Reinnervation of the hippocampal perforant pathway zone in Alzheimer's disease

The perforant pathway originates from the entorhinal cortex of the anterior parahippocampal gyrus and terminates on the outer dendritic branches of the granule cells of the dentate gyrus and pyramidal cells of the subiculum and hippocampus. It carries the principal cortical input to the hippocampal formation. Destruction of the perforant pathway in experimental animals leads to a partial deafferentation of its target neurons, followed by a robust sprouting of acetylcholinesterase (AChE) terminals in the deafferented perforant pathway zone. In Alzheimer's disease, the cells of origin of the perforant pathway are laden with neurofibrillary tangles. AChE staining in the terminal zone of the perforant pathway in Alzheimer's disease shows several distinct patterns that are not found in control brains. These changes are consistent with the results of experimental studies demonstrating reinnervation in laboratory mammals, including nonhuman primates. The results suggest that in Alzheimer's disease sprouting of AChE-containing systems occurs in the hippocampal formation in response to disease-related cellular damage in the entorhinal cortex.     

Synaptic loss reflected by secretoneurin‐like immunoreactivity in the human hippocampus in Alzheimer's disease

Secretoneurin is a recently described peptide derived by endoproteolytic processing from secretogranin II, previously named chromogranin C. In this study, we have investigated the distribution of secretoneurin-like immunoreactivity in the human hippocampus in controls and in Alzheimer's disease patients, and compared the staining pattern to that of calretinin. Secretoneurin-like immunoreactivity is present throughout the hippocampal formation. At the border of the dentate molecular layer and the granule cell layer, a band of dense secretoneurin immunostaining appeared. In this part, as in the area of the CA2 sector, the high density of secretoneurin-immunoreactivity coincided with calretinin-like immunoreactivity. The mossy fibre system displayed a moderate density of secretoneurin-immunoreactivity. In the entorhinal cortex, a particularly high density of secretoneurin-immunoreactivity was observed. The density of secretoneurin-like immunoreactivity was significantly reduced in the innermost part of the molecular layer and in the outer molecular layer of the dentate gyrus in Alzheimer's disease. For calretinin-like immunoreactivity, a less pronounced decrease was found in the innermost part of the molecular layer. About 40–60% of neuritic plaques were secretoneurin-immunopositive. This study shows that secretoneurin is distinctly distributed in the human hippocampus and that significant changes of secretoneurin-like immunoreactivity occur in Alzheimer's disease, reflecting synaptic loss.     

Tau–amyloid interactions in the rTgTauEC model of early Alzheimer's disease suggest amyloid‐induced disruption of axonal projections and exacerbated axonal pathology

Early observations of the patterns of neurofibrillary tangles and amyloid plaques in Alzheimer's disease suggested a hierarchical vulnerability of neurons for tangles, and a widespread nonspecific pattern of plaques that nonetheless seemed to correlate with the terminal zone of tangle‐bearing neurons in some instances. The first neurofibrillary cortical lesions in Alzheimer's disease occur in the entorhinal cortex, thereby disrupting the origin of the perforant pathway projection to the hippocampus, and amyloid deposits are often found in the molecular layer of the dentate gyrus, which is the terminal zone of the entorhinal cortex. We modeled these anatomical changes in a transgenic mouse model that overexpresses both P301L tau (uniquely in the medial entorhinal cortex) and mutant APP/PS1 (in a widespread distribution) to examine the anatomical consequences of early tangles, plaques, or the combination. We find that tau uniformly occupies the terminal zone of the perforant pathway in tau‐expressing mice. By contrast, the addition of amyloid deposits in this area leads to disruption of the perforant pathway terminal zone and apparent aberrant distribution of tau‐containing axons. Moreover, human P301L tau‐containing axons appear to increase the extent of dystrophic axons around plaques. Thus, the presence of amyloid deposits in the axonal terminal zone of pathological tau‐containing neurons profoundly impacts their normal connectivity. J. Comp. Neurol. 521:4236–4248, 2013. © 2013 Wiley Periodicals, Inc.     

