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PubMed2004

The dual response of protein kinase Fyn to neural trauma: early induction in neurons and delayed induction in reactive astrocytes.

In the developing central nervous system, a src-related protein-tyrosine kinase fyn participates in the myelination process, neuronal growth, and cytoskeletal organization. In adults, fyn has been implicated in learning and memory formation. To test if fyn expression is modulated by neuronal activity, we performed quantitative in situ hybridization (ISH) using brain sections of the adult rats that had undergone either kainic acid (KA)-induced seizures or neuronal deafferentation (entorhinal cortex lesion, ECL). In the KA model, a few hours after seizure activities, fyn mRNA was elevated in the dentate gyrus (DG) (+45%), cerebral cortex layer III (+35%), and piriform cortex (+25%). Conversely, fyn mRNA consistently decreased in the hippocampal neurons after transection of the major axonal inputs from the entorhinal cortex. Although fyn expression in the brain has been allegedly limited to neurons and oligodendrocytes, we provide in this study the first evidence that fyn mRNA is highly expressed in the astrocytes involved in reactive gliosis. In the KA model, the occurrence of fyn-overexpressing astrocytes increased with the progress of neuronal damage in the CA1 and CA3 regions of the hippocampus. In contrast, fyn-overexpressing astrocytes were not observed in the granular cell layer of dentate gyrus (DG), where neurons were not damaged. Likewise, in the ECL model, the most drastic change in fyn mRNA expression took place at the reactive astrocytes near the stab wound sites, where fyn mRNA levels were doubled 4-10 d after the lesion. Collectively, our data suggest that (i) an early induction of fyn mRNA in neurons is linked to neuronal activity, and (ii) the delayed induction of fyn mRNA in reactive astrocytes near the damaged cells may play novel signaling roles during glial response.

Animals↗
PubMed2004

Repair of the entorhino-hippocampal projection in vitro.

The repair of axonal projections and the reconstruction of neuronal circuits after CNS lesions or during neurodegenerative disease are major challenges in restorative neuroscience. We have explored the potential of transplanted immature neurons to repair a specific axonal projection in an entorhino-hippocampal slice culture model system. When slices of immature entorhinal cortex (EC) from tau-GFP transgenic mice were cultured next to slices from postnatal hippocampus, an axonal projection from the E18 embryonic entorhinal cortex to the dentate gyrus of the postnatal hippocampus developed, which was similar to that observed in control cultures. Even more immature neuronal precursors in slices from E15 developing cerebral cortex differentiated and established an axonal projection to the hippocampal slice. This projection terminated specifically in the outer molecular layer of the dentate gyrus, the normal target area of the entorhino-hippocampal projection. When embryonic tissue from the presumptive brainstem area was used, there was still a subpopulation of fibers with a specific termination in the outer molecular layer, but few specific fibers were found in cocultures with embryonic midbrain. Our results show that very immature cortical neurons are potentially able to form an entorhino-hippocampal projection that terminates in a correct lamina-specific fashion in the dentate gyrus. These findings support the idea that immature neuronal precursor cells could be used for the reconstruction of specific neuronal circuits.

Animals↗
PubMed2005

Effect of apolipoprotein E deficiency on reactive sprouting in the dentate gyrus of the hippocampus following entorhinal cortex lesion: role of the astroglial response.

