Feedforward excitation of the hippocampus by afferents from the entorhinal cortex: redefinition of the role of the trisynaptic pathway.

For the past 3 decades, functional characterizations of the hippocampus have emphasized its intrinsic trisynaptic circuitry, which consists of successive excitatory projections from the entorhinal cortex to the dentate gyrus, from granule cells of the dentate to the CA3/4 pyramidal cell region, and from CA3/4 to the CA1/2 pyramidal cell region. Despite unequivocal anatomical evidence for a monosynaptic projection from entorhinal to CA3 and CA1/2, few in vivo electrophysiological studies of the direct pathway have been reported. In the experiments presented here, we stimulated axons of entorhinal cortical neurons in vivo and recorded evoked single unit and population spike responses in the dentate, CA3, and CA1 of hippocampus, to determine if pyramidal cells are driven primarily via the monosynaptic or trisynaptic pathways. Our results show that neurons within the three subfields of the hippocampus discharge simultaneously in response to input from a given subpopulation of entorhinal cortical neurons and that the initial monosynaptic excitation of pyramidal cells then is followed by weaker excitatory volleys transmitted through the trisynaptic pathway. In addition, we found that responses of CA3 pyramidal cells often precede those of dentate granule cells and that excitation of CA3 and CA1 pyramidal cells can occur in the absence of granule cell excitation. In total, these results argue for a different conceptualization of the functional organization of the hippocampus with respect to the propagation of activity through its intrinsic pathways: input from the entorhinal cortex initiates a two-phase feedforward excitation of pyramidal cells, with the dentate gyrus providing feedforward excitation of CA3, and with both the dentate and CA3 providing feedforward excitation of CA1.     

Remodeling of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor subunit composition in hippocampal neurons after global ischemia

Transient global ischemia induces selective delayed cell death, primarily of principal neurons in the hippocampal CA1. However, the molecular mechanisms underlying ischemia-induced cell death are as yet unclear. The present study shows that global ischemia triggers a pronounced and cell-specific reduction in GluR2 [the subunit that limits Ca(2+) permeability of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors] in vulnerable CA1 neurons, as evidenced by immunofluorescence of brain sections and Western blot analysis of microdissected hippocampal subfields. At 72 h after ischemia (a time before cell death), virtually all CA1 pyramidal neurons exhibited greatly reduced GluR2 immunolabeling throughout their somata and dendritic processes. GluR2 immunolabeling was unchanged in pyramidal cells of the CA3 and granule cells of the dentate gyrus, regions resistant to ischemia-induced damage. Immunolabeling of the AMPA receptor subunit GluR1 was unchanged in CA1, CA3, and dentate gyrus. Western analysis indicated that GluR2 subunit abundance was markedly reduced in CA1 at 60 and 72 h after the ischemic insult; GluR1 abundance was unchanged in all subfields at all times examined. These findings, together with the previous observation of enhanced AMPA-elicited Ca(2+) influx in postischemic CA1 neurons, show that functional GluR2-lacking, Ca(2+)-permeable AMPA receptors are expressed in vulnerable neurons before cell death. Thus, the present study provides an important link in the postulated causal chain between global ischemia and delayed death of CA1 pyramidal neurons.     

Age-related anatomical changes in the rat hippocampus: retardation by choline alfoscerate treatment

The age-related anatomical changes in the rat hippocampus were evaluated in male Sprague-Dawley rats of 3 (young), 12 (mature) and 24 (aged) months by counting the number of nerve cells in the CA1 and CA3 fields and in the dentate gyrus and by measuring the density of Nissl bodies in the cytoplasm of the pyramidal and granule neurons of the above areas. Moreover, the effect of 3 months choline alfoscerate treatment on the anatomical parameters examined was evaluated. The number of pyramidal neurons of the CA1 field and of granule neurons of the dentate gyrus was not significantly changed between young and mature animals, but it was decreased in aged rats. The number of pyramidal neurons of the CA3 field showed a progressive age-dependent reduction. The density of Nissl bodies was the highest in the cytoplasm of pyramidal or granule neurons in mature rats followed in descending order by young and aged animals. Choline alfoscerate treatment counteracted the age-related loss of nerve cells in the 3 hippocampal portions examined and slow-drown the decrease of Nissl bodies in the cytoplasm of pyramidal or of granule neurons in the hippocampus. The significance of changes induced by choline alfoscerate in the hippocampus of aged rats and the possible mechanism of action of the compound are discussed.     

RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory

Learning and memory have been closely linked to strengthening of synaptic connections between neurons (i.e., synaptic plasticity) within the dentate gyrus (DG)–CA3–CA1 trisynaptic circuit of the hippocampus. Conspicuously absent from this circuit is area CA2, an intervening hippocampal region that is poorly understood. Schaffer collateral synapses on CA2 neurons are distinct from those on other hippocampal neurons in that they exhibit a perplexing lack of synaptic long-term potentiation (LTP). Here we demonstrate that the signaling protein RGS14 is highly enriched in CA2 pyramidal neurons and plays a role in suppression of both synaptic plasticity at these synapses and hippocampal-based learning and memory. RGS14 is a scaffolding protein that integrates G protein and H-Ras/ERK/MAP kinase signaling pathways, thereby making it well positioned to suppress plasticity in CA2 neurons. Supporting this idea, deletion of exons 2–7 of the RGS14 gene yields mice that lack RGS14 (RGS14-KO) and now express robust LTP at glutamatergic synapses in CA2 neurons with no impact on synaptic plasticity in CA1 neurons. Treatment of RGS14-deficient CA2 neurons with a specific MEK inhibitor blocked this LTP, suggesting a role for ERK/MAP kinase signaling pathways in this process. When tested behaviorally, RGS14-KO mice exhibited marked enhancement in spatial learning and in object recognition memory compared with their wild-type littermates, but showed no differences in their performance on tests of nonhippocampal-dependent behaviors. These results demonstrate that RGS14 is a key regulator of signaling pathways linking synaptic plasticity in CA2 pyramidal neurons to hippocampal-based learning and memory but distinct from the canonical DG–CA3–CA1 circuit.     

Sexual dimorphism in regulation of type II corticosteroid receptor immunoreactivity in the rat hippocampus.

To determine whether there are sex differences in the distribution of type II corticosteroid receptor-immunoreactive (type II-ir) cells in the rat hippocampus, we carried out a quantitative morphometric immunocytochemical study using a mouse monoclonal antibody, BUGR2. We report that in adrenally intact male and female rats, high densities of cells with nuclear type II-ir were observed in the pyramidal layer of field CA1 and the granular layer of the dentate gyrus. In intact males very few cells, presumably glia, in the stratum oriens showed type II-ir. In contrast, in females, interneurons with diffuse or cytoplasmic type II-ir were observed in the stratum oriens of CA1 and CA3. There were also sex differences in the regulation of type II-ir by corticosterone, the predominant glucocorticoid, and female sex steroids. In male rats the density of cells with nuclear type II-ir in all parts of Ammon's horn and the dentate gyrus was decreased significantly after adrenalectomy (adx). In contrast, in females such reductions were observed only in the pyramidal layer of CA1 and the granular layer of the dentate gyrus. In both sexes, cells with intense diffuse or mainly cytoplasmic type II-ir were observed in the pyramidal layer and stratum oriens after adx. The loss of nuclear type II-ir in the hippocampus of adx females was not affected significantly by ovariectomy. In adx males, nuclear Type II-ir was restored in CA1 and the dentate gyrus after treatment with corticosterone or progesterone. Cells in CA3 were, however, unresponsive to treatment with either hormone. In contrast, in adx females, treatment with either corticosterone or progesterone restored nuclear type II-ir to cells in all regions of the hippocampus. In both adx males and females, cytoplasmic type II-ir observed in some cells in the pyramidal layer and stratum oriens, was abolished completely by corticosterone, and partially by progesterone treatment. In both adx males and females, estradiol treatment did not affect significantly the pattern of type II-ir. Sex differences in the distribution of type II-ir interneurons in intact rats and the regulation of the intracellular location of type II-ir of adx rats by corticosterone and progesterone, may be important determinants of sex differences in the modulation of hippocampal function by glucocorticoids.     