AMPA-selective glutamate receptor subtype immunoreactivity in the hippocampal formation of patients with Alzheimer's disease

Immunocytochemical techniques were employed in order to examine the distribution and relative intensity of the AMPA receptor subunits GluR1 and GluR2/3 within the hippocampal formation of normal controls and Alzheimer's disease (AD) cases. Throughout our investigation we examined cases exhibiting a wide range of pathologic severity, thus allowing us to correlate our immunohistochemical data with the extent of pathology. Specifically, we investigated the distribution of these receptor subunits in hippocampal sectors that are particularly vulnerable to AD pathology (i. e., CA1 and subiculum) and compared these findings with those obtained following examination of sectors that are generally resistant to pathologic change (i. e., CA2/3, dentate gyrus). Within vulnerable sectors we observed a variable loss of GluR1 and GluR2/3 immunolabeling. The degree to which these proteins were reduced appeared to correlate with the extent of neurofibrillary pathology and cell loss. Despite the loss of labeled cells, the intensity of immunolabeling within the remaining neurons was comparable with, and in many instances even greater than, that observed in control cases. Within resistant sectors, the distribution of immunoreactive elements was comparable in both case groups yet the intensity of immunolabeling was markedly increased in AD cases, particularly in the molecular layer of the dentate gyrus and in the stratum lucidum of CA3 (i. e., the termination zones of perforant pathway and mossy fibers). In addition, within AD cases dramatic increases were observed within the supragranular and polymorphic layer of the dentate gyrus (i. e., the terminal zones of sprouting mossy fiber collaterals). The increase in GluR1 and GluR2/3 immunolabeling is hypothesized to occur in response to the deafferentation of selected glutamatergic pathways. Moreover, our data support that hippocampal plasticity is preserved, even in severe AD cases, and suggest a critical role for AMPA receptor subunits in this plasticity and in maintaining hippocampal functioning. © 1995 Wiley-Liss, Inc.     

Long-term potentiation recruits a trisynaptic excitatory associative network within the mouse dentate gyrus

Granule cells of the hippocampal dentate gyrus receive two powerful excitatory inputs: the perforant path, originating from the entorhinal cortex, and the associational pathway, originating from mossy cells, the principal neurons of the dentate gyrus hilus. We examined the electrophysiological properties of the less well-studied associational pathway and its interaction with the perforant path in the intact mouse hippocampus and then tested homosynaptic, trans-synaptic and associative long-term potentiation of these pathways. The associational pathway was either monosynaptically activated by stimulation within the inner molecular layer or trisynaptically activated after stimulation of the perforant path. Laminar profiles of extracellularly recorded associational pathway field potentials demonstrated a bell-shaped curve with a peak in the inner molecular layer. Tetanization of the perforant path induced not only homosynaptic potentiation of the perforant path (162.4 +/- 6.7% at 0.5-1.5 h after tetanus) but also heterosynaptic potentiation of the associational pathway (115.7 +/- 4.9%). Direct tetanization of the associational pathway within the inner molecular layer was ineffective in either the septo-temporal (97.2 +/- 4.5%) or temporal-septal (104.4 +/- 4.6%) direction. In contrast, conjoint tetanization of the associational pathway with the perforant path potentiated the associational pathway responses in both the septo-temporal (123.4 +/- 5.8%) and the temporal-septal (124.8 +/- 7.3%) directions. Paired-pulse facilitation was attenuated by long-term potentiation in the perforant path and the associational pathway, suggesting pre-synaptic involvement. These results demonstrate that long-term potentiation of the associational pathway and the perforant path is a product of the network properties of the dentate gyrus rather than of each monosynaptic input alone. The architecture of this neural network may be designed for flexible dynamic associations of the afferent perforant path inputs to configure encoded information within hippocampal neuronal ensembles.     

Selective deposition of amyloid-β protein in the entorhinal-dentate projection of a transgenic mouse model of alzheimer's disease