This study investigated the effect of apolipoporotein E (apoE) deficiency on hippocampal reactive sprouting responses of the septohippocampal cholinergic (SHC) and commissural/associational fibers (C/A) following an electrolytic lesion of the entorhinal cortex (ECL), using apoE knockout (apoEKO) and age-matched control wild-type mice. Based on recent evidence suggesting that apoE plays a role in the modulation of glial inflammation, we also tested the hypothesis that the pattern of the astroglial response to ECL might be related to the defective reinnervation previously reported in apoEKO mice. Consistent with our hypothesis, we report a differential pattern of astroglial response that concurred with impairments in the sprouting of the SHC and corresponding synaptic replacement in apoEKO mice at 14 and 30 days post-lesion (DPL), a time range covering the onset of axonal/terminal sprouting to synaptogenesis. We also report a limited sprouting of the C/A fiber system in apoEKO relative to control mice at 30 DPL, a period of active dendritic remodeling. The results of the present study confirm and extend previous findings that apoEKO mice display impaired regenerative capacity in response to ECL and argue that in addition to the effect of apoE on lipid trafficking, apoE may also influence the astroglial response to damage, and that both of these effects account for the defective reinnervation observed in apoEKO mice.

Animals↗
PubMed2005

Denervation-induced spatiotemporal upregulation of ephrin-A2 in the mouse hippocampus after transections of the perforant path.

Transections of the entorhinal afferent fibers to hippocampus, perforant path (PP), result in the denervation in specific hippocampal subregions, which is followed by a series of plastic events including axon sprouting and reactive synaptogenesis. Many growth-associated molecules are thought to participate in these events. In the present study, we proved the upregulation of ephrin-A2 in the denervated areas of the ipsilateral hippocampus following PP transections. Interestingly, when the elevation of ephrin-A2 reached the maximum axon sprouting in the denervated areas almost finished, implying the possible inhibitory effect of ephrin-A2 on sprouting. In addition, ephrin-A2 expression was observed in synapses during reactive synaptogenesis, suggesting that this molecule might also be implicated in the formation and maturation of synapses in the denervated areas.

Animals↗
PubMed2006

Validation of two reference genes for mRNA level studies of murine disease models in neurobiology.

Reverse transcription of extracted cellular RNA combined with real-time PCR is now an established method for sensitive detection and quantification of specific mRNA level changes in experimental models of neurological diseases. To neutralize the impact of experimental error and make quantification more precise, normalization of test gene data using data from a constantly expressed gene, a reference gene that is tested along with the test gene, is required. There is no single gene constantly expressed under all experimental conditions. For a given set of conditions or a given disease model, identification of an unaffected reference gene is necessary. In this report, we present our findings from evaluation and validation of the genes encoding hypoxanthine guanine phosphoribosyl transferase 1 (HPRT1) and glyceraldehyde phosphate dehydrogenase (GAPDH) as individual reference genes in mRNA level studies involving four murine neurological disease models. We find both genes are suitable as a reference gene with these four models, provided quantification of subtle changes are avoided. We furthermore demonstrate that above a certain threshold of test mRNA level changes and given high quality RNA processing, normalization to total RNA alone provides for equally reliable quantitative mRNA level results.

Animals↗
PubMed2005

Differential actions of nerve growth factor receptors TrkA and p75NTR in a rat model of epileptogenesis.

Kindling, an experimental model of epileptogenesis, and activation-induced synaptic reorganization are modulated by nerve growth factor (NGF), but whether NGF acts via its high-affinity receptor TrkA and/or the common neurotrophin receptor p75NTR is unknown. We previously demonstrated, and confirmed in this study, that inhibition of NGF binding to both TrkA and p75NTR inhibited kindling and decreased kindling-induced mossy fiber sprouting. We now report specific inhibition of TrkA.NGF binding, but not p75NTR.NGF binding, retarded perforant path kindling progression. However, mossy fiber sprouting was inhibited by either selective TrkA.NGF or p75NTR.NGF antagonists. Our results suggest that TrkA, but not p75NTR, plays a role in kindling, while both receptors modulate kindling-induced mossy fiber sprouting. This implicates different mechanisms of neurotrophin action on kindling (mediated by TrkA) and neuronal sprouting (mediated by both TrkA and p75NTR) and suggests that sprouting involves kindling-independent neurotrophin action via p75NTR.

Animals↗
PubMed2006

Reduced reactivity to novelty, impaired social behavior, and enhanced basal synaptic excitatory activity in perforant path projections to the dentate gyrus in young adult mice deficient in the neural cell adhesion molecule CHL1.