Generation of Neurons in the Rat Dentate Gyrus and Hippocampus: Effects of Prenatal and Postnatal Treatment with Ethanol

Neurons in the rat hippocampal formation (the dentate gyrus and the hippocampus) are born over a protracted period, from gestational day (G) 15 into adulthood. Dentate gyral neurons born prenatally are generated from the ventricular zone, whereas those born postnatally are derived from a secondary proliferative zone, the intrahilar zone. In contrast, hippocampal pyramidal neurons are generated only prenatally from the ventricular zone. In the neocortex, ethanol depresses the proliferation of cells in the ventricular zone and stimulates the proliferation of cells in the secondary proliferative zone. The present study tests the hypotheses that prenatal treatment with ethanol has a different effect on the generation of dentate gyral neurons than does postnatal ethanol treatment, and that these differences are determined by the timing of the ethanol exposure relative to the period and site of neuronal generation. Rats were treated with ethanol between G6 and G21 or between postnatal day (P) 4 and P12. They were given an injection of [³H]thymidine on G15, G18, G21, P6, P9, or P12. Rats were killed on P30–P35. The tissue was processed by standard autoradiographic methods and assessed using rigorous stereological procedures. The total number of neurons and the density of radiolabeled neurons in both the dentate gyrus and the CA1 region of the hippocampus were determined. Prenatal ethanol treatment decreased the total number of neurons in the CA1 segment of the hippocampus and had little impact on neuronal number in the dentate gyrus. Likewise, the number of hippocampal and dentate gyral neurons generated daily was significantly lower in ethanol-treated rats than in controls. Postnatal treatment to ethanol, however, significantly increased the total number of dentate gyral neurons and the density of neurons generated postnatally. These postnatal changes depended on the blood ethanol concentration (BEC). At moderate BECs, the total number of neurons in the dentate gyrus and the number of neurons generated was increased. At high BECs, however, neuronal number and neuronal generation were decreased. Postnatal ethanol treatment had no effect on the number of (total or radiolabeled) CA1 neurons. Thus, pre- and postnatal exposure to ethanol have opposite effects both on the number of neurons in the dentate gyrus and on the generation of neurons. These paradoxical effects likely result from three causes: the differential effects of ethanol on the two proliferative zones, the critical period of neuronal development, and the potentially opposite effects of moderate and high BEC.     

转基因小鼠脑组织中突触素和发动蛋白Ⅰ及衔接蛋白180表达的变化

目的探讨瑞典型淀粉样前体蛋白突变基因转基因小鼠脑组织中突触素(synaptophysin)、发动蛋白Ⅰ(dynamin Ⅰ)及衔接蛋白180(AP180)表达变化。方法选择6只瑞典型淀粉样前体蛋白突变基因转基因小鼠为转基因组,另选5只小鼠为对照组。采用免疫组织化学染色法检测小鼠海马及颞叶皮质synaptophysin、dynamin Ⅰ及AP180的表达,图像分析半定量;免疫组织化学双染法观察转基因小鼠脑组织中synaptophysin与β淀粉样蛋白(Aβ)_(1-42)在老年斑表达部位的关系。结果与对照组比较,转基因组小鼠脑组织齿状回分子层、海马CA1、CA3及内嗅区皮质各层synaptophysin平均灰度值明显增高(P0.05,P0.01);齿状回颗粒细胞、海马CA1锥体细胞及内嗅区皮质各层dynamin Ⅰ平均灰度值明显增高(P0.05,P0.01);齿状回分子层、海马CA4、CA1、内嗅区皮质各层及颞叶皮质Ⅱ～Ⅴ层AP180平均灰度值明显增高(P0.05,P0.01)。免疫组织化学双染显示转基因组小鼠老年斑内有synaptophysin和Aβ_(1-42)共同存在。结论转基因小鼠脑组织中synaptophysin、dynamin Ⅰ及AP180表达降低,提示出现不同程度突触丧失及突触囊泡回收功能缺陷,可能是该小鼠认知功能障碍的原因之一。     