Early and selective deposition of amyloid beta protein(Aβ) is thought to be a pathological feature central to Alzheimer's disease (AD). It has been a great challenge to identify the mechanism(s) responsible for the selectivity of Aβ deposition and the deposition into a temporal sequence of the pathogenesis in this disorder. We now report that the transgenic mouse (PDAPP), which overexpresses the human amyloid precursor protein containing the familial AD mutation (APP_717V-F), develops brain region-specific Aβ deposits along with some pathologies associated with AD. By using monoclonal antibodies that recognize multiple sites on the human Aβ peptide, we show that Aβ deposits are localized primarily to the entorhinal cortex and hippocampal/dentate gyrus regions. Aβ deposition exhibited consistent laminar distribution throughout the hippocampal formation that was confined mostly to a dense terminal field in the outer portion of the stratum moleculare of the dentate gyrus and the stratum lacunosum of the hippocampus proper of 13-month-old heterozygous PDAPP mice. Aβ deposits were also observed in the supragranular zone of the dentate gyrus. Similarly, laminar distribution of Aβ deposits were evident in the entorhinal cortex, most notably in the molecular layer and in laminar layer II–III. The defined laminar pattern of the Aβ deposition, which resembles that of AD, suggests that intrinsic factors in the perforant path, the major projection from the entorhinal cortex to the hippocampal formation, and their respective local paths contribute, at least in part, to the extracellular Aβ deposition in the transgenic mouse model of AD. J. Neurosci. Res. 53:177–186, 1998. © 1998 Wiley-Liss, Inc.     

Rapid Aging in the Perforant Path Projections to the Rodent Dentate Gyrus

Why layers II/III of entorhinal cortex (EC) deteriorate in advance of other regions during the earliest stages of Alzheimer''s disease is poorly understood. Failure of retrograde trophic support from synapses to cell bodies is a common cause of neuronal atrophy, and we accordingly tested for early-life deterioration in projections of rodent layer II EC neurons. Using electrophysiology and quantitative imaging, changes in EC terminals during young adulthood were evaluated in male rats and mice. Field excitatory postsynaptic potentials, input/output curves, and frequency following capacity by lateral perforant path (LPP) projections from lateral EC to dentate gyrus were unchanged from 3 to 8–10 months of age. In contrast, the unusual presynaptic form of long-term potentiation (LTP) expressed by the LPP was profoundly impaired by 8 months in rats and mice. This impairment was accompanied by a reduction in the spine to terminal endocannabinoid signaling needed for LPP-LTP induction and was offset by an agent that enhances signaling. There was a pronounced age-related increase in synaptophysin within LPP terminals, an effect suggestive of incipient pathology. Relatedly, presynaptic levels of TrkB—receptors mediating retrograde trophic signaling—were reduced in the LPP terminal field. LTP and TrkB content were also reduced in the medial perforant path of 8- to 10-month-old rats. As predicted, performance on an LPP-dependent episodic memory task declined by late adulthood. We propose that memory-related synaptic plasticity in EC projections is unusually sensitive to aging, which predisposes EC neurons to pathogenesis later in life.SIGNIFICANCE STATEMENT Neurons within human superficial entorhinal cortex are particularly vulnerable to effects of aging and Alzheimer''s disease, although why this is the case is not understood. Here we report that perforant path projections from layer II entorhinal cortex to the dentate gyrus exhibit rapid aging in rodents, including reduced synaptic plasticity and abnormal protein content by 8–10 months of age. Moreover, there was a substantial decline in the performance of an episodic memory task that depends on entorhinal cortical projections at the same ages. Overall, the results suggest that the loss of plasticity and related trophic signaling predispose the entorhinal neurons to functional decline in relatively young adulthood.     

Neurotoxic effects of high-dose piperine on hippocampal synaptic transmission and synaptic plasticity in a rat model of memory impairment

In recent years, piperine has attracted much attention due to its various biological effects as a neuroprotective agent. Therefore, clarification of the possible side effects of piperine is important to identify its potential pharmacological action. Thus, the effects of piperine on the long-term plasticity of perforant pathway to dentate gyrus synapses were studied in hippocampus of an animal model of Alzheimer's disease (AD).Adult male rats were injected with intracerebroventricular (ICV) streptozotocin (STZ) bilaterally, on days 1 and 3 (3 mg/kg). The STZ-injected rats were treated with different doses of piperine for 4 weeks before being used in behavioral, electrophysiological and histopathological experiments. The passive-avoidance test was conducted on all animals in order to determine the cognitive performance. Rats were placed in a stereotaxic frame to implant a recording electrode in the hippocampal dentate gyrus and a stimulating electrode in the perforant path. Additionally, we assessed the density of survived neurons stained by cresyl violet.In this study, chronic administration of piperine low dose improved the ICV-STZ induced learning and long-term potentiation (LTP) impairments with no significant effect on baseline synaptic activity. In contrast, remarkable learning and long-term plasticity impairments were observed in rats treated by high dose of piperine in comparison to the other groups. Interestingly, this impaired hippocampal LTP was accompanied by an obvious alteration in baseline activity and significantly decreased neuronal numbers within the hippocampus. Therefore, our data provides a new understanding of the piperine supplementation effects on hippocampal electrophysiological profile although the consequences may be either beneficial or detrimental.     