The neural cell adhesion molecule CHL1 is implicated in neural development in the mouse and has been related to psychiatric disorders in humans. Here we report that mice constitutively deficient for CHL1 display reduced reactivity to environmental stimuli and reduced expression of social behaviors, whereas cognitive, motor and olfactory functions are normal. Basal synaptic transmission and plasticity in seven major excitatory connections in the hippocampus were analyzed to test whether dysfunctions in this brain region, which controls complex behaviors, correlate with the behavioral alterations of CHL1 deficient mice. We found that basal synaptic transmission in lateral and medial perforant path projections to the dentate gyrus is elevated in CHL1-deficient mice. Taking in consideration the function of these synapses in processing information from cortical areas, we hypothesize that constitutive ablation of CHL1 leads to reduced capability to react to external stimuli due to dysfunctions in the dentate gyrus.

Animals↗
PubMed2003

Semi-quantitative expression analysis of ephrin mRNAs in the deafferented hippocampus.

To search for gene expression changes probably responsible for deafferentation-induced reorganization in the brain, we have analyzed the expression of mRNAs for ephrin-A1, -A2, -A3, -A5 and -B1 in the rat hippocampus following transection of the entorhinal afferents by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). We found that their expression in the deafferented hippocampus increased significantly by 7 days, reached the maximum at 14 days and almost recovered to control levels by 60 days post-lesion. It is notable that the up-regulation of ephrin mRNAs occurs during the reorganization in the deafferented hippocampus, suggesting that ephrins may be involved in the plasticity events of the adult brain after lesion.

Analysis of Variance↗
PubMed2005

NMDA receptor antagonists block heterosynaptic long-term depression (LTD) but not long-term potentiation (LTP) in the CA3 region following lateral perforant path stimulation.

High-frequency stimulation of lateral perforant path is accompanied by a heterosynaptic long-term depression (LTD) of medial perforant path synaptic responses in both the dentate gyrus and the CA3 region of the hippocampus. We reported previously that LTP induction at lateral perforant path-CA3 synapses is unaffected by NMDA antagonists. However, it is not known if heterosynaptic LTD that is observed in the CA3 region following lateral perforant path stimulation also is independent from NMDA receptors. We address this question in anesthetized adult rats using systemic administration of the competitive NMDA receptor antagonist CPP. Induction of lateral perforant path-CA3 LTP produced a sustained heterosynaptic depression of medial perforant path-CA3 responses. Systemic administration of CPP (10 mg/kg) was ineffective in blocking the induction of LTP at lateral perforant path-CA3 responses. However, heterosynaptic LTD of medial perforant path-CA3 responses was blocked completely by CPP. These data indicate that NMDA receptors are not required for the induction of lateral perforant path-CA3 LTP, but are involved in the induction of heterosynaptic LTD that accompanies lateral perforant path activity. The requirement for NMDA receptors for heterosynaptic LTD suggests one functional role of NMDA receptors at termination fields of the lateral perforant path.

Adaptation, Physiological↗
PubMed2004

White matter hemisphere asymmetries in healthy subjects and in schizophrenia: a diffusion tensor MRI study.