Melatonin promotes neurogenesis in dentate gyrus in the pinealectomized rat

Abstract:  It was previously shown that pinealectomy causes delayed loss of pyramidal neurons in rat hippocampal layers CA1/3 and that this is reversed by melatonin supplementation. Here, we used immunohistologic detection of doublecortin, a protein expressed in newborn neurons, to determine if melatonin supplementation promotes neurogenesis after pinealectomy. It was found that melatonin supplementation significantly increased the number of doublecortin immunoreactive neurons in the dentate gyrus over the postsurgical intervals of 2, 4, 6, 8, 10 and 17 months. The increase was most evident at 6 months postsurgery and thereafter, and was apparent despite a severe decline in doublecortin-labeled cells over the 17 month postsurgical interval in all groups of rats. Doublecortin immunoreactive cells were not observed in the pyramidal layer itself. These results indicate that melatonin promotes neurogenesis in the dentate gyrus of pinealectomized rats. However, it is equivocal that these newborn neurons migrate to the pyramidal layer and account for the reappearance of neurons at this location in these rats. This study provides further evidence for a role of melatonin in promoting neurogenesis, adding another role to its already remarkably pleiotropic profile. The scope and significance of this newly discovered role remains to be determined.     

Intrahippocampal colchicine alters hypothalamic corticotropin-releasing hormone and hippocampal steroid receptor mRNA in rat brain.

The hippocampus appears to be an important modulator of the negative feedback effects of glucocorticoids on the hypothalamic-pituitary-adrenal axis. It is not known if hippocampal subfields CA1-4 or the dentate gyrus differentially alter gene expression of corticotropin-releasing hormone (CRH) in the paraventricular nucleus (PVN) of the hypothalamus. We, therefore, examined the effects of selective destruction of dentate gyrus granule cells, which send excitatory glutaminergic inputs to subfields CA4, CA3 and CA2, on CRH expression in the PVN. To determine the possible involvement of steroid receptors in the regulation of CRH expression, we examined the effects of intrahippocampal colchicine on gene expression of the mineralocorticoid (MR; type I) and glucocorticoid (GR; type II) receptors in hippocampal CA fields and dentate gyrus. Colchicine produced a selective loss of dentate gyrus granule cells without affecting pyramidal cells in CA1-4 as early as 1 day after injection; granule cells were completely destroyed after 3 days. CRH mRNA levels were reduced by 38-48% in the PVN 2-14 days after colchicine. MR mRNA levels were decreased in dorsal and ventral CA fields 1-7 days after colchicine. GR mRNA levels were relatively unchanged, showing a slight decrease only in dorsal CA fields on days 2-7. Unexpectedly, CRH was transiently expressed in dorsal and ventral CA fields 1-3 days after colchicine. In the same time period, mRNA levels of inositol 1,4,5-trisphosphate kinase were decreased, suggesting that increases in neural metabolic activity, indicated by this marker, are not responsible for the transient CRH effect. The results suggest that the dentate gyrus is important for maintenance of steroid hormone receptor mRNA levels in the hippocampus and CRH expression in the hypothalamic PVN, and that CRH gene expression is differentially regulated in the hypothalamus and hippocampus.     

Human neurons express type I GnRH receptor and respond to GnRH I by increasing luteinizing hormone expression