Impaired neurogenesis is an early event in the etiology of familial Alzheimer's disease in transgenic mice

Formation of new neurons in the adult brain takes place in the subventricular zone and in the subgranule layer of the dentate gyrus throughout life. Neurogenesis is thought to play a role in hippocampus‐ and olfaction‐dependent learning and memory. However, whether impairments in neurogenesis take place in learning and memory disorders, such as Alzheimer's disease, is yet to be established. Importantly, it remains to be elucidated whether neurogenic impairments play a role in the course of the disease or are the result of extensive neuropathology. We now report that transgenic mice harboring familial Alzheimer's disease‐linked mutant APPswe/PS1ΔE9 exhibit severe impairments in neurogenesis that are evident as early as 2 months of age. These mice exhibit a significant reduction in the proliferation of neural progenitor cells and their neuronal differentiation. Interestingly, levels of hyperphosphorylated tau, the cytotoxic precursor of the Alzheimer's disease hallmark neurofibrillary tangles, are particularly high in the neurogenic niches. Isolation of neural progenitor cells in culture reveals that APPswe/PS1ΔE9‐expressing neurospheres exhibit impaired proliferation and tau hyperphosphorylation compared with wildtype neurospheres isolated from nontransgenic littermates. This study suggests that impaired neurogenesis is an early critical event in the course of Alzheimer's disease that may underlie memory impairments, at least in part, and exacerbate neuronal vulnerability in the hippocampal formation and olfaction circuits. Furthermore, impaired neurogenesis is the result of both intrinsic pathology in neural progenitor cells and extrinsic neuropathology in the neurogenic niches. Finally, hyperphosphorylation of the microtubule‐associated protein tau, a critical player in cell proliferation, neuronal maturation, and axonal transport, is a major contributor to impaired neurogenesis in Alzheimer's disease. © 2010 Wiley‐Liss, Inc.     

AMPA-selective glutamate receptor subtype immunoreactivity in the aged human hippocampal formation

It has been hypothesized that, in Alzheimer's disease, glutamate-mediated excitotoxicity contributes to the degeneration of selected populations of neurons. In the present study, immunocytochemical techniques were used to determine the distribution and anatomical features of GluR1- and GluR2/3-immunolabeled cell bodies and processes within the hippocampal formation of normal (i.e., no pathology) elderly humans. The results of this study provide an essential baseline with which to compare the expression and distribution of glutamate receptor subunits within the brains of patients with Alzheimer's disease. With respect to GluR1 immunoreactivity, the molecular layer of the dentate gyrus displays the most intense immunolabeling of any hippocampal structure. Contributing to this intense labeling are apical dendrites that arise from neurons within the adjacent granule cell layer. Interestingly, GluR1-labeled neurons account for a relatively small percentage of the total number of neurons as revealed by Nissl staining in the granule cell layer. In contrast, GluR2/3-labeled neurons are densely distributed throughout the granule cell layer, yet they provide relatively few processes to the adjacent molecular layer compared to GluR1-positive processes. GluRl labeling is also prominent within the CA fields of Ammon's horn, with CA2 > CA3 > CA1 ≥ CA4. Most prominent within the CA fields are the labeled dendrites of pyramidal neurons. In many instances, apical dendrites can be traced into the adjacent stratum radiatum, where they impart a deep striated appearance to this region of the hippocampus. Robust GluR2/3 labeling is also observed within the pyramidal layer of Ammon's horn, with an order of staining intensity similar to that observed for GluRl. However, unlike GluRl labeling, which is localized predominantly along dendrites, GluR2/3 labeling is observed primarily in association with ceh bodies. Collectively, these data suggest that the molecular composition of the AMPA receptor complex may differ between the dendrite and soma of granule and pyramidal neurons within the hippocampal formation, so functionally we may predict that these two regions of the neuron would respond differently following glutamate receptor stimulation. © 1995 Wiley-Liss, Inc.     

