely induced in the same rats. This might be due to high levels of the cerebellar calcium-binding proteins parvalbumin and 28-kDa calbindin-D, which might have a protective effect against the kainic acid-inducible damage.

Animals↗
PubMed2003

Membrane properties of identified lateral and medial perforant pathway projection neurons.

The physiological characteristics of neurons that project to the hippocampus and dentate gyrus via the medial perforant pathway (projection neurons) are well known, but the characteristics of neurons that project to these areas via the lateral perforant pathway (projection neurons) are less well known. We have used retrograde tracing and whole-cell recording in brain slices to compare the membrane and firing properties of medial perforant pathway and lateral perforant pathway projection neurons in layer II of the medial and lateral entorhinal cortex. The properties of medial perforant pathway projection neurons were identical to those reported previously for spiny stellate neurons in the medial entorhinal cortex. In contrast, lateral perforant pathway projection neurons were characterized by a higher input resistance, a lack of time-dependent inward (anomalous) rectification, and a lack of prominent depolarizing spike afterpotentials. Voltage-clamp recordings suggest that the absence of anomalous rectification in lateral perforant pathway projection neurons is due to smaller hyperpolarization activated cation currents in these cells, and the lack of depolarizing afterpotential may be due to smaller low-threshold calcium currents. Persistent sodium current was also smaller in lateral perforant pathway projection neurons, but the difference in persistent sodium current between medial perforant pathway and lateral perforant projection neurons was much less pronounced than the difference in low voltage activated currents. These results underscore the functional differences between the medial entorhinal cortex and lateral entorhinal cortex, and may help to explain the differing abilities of these cortical areas to participate in certain types of network activity.

Action Potentials↗
PubMed2005

Detection of entorhinal layer II using 7Tesla [corrected] magnetic resonance imaging.

The entorhinal cortex lies in the mediotemporal lobe and has major functional, structural, and clinical significance. The entorhinal cortex has a unique cytoarchitecture with large stellate neurons in layer II that form clusters. The entorhinal cortex receives vast sensory association input, and its major output arises from the layer II and III neurons that form the perforant pathway. Clinically, the neurons in layer II are affected with neurofibrillary tangles, one of the two pathological hallmarks of Alzheimer's disease. We describe detection of the entorhinal layer II islands using magnetic resonance imaging. We scanned human autopsied temporal lobe blocks in a 7T human scanner using a solenoid coil. In 70 and 100 microm isotropic data, the entorhinal islands were clearly visible throughout the anterior-posterior extent of entorhinal cortex. Layer II islands were prominent in both the magnetic resonance imaging and corresponding histological sections, showing similar size and shape in two types of data. Area borders and island location based on cytoarchitectural features in the mediotemporal lobe were robustly detected using the magnetic resonance images. Our ex vivo results could break ground for high-resolution in vivo scanning that could ultimately benefit early diagnosis and treatment of neurodegenerative disease.

Entorhinal Cortex↗
PubMed2000

Role of afferent innervation and neuronal activity in dendritic development and spine maturation of fascia dentata granule cells.

By using slice cultures of hippocampus as a model, we have studied the development of dendritic spines in fascia dentata granule cells. We raised the question as to what extent spine development is dependent on a major afferent input to these neurons, the fibers from the entorhinal cortex and neuronal activity mediated by these axons. Our results can be summarized as follows: (i) the entorhino-hippocampal projection develops in an organotypic manner in co-cultures of entorhinal cortex and hippocampus. Like in vivo, entorhinal fibers, labeled by anterograde tracing with biocytin, terminate in the outer molecular layer of the fascia dentata. (ii) The layer-specific termination of entorhinal fibers is not altered by the blockade of neuronal activity with tetrodotoxin. Likewise, the differentiation of the dendritic arbor of postsynaptic granule cells does not require neuronal activity. Blockade of neuronal activity did not affect the mean spine number of granule cell dendrites in entorhino-hippocampal co-cultures, but led to a relative increase in thin, long filiform spines that are characteristic of immature neurons. (iii) The maturation of the granule cell dendritic arbor is, however, controlled by the afferent fibers from the entorhinal cortex in an activity-independent manner. In single slice cultures of hippocampus lacking entorhinal input, Golgi-impregnated granule cells have much shorter, less branched dendrites when compared with granule cells in entorhino-hippocampal co-cultures. This reduction in dendritic length in granule cells lacking entorhinal input results in a lower mean total number of spines per neuron, but the mean number of spines per microm is not reduced in the absence of entorhinal innervation. These results indicate that innervation by fibers from the entorhinal cortex, but not neuronal activity mediated via these axons, is essential for the normal development of the granule cell dendritic arbor. Neuronal activity is required, however, for the maturation of dendritic spines.

Animals↗
PubMed2001

Altered apolipoprotein D expression in the brain of patients with Alzheimer disease.

The etiology of late-onset Alzheimer disease is poorly understood. Predisposing factors such as the apolipoprotein E4 allele, as well as protective factors (e.g., antioxidants) have been proposed to play a role in the disease's process. A search for predisposing factors contributing to sporadic late-onset Alzheimer disease was initiated using the differential display technique. RNA expression profiles of the entorhinal cortex and the cerebellum of Alzheimer-diseased and normal patients were compared. The entorhinal cortex is the first brain region to accumulate neurofibrillary tangles during disease progression, whereas the cerebellum is spared. In the Alzheimer cases of this study, one signal showing preferential expression in the entorhinal cortex corresponded to the apolipoprotein D gene. This preferential expression might be genuine at the RNA level as suggested by the in situ hybridization method used. In addition, immunohistochemical experiments showed higher percentages of Apolipoprotein D reactive pyramidal neurons in the entorhinal cortex and region 1 of Ammon's horn in diseased patients. This increase correlated with the number of neurofibrillary tangles in Alzheimer as well as in normal patients. Colocalization of Apolipoprotein D proteins and neurofibrillary tangles in the same neuron was rare. Thus, these results suggest that in Alzheimer disease and aging, apolipoprotein D gene expression is increased in stressed cortical neurons before they possibly accumulate neurofibrillary tangles.

Adult↗