Gonadotropin-releasing hormone receptor I (GnRHR I) has been localized to the limbic system of the rat brain, although the functional consequences of GnRH signaling through these receptors is unknown. In this paper, we characterize the expression of GnRHR I in the human hippocampus and cortex, and the functionality of GnRHR I in human neuroblastoma cells. Robust GnRHR I immunoreactivity was detected in the cell body as well as along the apical dendrites of pyramidal neurons in the CA2, CA1, and end plate, but was clearly lower in the subiculum of the hippocampus. Immunolabeling was also evident in cortical neurons, including those located in the entorhinal cortex and occipitotemporal gyrus but was not observed within the granular layer of the dentate gyrus. No differences in immunohistochemical staining were observed between control and Alzheimer's disease brain. GnRHR I mRNA and protein (mature, immature, and other variant) expression was detected in human neuroblastoma cells (M17, SH-SY5Y) and rat embryonic primary neurons and varied with differentiation and GnRH treatment. Since GnRHR I was expressed by extrapituitary cells, and hypothalamic GnRH I secretion markedly increases post-menopause/andropause, we treated human M17 neuroblastoma cells cultured in serum-free conditions with GnRH I for 6 h and measured LH expression. M17 neuroblastoma cells express LHbeta mRNA, while immunoblot analysis indicated the presence of three LH variants (approximately 30, 47, and 60 kDa) that were upregulated by low concentrations of GnRH I, but down-regulated at higher GnRH I concentrations. LH expression was also found to increase in differentiating embryonic rat primary cortical neurons. Our results demonstrate that neurons expressing GnRHR I are functional, responding to GnRH I by upregulating LH production. Post-reproductive surges in GnRH I secretion may explain the accumulation of LH in pyramidal neurons of the aged human and rat.     

Dentate gyrus-specific manipulation of beta-Ca2+/calmodulin-dependent kinase II disrupts memory consolidation

Although the functions of alpha-Ca(2+)/calmodulin-dependent kinase II (CaMKII) have been studied extensively, the role of betaCaMKII, a coconstituent of the CaMKII holoenzyme in synaptic plasticity, learning, and memory has not been examined in vivo. Here we produce a transgenic mouse line in which the inducible and reversible manipulation of betaCaMKII activity is restricted to the hippocampal dentate gyrus, the region where long-term potentiation was originally discovered. We demonstrate that betaCaMKII activity in the dentate gyrus selectively impaired long-term potentiation in the dentate perforant path, but not in the CA1 Schaffer collateral pathway. Although the transgenic mice showed normal 1-day memories, they were severely impaired in 10-day contextual fear memory. Systematic manipulations of dentate betaCaMKII activity during various distinct memory stages further reveal the initial day within the postlearning consolidation period as a critical time window that is highly sensitive to changes in betaCaMKII activity. This study provides evidence not only for the functional role of betaCaMKII in the dentate gyrus plasticity and hippocampal memory, but also for the notion that the mismatch between the actual learning pattern and reactivation patterns in the dentate gyrus circuit can underlie long-term memory consolidation.     

Down-regulation of neurosteroid biosynthesis in corticolimbic circuits mediates social isolation-induced behavior in mice

Allopregnanolone (ALLO), synthesized by pyramidal neurons, is a potent positive allosteric modulator of the action of GABA at GABA(A) receptors expressing specific neurosteroid binding sites. In the brain, ALLO is synthesized from progesterone by the sequential action of two enzymes: 5alpha-reductase type I (5alpha-RI) and 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD). In the cortex, hippocampus, and amygdala, these enzymes are colocalized in principal glutamatergic output neurons [Agís-Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E, Guidotti A (2006) Proc Natl Acad Sci USA 103:14602-14607], but they are not detectable in GABAergic interneurons. Using RT-PCR and in situ hybridization, this study compares 5alpha-RI and 3alpha-HSD mRNA brain expression levels in group housed and in socially isolated male mice for 4 weeks. In these socially isolated mice, the mRNA expression of 5alpha-RI was dramatically decreased in hippocampal CA3 glutamatergic pyramidal neurons, dentate gyrus granule cells, glutamatergic neurons of the basolateral amygdala, and glutamatergic pyramidal neurons of layer V/VI frontal (prelimbic, infralimbic) cortex (FC). In contrast, 5alpha-RI mRNA expression failed to change in CA1 pyramidal neurons, central amygdala neurons, pyramidal neurons of layer II/III FC, ventromedial thalamic nucleus neurons, and striatal medium spiny and reticular thalamic nucleus neurons. Importantly, 3alpha-HSD mRNA expression was unchanged by protracted social isolation (Si). These data suggest that, in male mice, after 4 weeks of Si, the expression of 5alpha-RI mRNA, which is the rate-limiting-step enzyme of ALLO biosynthesis, is specifically down-regulated in glutamatergic pyramidal neurons that converge on the amygdala from cortical and hippocampal regions. In socially isolated mice, this down-regulation may account for the appearance of behavioral disorders such as anxiety, aggression, and cognitive dysfunction.     