Progression of hippocampal degeneration in amyotrophic lateral sclerosis with or without memory impairment: distinction from Alzheimer disease

The hippocampal involvement in amyotrophic lateral sclerosis (ALS) patients has been known for more than a decade, however, its relationship to clinical manifestations including memory deficits and topographical differentiation from Alzheimer disease (AD) remain unclear. In order to clarify the anatomopathological features in the hippocampus and their relevance to disease-specific memory deficits in ALS patients, topography and cytopathology of the hippocampal lesions along the perforant pathway were quantitatively and semiquantitatively surveyed in 14 ALS patients with extramotor involvement. These pathological findings were compared with clinical characteristics assessed from their clinical records. Cytoplasmic inclusions initially appear in the granular cells of the dentate gyrus (DG) and superficial small neurons of the transentorhinal cortex (TEC) with mild subicular degeneration (stage I: inclusion stage). Subsequent gliosis and neuronal loss of the TEC, concomitant with presynaptic degeneration of the outer molecular layer of the DG, suggests an extension of the degeneration through the perforant pathway (stage II: early perforant stage). In a more advanced stage, the presynaptic degeneration is more evident with moderate to severe neuronal loss in the TEC (stage III: advanced perforant stage). This advanced stage was associated with episodic memory deficits mimicking AD in some ALS patients. This ALS pathology initiated by cytoplasmic inclusions and neuronal loss in layer II–III of the TEC is different from neurofibrillary tangles of AD, dominant in layer II–III of the entorhinal cortex. Because this involvement of the TEC-molecular DG projection and subiculum is specific to ALS, it will provide a basis for clinical characterization of memory deficits of ALS, which could be distinct from those of AD.     

Down‐regulation of MET in hippocampal neurons of Alzheimer's disease brains

We found that mRNA of MET, the receptor of hepatocyte growth factor (HGF), is significantly decreased in the hippocampus of Alzheimer's disease (AD) patients. Therefore, we tried to determine the cellular component‐dependent changes of MET expressions. In this study, we examined cellular distribution of MET in the cerebral neocortices and hippocampi of 12 AD and 11 normal controls without brain diseases. In normal brains, MET immunoreactivity was observed in the neuronal perikarya and a subpopulation of astrocytes mainly in the subpial layer and white matter. In AD brains, we found marked decline of MET in hippocampal pyramidal neurons and granule cells of dentate gyrus. The decline was more obvious in the pyramidal neurons of the hippocampi than that in the neocortical neurons. In addition, we found strong MET immunostaining in reactive astrocytes, including those near senile plaques. Given the neurotrophic effects of the HGF/MET pathway, this decline may adversely affect neuronal survival in AD cases. Because it has been reported that HGF is also up‐regulated around senile plaques, β‐amyloid deposition might be associated with astrocytosis through the HGF signaling pathway.     

7.0T nuclear magnetic resonance evaluation of the amyloid beta(1–40) animal model of Alzheimer's disease: comparison of cytology verification

3.0T magnetic resonance spectroscopic imaging is a commonly used method in the research of brain function in Alzheimer's disease.However,the role of 7.0T high-field magnetic resonance spectroscopic imaging in brain function of Alzheimer's disease remains unclear.In this study,7.0T magnetic resonance spectroscopy showed that in the hippocampus of Alzheimer's disease rats,the N-acetylaspartate wave crest was reduced,and the creatine and choline wave crest was elevated.This finding was further supported by hematoxylin-eosin staining,which showed a loss of hippocampal neurons and more glial cells.Moreover,electron microscopy showed neuronal shrinkage and mitochondrial rupture,and scanning electron microscopy revealed small size hippocampal synaptic vesicles,incomplete synaptic structure,and reduced number.Overall,the results revealed that 7.0T high-field nuclear magnetic resonance spectroscopy detected the lesions and functional changes in hippocampal neurons of Alzheimer's disease rats in vivo,allowing the possibility for assessing the success rate and grading of the amyloid beta(1–40) animal model of Alzheimer's disease.     

