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Unchanged glutamine synthetase activity and increased NMDA receptor density in epileptic human neocortex: implications for the pathophysiology of epilepsy.

We investigated whether alterations in glutamate metabolising glutamine synthetase activity occur in human epileptic neocortex, as shown previously for human epileptic hippocampus [Eid, T., Thomas, M.J., Spencer, D.D., Rundén-Pran, E., Lai, J.C.K., Malthankar, G.V., Kim, J.H., Danbolt, N.C., Ottersen, O.P., de Lanerolle, N.C., 2004. Loss of glutamine synthetase in the human epileptic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy. Lancet 363, 28-37]. Glutamine synthetase activity was equivalent in both non-epileptic and epileptic human neocortex. Epileptic tissue, however, was characterised by a 37% increase in the density of synaptosomal NMDA receptor sites compared to non-epileptic tissue, as revealed by a radioligand binding assay (B max(non-epileptic) 1.45 pmol/mg protein and B max(epileptic) 1.99 pmol/mg protein, P < 0.05). Our findings shed some doubts on a role of glutamine synthetase in the pathophysiology of epilepsy in the neocortex. However, the detection of a significantly reduced enzymatic activity in the epileptic amygdala supports the assumption that the enzyme defect is localized to the epileptic mesial temporal lobe of corresponding patients.

Adolescent↗

17beta-estradiol reduces neuronal apoptosis induced by HIV-1 gp120 in the neocortex of rat.

The human immunodeficiency virus type 1 (HIV-1) coat glycoprotein gp120 represents a likely contributor to the development of HIV-1 associated dementia (HAD), a neurological syndrome often observed in AIDS patients and characterised by significant neuronal loss in the neocortex. Since recent studies have highlighted that female sex hormones represent potential neuroprotective agents against damage produced by acute and chronic injuries in the adult brain, we have investigated whether estrogens exert protection in a rat model of gp120 neurotoxicity. Our results demonstrate that systemic administration of 17beta-estradiol (E2, 0.02-0.2 mg/kg) significantly reduces apoptotic cell death observed in the neocortex of rat following subchronic i.c.v. administration of gp120 (100 ng/rat/day). Furthermore, both tamoxifen and ICI182,780, two selective antagonists of estrogen receptors (ER) in the brain, reverted the neuroprotective effect of E2. The molecular mechanism of estrogenic neuroprotection does not appear to involve modulation of the antiapoptotic Bcl-2 or the proapoptotic Bax since we failed to observe changes in the levels of the two proteins in the neocortical tissue after gp120 and/or E2 treatment. However, we detected increased levels of IL-1beta in the neocortex of rats injected with gp120, as early as 6h after drug administration, and this effect was potentiated following pretreatment with E2. Taken together, our results demonstrate that E2 exerts neuroprotection against gp120 neurotoxicity in vivo through a mechanism involving ER activation and, possibly, via modulation of neocortical levels of IL-1beta.

Animals↗

ErbB1 receptor ligands attenuate the expression of synaptic scaffolding proteins, GRIP1 and SAP97, in developing neocortex.

Scaffolding proteins containing postsynaptic density-95/discs large/zone occludens-1 (PDZ) domains interact with synaptic receptors and cytoskeletal components and are therefore implicated in synaptic development and plasticity. Little is known, however, about what regulates the expression of PDZ proteins and how the levels of these proteins influence synaptic development. Here, we show that ligands for epidermal growth factor receptors (ErbB1) decrease a particular set of PDZ proteins and negatively influence synaptic formation or maturation. In short-term neocortical cultures, concentrations of epidermal growth factor and amphiregulin (2-9 pM) decreased the expression of glutamate receptor interacting protein 1 (GRIP1) and synapse-associated protein 97 kDa (SAP97) without affecting postsynaptic density-95 (PSD-95) levels and glial proliferation. In long-term cultures, epidermal growth factor treatment resulted in a decrease in the frequency of pan-PDZ-immunoreactive aggregates on dendritic processes. A similar activity on the same PDZ proteins was observed in the developing neocortex following epidermal growth factor administration to rat neonates. Immunoblotting revealed that administered epidermal growth factor from the periphery activated brain ErbB1 receptors and decreased GRIP1 and SAP97 protein levels in the neocortex. Laser-confocal imaging indicated that epidermal growth factor administration suppressed the formation of pan-PDZ-immunoreactive puncta and dispersed those structures in vivo as well. These findings revealed a novel negative activity of ErbB1 receptor ligands that attenuates the expression of the PDZ proteins and inhibits postsynaptic maturation in developing neocortex.

Adaptor Proteins, Signal Transducing↗

DYX1C1 functions in neuronal migration in developing neocortex.