An immunohistochemical study of parvalbumin containing interneurons in the gerbil hippocampus after cerebral ischemia

We investigated postischemic changes of non-pyramidal neurons in the gerbil hippocampus 1 h - 7 days after 10 min of cerebral ischemia, with parvalbumin and microtubule-associated protein 2 (MAP2)-immunohistochemistry. Parvalbumin-immunoreactive interneurons in the hippocampus were unaffected up to 24 h after ischemia. A slight reduction of the immunoreactivity in neuronal processes was seen in the hippocampal CA1 sector 48 h after ischemia. Seven days after ischemia, a marked loss of parvalbumin-immunoreactive interneurons was observed in the hippocampal CA1 and CA3 sectors. Furthermore, reduced staining in the dentate granular and molecular layers was observed. MAP2-immunoreactive pyramidal neurons in the hippocampus were unchanged up to 48 h after ischemia. Seven days after ischemia, a severe loss of MAP2 immunoreactivity was found in the hippocampal CA1 and CA3 neurons and dentate hilar neurons. However, scattered CA1 neurons, most likely interneurons, preserved MAP2 immunoreactivity. The results demonstrate that transient cerebral ischemia can cause a loss of parvalbumin-immunoreactive interneurons in the hippocampus. Furthermore, some interneurons seem to lose parvalbumin synthesis. Although dentate granule cells are resistant to ischemia, considerable reductions of afferent input was suggested by parvalbumin staining.     

Reduced seizure threshold and hippocampal cell loss in rats exposed to alcohol during the brain growth spurt

BACKGROUND: Epilepsy is a prominent sign of neurologic dysfunction in some children with fetal alcohol syndrome (FAS). However, it is unknown whether the epileptic disorders in these children are directly due to the neuroteratogenic effects of alcohol or to some other factor accompanying maternal alcoholism. The hippocampus is vulnerable to alcohol-induced pathologic changes, and dysfunction of the hippocampus often manifests as epilepsy. We examined the effect of alcohol exposure during development on the seizure threshold and examined the relationship between alteration of seizure threshold and alcohol-induced neuronal loss from the hippocampus. METHODS: Rat pups received 0.85, 2.5, or 3.75 g/kg of alcohol via intragastric intubation daily over postnatal days (PD) 4-9. An intubated control and a suckle control group were also included. To assess the effect of a single day of alcohol exposure, an additional group received 3.75 g/kg of alcohol on PD 4 alone. Behavioral seizure thresholds were determined by intravenous infusion of the proconvulsant, pentylenetetrazol (PTZ), on PD 31 or on PD 90. In addition, electrographic seizure thresholds were determined by recording extracellular field potentials from the dentate gyrus. The number of hippocampal CA1 pyramidal cells, CA3 pyramidal cells, and granule cells of the dentate gyrus were determined by stereology. RESULTS: Daily exposure to alcohol resulted in a dose-dependent decrease in the seizure threshold and in the selective loss of CA1 pyramidal cells. Reduction in the seizure threshold was significantly correlated with loss of CA1 pyramidal cells. Recordings of extracellular field potentials confirmed the alcohol-induced reduction in seizure threshold, demonstrated that PTZ-induced seizures involve hippocampal-parahippocampal circuitry, and provided evidence that the hippocampal formation is the generator of the PTZ-induced seizures in alcohol-exposed animals. CONCLUSIONS: These findings demonstrate that exposure of the developing brain to alcohol can permanently reduce the threshold for both behavioral and electrographic seizures and can selectively kill hippocampal CA1 pyramidal cells. Both the pathologic findings and the physiologic recordings support the concept that the reduced seizure threshold in alcohol-exposed animals is due to hippocampal pathology.     