Effects of entorhinal cortex lesion on learning behavior and on hippocampus in the rat

The initial stage of Alzheimer's disease is characterized by a neuropathological change in the entorhinal cortex. In a previous study it was shown that rats with excitotoxic lesion of entorhinal cortex showed an impaired acquisition of passive and active avoidance responses. In this study a rat with excitotoxic lesion of the entorhinal cortex was tested for ‘more operant’ behavioral learning (i.e., positive reinforcement operant learning). The hippocampus was also examined histologically as acetylcholinesterase-stained sections, and as synaptophysin immunostained sections and examined biochemically by liquid chromatography. Eight weeks after operation, the bilateral entorhinal cortex lesioned rats showed an impaired acquisition of positive reinforcement operant learning. The lesioned side of unilateral entorhinal cortex lesioned rats showed a decrease of acecylcholinesterase-positive fibers in the CA3, the dentate gyrus, and of synaptophysin-positive substances in the CA3. Biochemical study showed a decreased level of acetylcholine in the CA3, and in the dentate gyrus. The histological and biochemical findings are interpreted as indicating that the entorhinal cortex of the rat provides the major extrinsic synaptic input to the hippocampal formation via the circuit which serves as a relay passage through the dentate gyrus and via direct projections into the hippocampus. Behavioral findings confirmed the importance of the entorhinal cortex in memory acquisition and indicated that rats with a partial neuronal loss in the entorhinal cortex may be a useful model for the memory disturbance of Alzheimer's disease.     

Morphological changes in the human cerebral cortex in dementia]

Many diseases of the brain leading to impairment of intellectual capacities are associated with morphological changes in the anteromedial portions of the temporal lobe. Among these are Alzheimer's disease, Parkinson's disease and the syndrome of dementia with argyrophilic grains. The hallmarks of Alzheimer's disease are intraneuronal neurofibrillary changes and extracellular amyloid deposits. The neurofibrillary changes consist of neurofibrillary tangles, neuritic plaques and neuropil threads. The distribution pattern of neurofibrillary changes differs from the distribution of amyloid deposits. The neurofibrillary changes exhibit a distinct but varying distribution pattern in different areas of the cerebral cortex. In fully developed Alzheimer's disease, both the hippocampal formation and isocortical association areas are severely involved while the brunt of the pathology is found in the entorhinal region. The entorhinal region receives information from various isocortical association areas and limbic circuits and projects to the hippocampal formation via the perforant path. This fibre tract is mainly generated by projection neurons within the superficial entorhinal cell layer. In Alzheimer's disease virtually all projection neurons within this layer are destroyed by neurofibrillary tangles. In cases of Parkinson's disease with progressive cognitive decline the neurofibrillary changes are confined to the outer cellular layer of the entorhinal region. In cases of "dementia with argyrophilic grains" the argyrophilic grains are predominantly encountered in the hippocampal formation and in the outer layers of the entorhinal region.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sensory modulation of hippocampal transmission. I. Opposite effects on CA1 and dentate gyrus synapsis

Neuronal transmission through hippocampal subfields exhibits a high degree of modulation and appears dependent on the behavioral state and hippocampal EEG. Sensory inputs, which profoundly modify the hippocampal EEG, may be involved in modulating hippocampal excitability. Field responses of the CA1 region, evoked by ipsilateral CA3 or perforant path stimulation, as well as dentate gyrus potentials evoked by perforant path stimulation were recorded in paralyzed and locally anesthetized rats and studied before, during and after sensory stimulation, consisting of gentle stroking of the animal's fur. On some occasions the CA1 was also antidromically driven from the posterior alveus in order to study the recurrent inhibitory loop and paired pulses were applied to the perforant pathway to study recurrent inhibition in the dentate gyrus. Evoked responses were averaged and field excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude measured. In addition the positive wave which follows the population spike, which corresponds in part to the recurrent IPSP, was also evaluated. Sensory stimulation, which evoked a high-amplitude 5-6 Hz theta (theta)-rhythm in the hippocampal EEG, drastically depressed the efficacy of Schaffer collateral volleys in discharging the CA1 cells. The EPSP-PS curves, however, were not altered revealing that cellular excitability was unaffected. The inhibitory CA1 loop appeared to be unaltered. In contrast, the dentate gyrus responses to perforant pathway stimulation were enhanced during periods of sensory stimulation and the cellular excitability increased, as judged by the shift to the left of EPSP-PS relation. In addition, the recurrent inhibition appeared to be reduced during sensory stimulation. Present results demonstrate that sensory stimulation causes modulation of information transfer through the hippocampus. This modification of hippocampal transmission may serve to properly gate the information reaching the CA1 and dentate gyrus.     