Hemisphere asymmetry was explored in normal healthy subjects and in patients with schizophrenia using a novel voxel-based tensor analysis applied to fractional anisotropy (FA) of the diffusion tensor. Our voxel-based approach, which requires precise spatial normalization to remove the misalignment of fiber tracts, includes generating a symmetrical group average template of the diffusion tensor by applying nonlinear elastic warping of the demons algorithm. We then normalized all 32 diffusion tensor MRIs from healthy subjects and 23 from schizophrenic subjects to the symmetrical average template. For each brain, six channels of tensor component images and one T2-weighted image were used for registration to match tensor orientation and shape between images. A statistical evaluation of white matter asymmetry was then conducted on the normalized FA images and their flipped images. In controls, we found left-higher-than-right anisotropic asymmetry in the anterior part of the corpus callosum, cingulum bundle, the optic radiation, and the superior cerebellar peduncle, and right-higher-than-left anisotropic asymmetry in the anterior limb of the internal capsule and the anterior limb's prefrontal regions, in the uncinate fasciculus, and in the superior longitudinal fasciculus. In patients, the asymmetry was lower, although still present, in the cingulum bundle and the anterior corpus callosum, and not found in the anterior limb of the internal capsule, the uncinate fasciculus, and the superior cerebellar peduncle compared to healthy subjects. These findings of anisotropic asymmetry pattern differences between healthy controls and patients with schizophrenia are likely related to neurodevelopmental abnormalities in schizophrenia.

Adult↗
PubMed2005

Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo.

Aggregation of the amyloid-beta (Abeta) peptide in the extracellular space of the brain is central to Alzheimer's disease pathogenesis. Abeta aggregation is concentration dependent and brain region specific. Utilizing in vivo microdialysis concurrently with field potential recordings, we demonstrate that Abeta levels in the brain interstitial fluid are dynamically and directly influenced by synaptic activity on a timescale of minutes to hours. Using an acute brain slice model, we show that the rapid effects of synaptic activity on Abeta levels are primarily related to synaptic vesicle exocytosis. These results suggest that synaptic activity may modulate a neurodegenerative disease process, in this case by influencing Abeta metabolism and ultimately region-specific Abeta deposition. The findings also have important implications for treatment development.

Action Potentials↗
PubMed2006

Distance-dependent differences in synapse number and AMPA receptor expression in hippocampal CA1 pyramidal neurons.

The ability of synapses throughout the dendritic tree to influence neuronal output is crucial for information processing in the brain. Synaptic potentials attenuate dramatically, however, as they propagate along dendrites toward the soma. To examine whether excitatory axospinous synapses on CA1 pyramidal neurons compensate for their distance from the soma to counteract such dendritic filtering, we evaluated axospinous synapse number and receptor expression in three progressively distal regions: proximal and distal stratum radiatum (SR), and stratum lacunosum-moleculare (SLM). We found that the proportion of perforated synapses increases as a function of distance from the soma and that their AMPAR, but not NMDAR, expression is highest in distal SR and lowest in SLM. Computational models of pyramidal neurons derived from these results suggest that they arise from the compartment-specific use of conductance scaling in SR and dendritic spikes in SLM to minimize the influence of distance on synaptic efficacy.

Animals↗
PubMed2004

Initiation of electrographic seizures by neuronal networks in entorhinal and perirhinal cortices in vitro.

The hippocampus is often considered to play a major role in the pathophysiology of mesial temporal lobe epilepsy. However, emerging clinical and experimental evidence suggests that parahippocampal areas may contribute to a greater extent to limbic seizure initiation, and perhaps epileptogenesis. To date, little is known about the participation of entorhinal and perirhinal networks to epileptiform synchronization. Here, we addressed this issue by using simultaneous field potential recordings in horizontal rat brain slices containing interconnected limbic structures that included the hippocampus proper. Epileptiform discharges were disclosed by bath applying the convulsant drug 4-aminopyridine (50 microM) or by superfusing Mg(2+)-free medium. In the presence of 4-aminopyridine, slow interictal- (duration=2.34+/-0.29 s; interval of occurrence=25.75+/-2.11 s, n=16) and ictal-like (duration=31.25+/-3.34 s; interval of occurrence=196.96+/-21.56 s, n=17) discharges were recorded in entorhinal and perirhinal cortices after abating the propagation of CA3-driven interictal activity to these areas following extended hippocampal knife cuts. Simultaneous recordings obtained from the medial and lateral entorhinal cortex, and from the perirhinal cortex revealed that interictal and ictal discharges could initiate from any of these areas and propagate to the neighboring structure with delays of 8-66 ms. However, slow interictal- and ictal-like events more often originated in the medial entorhinal cortex and perirhinal cortex, respectively. Cutting the connections between entorhinal and perirhinal cortices (n=10), or functional inactivation of cortical areas by local application of a glutamatergic receptor antagonist (n=11) made independent epileptiform activity occur in all areas. These procedures also shortened ictal discharge duration in the entorhinal cortices, but not in the perirhinal area. Similar results could be obtained by applying Mg(2+)-free medium (n=7). These findings indicate that parahippocampal networks provide independent epileptiform synchronization sufficient to sustain limbic seizures as well as that the perirhinal cortex plays a preferential role in in vitro ictogenesis.