G protein mRNA mapped in rat brain by in situ hybridization.

Guanine nucleotide-binding regulatory proteins (G proteins) mediate many receptor-coupled signal transduction events. We have localized in rat brain by in situ hybridization the mRNA for the G protein subunits--G alpha s, G alpha o, and G beta. Oligonucleotide probes were radiolabeled by a technique that resulted in a probe of defined specific activity and uniform length. mRNA species encoding G alpha s and G beta occur in high densities heterogeneously throughout the brain, especially in large neuronal cell bodies--e.g., hippocampal pyramidal cells, granule cells of the dentate gyrus, hypothalamic nuclei, and neurons of brainstem nuclei and the reticular formation. G alpha o mRNA has a more limited distribution and abundance, being detectable in the claustrum, endopiriform nucleus, habenula, hippocampal pyramidal cells, granule cells of the dentate gyrus, and cerebellar Purkinje cells.     

Morphine and opioid peptides reduce inhibitory synaptic potentials in hippocampal pyramidal cells in vitro without alteration of membrane potential.

We used intracellular recording in the hippocampal slice in vitro to characterize further the mechanisms behind the unusual excitatory action of opiates and opioid peptides on hippocampal pyramidal cells in vivo. No significant effect on resting membrane potential, input resistance, or action potential size in cortical area 1 (CA1) pyramidal cells was observed with morphine sulfate, beta-endorphin, [Met5]enkephalin, or [D-Ala2, D-Leu5]enkephalin at 1-50 microM. However, in all cells studied, these agents markedly reduced the size of inhibitory postsynaptic potentials generated by stimulation of the stratum radiatum or alveus. Excitatory postsynaptic potentials were also diminished in many of these cells. The effects of the opioids were antagonized by naloxone. These results are consistent with excitation of pyramidal neurons by a disinhibitory mechanism.     

Reversible antisense inhibition of Shaker-like Kv1.1 potassium channel expression impairs associative memory in mouse and rat

Long-term memory is thought to be subserved by functional remodeling of neuronal circuits. Changes in the weights of existing synapses in networks might depend on voltage-gated potassium currents. We therefore studied the physiological role of potassium channels in memory, concentrating on the Shaker-like Kv1.1, a late rectifying potassium channel that is highly localized within dendrites of hippocampal CA3 pyramidal and dentate gyrus granular cells. Repeated intracerebroventricular injection of antisense oligodeoxyribonucleotide to Kv1.1 reduces expression of its particular intracellular mRNA target, decreases late rectifying K⁺ current(s) in dentate granule cells, and impairs memory but not other motor or sensory behaviors, in two different learning paradigms, mouse passive avoidance and rat spatial memory. The latter, hippocampal-dependent memory loss occurred in the absence of long-term potentiation changes recorded both from the dentate gyrus or CA1. The specificity of the reversible antisense targeting of mRNA in adult animal brains may avoid irreversible developmental and genetic background effects that accompany transgenic “knockouts”.     

Steel mutant mice are deficient in hippocampal learning but not long-term potentiation.

Mice carrying mutations in either the dominant white-spotting (W) or Steel (Sl) loci exhibit deficits in melanogenesis, gametogenesis, and hematopoiesis. W encodes the Kit receptor tyrosine kinase, while Sl encodes the Kit ligand, Steel factor, and the receptor-ligand pair are contiguously expressed at anatomical sites expected from the phenotypes of W and Sl mice. The c-kit and Steel genes are also both highly expressed in the adult murine hippocampus: Steel is expressed in dentate gyrus neurons whose mossy fiber axons synapse with the c-kit expressing CA3 pyramidal neurons. We report here that Sl/Sld mutant mice have a specific deficit in spatial learning. These mutant mice are also deficient in baseline synaptic transmission between the dentate gyrus and CA3 but show normal long-term potentiation in this pathway. These observations demonstrate a role for Steel factor/Kit signaling in the adult nervous system and suggest that a severe deficit in hippocampal-dependent learning need not be associated with reduced hippocampal long-term potentiation.