Stimulation of Hippocampal Neurogenesis by Transcranial Focused Ultrasound and Microbubbles in Adult Mice

Transcranial focused ultrasound (FUS) and microbubble contrast agent, applied at parameters known to transiently increase blood-brain barrier permeability, were tested for the potential to stimulate hippocampal neurogenesis. In adult mice, FUS treatment significantly increased the number of proliferating cells and newborn neurons in the dentate gyrus of the dorsal hippocampus. This provides evidence that FUS with microbubbles can stimulate hippocampal neurogenesis, a process involved in learning and memory and affected in neurological disorders, such as Alzheimer's disease.     

Neurodegenerative diseases: basic and clinical research Abstracts

Posrischemic changes in hippocampal non-principal cells Neuronal activity in rat hippocampus slices following in vivo brain ischemia Sulphur amino acids — endogenous ligands for glutamate receptors? Novel NMDA receptor agonists structurally related to ibotenic acid and aspartic acid HIV- 1 nef protein exhibits structural and functional similarity to Neurotoxins Glial reactions to ischemic lesions of the rat hippocampus Microglial and astroglial reactions to perforant path axonal degeneration Unbiased stereological estimation of the total number of neurons in the aging human hippocampus Macroscopic volume measurements on brains from senile demented patients and age-matched controls Cerebral atrophy in 18 males with aids. Stereologic estimate on formalin-fixed brains Absolute number of neurons in substantia nigra in Parkinson's disease The rat nigrostriatal, dopaminergic system studied in organotypic slice cultures of ventral mesencephalon and striatum Basal forebrain neurons in adult rats can reinnervate fetal frontal cortex grafted to frontal cortex lesions. A double-fluorescent tracing study Neuronal plasticity and astrocytic reaction in Alzheimer's disease Problems concerning the use of rating scales and psychometric tests in the study of dementia [^99mTc]-HMPA0 and SPECT of the brain in normal aging SPECT in Alzheimer's disease     

Alzheimer's disease: glutamate depletion in the hippocampal perforant pathway zone

The perforant pathway is the primary source of cortical input to the hippocampal formation. Its cells of origin, in the entorhinal cortex, are destroyed in Alzheimer's disease. Because the principal neurotransmitter of the perforant pathway's excitatory action is thought to be glutamate, we microdissected a portion of the pathway's terminal zone and assayed the excised tissue for glutamate. There was an 83% decrease in the level of free glutamate in subjects with Alzheimer's disease as compared to control subjects not affected by dementia (p less than 0.005). We believe that this diminution in the glutamate content is a direct neurochemical correlate of perforant pathway destruction and that disruption of this crucial corticolimbic pathway contributes to the memory dysfunction in Alzheimer's disease.     

Alterations of AMPA-selected glutamate subtype immunoreactivity in the dentate gyrus after perforant pathway lesion

Immunocytochemical techniques were employed to examine the changes in immunolabeling of the α-amino-3-hydroxy-5-methyl-4-isoaxolepropionate (AMPA) receptor subunits GluR1 and GluR2/3 within the dentate gyrus 1, 3, 7, 14, 30, and 90 days after a unilateral perforant pathway lesion in the rat brain. Completeness of the lesion was confirmed following examination of Nissl-stained tissue sections at all times post-lesion and acetylcholinesterase (AChE)-stained sections 14, 30 and 90 days post-lesion, the latter providing evidence of compensatory sprouting of cholinergic fibers in the outer molecular layer of the dentate gyrus. Compared to the non-lesioned hippocampus there was no difference in the staining pattern of AMPA receptor subunits in the dentate gyrus of the deafferented hippocampus 1, 3, 7 and 14 days following lesioning of the perforant pathway. In contrast, 30 and 90 days post-lesion, GluR1 immunolabeling was increased in the outer molecular layer of the dentate gyrus (i.e., deafferented zone) ipsilateral to lesion. Likewise, GluR2/3 immunolabeling was increased within the same region although the intensity of the response was less than that which was observed for GluR1. These data suggest that the loss of the perforant pathway fibers results in a compensatory increase in GluR1 and to a lesser extent GluR2/3 immunolabeling of the outer molecular layer at 30 and 90 days post-lesion and further suggest that AMPA receptor subunits play a role in perforant pathway signal transduction.