4-Aminopyridine↗
PubMed2004

Patterns of seizures, hippocampal injury and neurogenesis in three models of status epilepticus in galanin receptor type 1 (GalR1) knockout mice.

The neuropeptide galanin exhibits anticonvulsant effects in experimental epilepsy. Two galanin receptor subtypes, GalR1 and GalR2, are present in the brain. We examined the role of GalR1 in seizures by studying the susceptibility of GalR1 knockout (KO) mice to status epilepticus (SE) and accompanying neuronal injury. SE was induced in GalR1 KO and wild type (WT) mice by Li-pilocarpine, 60 min electrical perforant path stimulation (PPS), or systemic kainic acid (KA). Seizures were analyzed using Harmonie software. Cell injury was examined by FluoroJade B- and terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end labeling; neurogenesis was studied using bromodeoxyuridine labeling. Compared with WT littermates, GalR1 KO showed more severe seizures, more profound injury to the CA1 pyramidal cell layer, as well as injury to hilar interneurons and dentate granule cells upon Li-pilocarpine administration. PPS led to more severe seizures in KO, as compared with WT mice. No difference in the extent of neuronal degeneration was observed between the mice of two genotypes in CA1 pyramidal cell layer; however, in contrast to WT, GalR1 KO developed mild injury to hilar interneurons on the side of PPS. KA-induced seizures did not differ between GalR1 KO and WT animals, and led to no injury to the hippocampus in either of experimental group. No differences were found between KO and WT mice in both basal and seizure-induced neuronal progenitor proliferation in all seizure types. Li-pilocarpine led to more extensive glia proliferation in GalR1 KO than in WT, and in both mouse types in two other SE models. In conclusion, GalR1 mediate galanin protection from seizures and seizure-induced hippocampal injury in Li-pilocarpine and PPS models of limbic SE, but not under conditions of KA-induced seizures. The results justify the development and use of GalR1 agonists in the treatment of certain forms of epilepsy.

Animals↗
PubMed2006

Induction and activity-dependent reversal of persistent LTP and LTD in lateral perforant path synapses in vivo.

The reversibility of long-term potentiation (LTP) and heterosynaptic long-term depression (LTD) lasting weeks was examined in the lateral perforant path of freely moving adult Sprague-Dawley rats. LTP lasting weeks was rapidly reversed within minutes by high-frequency heterosynaptic stimulation of the medial perforant path, in an N-methyl-D-aspartate receptor-dependent manner. LTP reversal also occurred, albeit more slowly and to a lesser extent, when animals were given 1-3 weeks of overnight exposure to an enriched environment (EE). LTD likewise was reversed upon repeated EE exposure. A covert similarity between the degrees of LTP and LTD reversal was revealed when the small potentiation effect of EE treatment by itself on lateral path responses was taken into account. Despite its ability to reverse previously acquired synaptic plasticity, two weeks of EE treatment had no effect on animals' retention of the platform location in a spatial watermaze task, although it did facilitate new learning. These data are in agreement with the hypothesis that hippocampal synapses retain the capacity for rapid synaptic change even when otherwise relatively stable plasticity has previously been induced. Slow reversal of such plasticity did not correlate with a loss of memory retention, possibly because either slow changes permit reorganization of representations such that both old and new information can be accommodated, or else the new information is synaptically represented in orthogonal fashion to the old information.

Analysis of Variance↗
PubMed2005

Age-related impairments of synaptic plasticity in the lateral perforant path input to the dentate gyrus of galanin overexpressing mice.

In the present study, electrophysiological recordings were made from hippocampal slices obtained from mice overexpressing galanin under the promoter for the platelet-derived growth factor-B (GalOE mice). In these mice, a particularly strong galanin expression is seen in the granule cell layer/mossy fibers. Paired-pulse facilitation (PPF) of excitatory postsynaptic field potentials (fEPSPs) at the lateral perforant path (LPP)-dentate gyrus synapses was elicited in the dentate gyrus after stimulation with different interpulse intervals. Slices from young adult wild-type (WT) animals showed significant PPF of the 2nd EPSP evoked with paired-pulse stimuli, while PPF was reduced in slices from young adult GalOE mice, as well as aged WT mice, but were not observed at all in slices from aged GalOE animals. Application of the putative galanin antagonist M35 increased PPF in slices from aged WT mice as well as from adult and aged GalOE mice, but had no effect in slices taken from young adult WT mice. These data indicate that galanin is involved in hippocampal synaptic plasticity, in particular in age-related reduction of synaptic plasticity in the LPP input to the dentate gyrus. Galaninergic mechanisms may therefore represent therapeutic targets for treatment of age-related memory deficits and Alzheimer's disease.

Aging↗
PubMed2000

Bidirectional actions of docosahexaenoic acid on hippocampal neurotransmissions in vivo.

Docosahexaenoic acid (DHA), a 22-carbon fatty acid with six double bonds, is one of the major polyunsaturated fatty acids in fish oils or in the mammalian central nervous system and is believed to be essential for neuronal plasticity and development. In the present study, we evaluated the effect of DHA on hippocampal neurotransmissions using anesthetized rats. Field excitatory postsynaptic potential (fEPSP) evoked by stimulation of the Schaffer collaterals was recorded from the CA1 stratum radiatum. Following intracerebroventricular injection of DHA 25 nmol, the fEPSP slope decreased gradually in 30 min and was eventually suppressed by about 30%. On the other hand, when fEPSP was evoked by stimulation of the perforant path was recorded in the molecular layer of the dentate gyrus, an increase in fEPSP slope occurred over a similar time course after DHA injection. These phenomena were independent of N-methyl-D-aspartate receptor activity. Linoleic acid, one of polyunsaturated fatty acids, was virtually ineffective. Furthermore, we investigated the effect of DHA on hippocampal synaptic plasticity. Although DHA did not alter the profile of paired-pulse facilitation, it inhibited the induction of long-term potentiation in the CA1 area but not in the dentate gyrus. Thus, DHA exerts regionally different effects on hippocampal neurotransmission and may be a good tool for clarifying physiological functions of the hippocampus.

Animals↗
PubMed2000

Receptor blockade reveals a correspondence between hippocampal-dependent behavior and experience-dependent synaptic enhancement.

This study examined the involvement of N-methyl-D-aspartate receptors (NMDARs) in experience-dependent synaptic plasticity. Rats chronically received an NMDA receptor antagonist (AP5) or saline (SAL) and were exposed to individual cages (IC) or environmental enrichment (EC). AP5 impaired measures of hippocampal-dependent behavior and increased locomotor activity. Perforant path synaptic strength, measured in the in vitro hippocampal slice, was increased and long-term potentiation (LTP) was decreased for EC+SAL animals. The experience-dependent effects on synaptic function were inhibited by drug treatment. Measures of synaptic strength were correlated with hippocampal-dependent behavior and synaptic plasticity for EC animals. The results suggest a relationship between hippocampal-dependent behavior and experience-dependent modification of perforant path synaptic function through NMDAR activation.

2-Amino-5-phosphonovalerate↗