Rodent homologues of two candidate dyslexia susceptibility genes, Kiaa0319 and Dcdc2, have been shown to play roles in neuronal migration in developing cerebral neocortex. This functional role is consistent with the hypothesis that dyslexia susceptibility is increased by interference with normal neural development. In this study we report that in utero RNA interference against the rat homolog of another candidate dyslexia susceptibility gene, DYX1C1, disrupts neuronal migration in developing neocortex. The disruption of migration can be rescued by concurrent overexpression of DYX1C1, indicating that the impairment is not due to off-target effects. Transfection of C- and N-terminal truncations of DYX1C1 shows that the C-terminal TPR domains determine DYX1C1 intracellular localization to cytoplasm and nucleus. RNAi rescue experiments using truncated versions of DYX1C1 further indicate that the C-terminus of DYX1C1 is necessary and sufficient to DYX1C1's function in migration. In conclusion, DYX1C1, similar to two other candidate dyslexia susceptibility genes, functions in neuronal migration in rat neocortex.

Analysis of Variance↗

Selective block of rat and human neocortex GABA(B) receptors regulating somatostatin release by a GABA(B) antagonist endowed with cognition enhancing activity.

Previously, we have shown that presynaptic GABA(B) receptors regulating the release of various transmitters from CNS terminals can be differentially blocked by GABA(B) antagonists suggesting the existence of pharmacologically distinct GABA(B) receptor subtypes. We here examined the ability of CGP 36742 [(3-aminopropyl)n-butylphosphinic acid], a selective GABA(B) antagonist endowed with cognition enhancing activity, to block release-regulating GABA(B) receptors. In particular, CGP 36742 was tested against the inhibition of the depolarization-evoked release of GABA, glutamate, cholecystokinin and somatostatin produced by (-)baclofen in rat and human neocortex axon terminals. CGP 36742 potently antagonized (IC50 = 0.14 microM) the inhibition by (-)baclofen of somatostatin release from superfused rat neocortex synaptosomes. In contrast, the effects of (-)baclofen on GABA, glutamate and cholecystokinin release were insensitive to CGP 36742, at concentrations of up to 100 microM. In human neocortex synaptosomes CGP 36742 exhibited a pattern of selectivity identical to that in rat synaptosomes, although the antagonist was at least 10-fold less potent in human than in rat brain. CGP 36742 is the first compound displaying great selectivity for the GABA(B) presynaptic receptors regulating somatostatin release. Considering the proposed implication of the neuropeptide in cognitive processes, disinhibition of somatostatin release merits consideration as one of the mechanisms possibly involved in the behavioral activity of CGP 36742.

Adult↗

The alteration of corticotropin-releasing factor (CRF) receptor immunoreactivity in the gerbil hippocampus and neocortex following ischemic insults.

Recently, we suggested that the ectopic expression of corticotropin-releasing factor (CRF) is associated with processes linked to neuronal injury and/or degeneration in response to an ischemic insult. However, little experimental data currently links the CRF receptor directly to neuronal death induced by ischemia. Therefore, in the present study, we investigated the temporal and spatial changes in CRF receptor immunoreactivity in the hippocampus and the neocortex after transient ischemia. CRF receptor immunoreactivity in the hippocampus was reduced up to 24h after ischemia insult, as compared to the sham. Interestingly, CRF receptor immunoreactivity disappeared in the CA1 region of the hippocampus at 4 days in the post-ischemic group. The other regions of hippocampus maintained their immunoreactivities at this time point. On the other hand, in the neocortex, 3h after transient ischemia, the CRF receptor immunoreactivity was elevated in regions vulnerable to ischemia. At 12h post-ischemia, its immunoreactivity had decreased versus the sham operated animals. These results suggest that the selectively ectopic expression of CRF following ischemia, which we reported previously, may regulate inflammatory responses. In addition, these findings also suggest that the mechanisms of neuronal death as mediated by CRF receptor differ in the hippocampus and the neocortex.

Animals↗

Dendritic morphology and orientation of pyramidal cells of the neocortex in two groups of early postnatal undernourished-rehabilitated rats.

Postnatal undernutrition in animals and in humans leads to significant reduction in basal dendritic arborization of layer Vth pyramidal cells of the neocortex. Under the hypothesis that there are critical developmental periods for undernutrition to produce alterations in dendritic differentiation, we studied apical dendritic morphology and orientation of pyramidal cells from the deeper layers of the neocortex in rats undernourished until day 10 (UP10), until weaning (UP21) and in a control group (C). Neurons were stained by the Golgi-Cox method. The main findings are: (i) an increased number of atypically oriented pyramids with apical dendrites extremely short in (UP10) and (UP21) groups and, (ii) the presence of classical pyramids with significantly longer apical dendrites in layers V and VI in (UP10) and (UP21) groups than in the control group (C). We believe that undernutrition may disturb critically the early postnatal brain development by altering intrinsic factors and extracellular molecular signals that guide and regulate the apical dendritic growth of neocortex large pyramidal cells.

Animals↗

Time-related changes in connexin mRNA abundance in the rat neocortex during postnatal development.

Gap junction coupling between neurons is important for the temporal and spatial co-ordination of neocortical development and can be visualised by dye-coupling. Neuronal dye-coupling in the rat neocortex is extensive during the first 2 postnatal weeks and diminishes rapidly thereafter. We used RT (reverse transcriptase)-PCR to investigate the time-related changes in mRNA expression for the connexins (Cx) Cx 26, Cx 30, Cx 32, Cx 36, Cx 37, Cx 40, Cx 43, Cx 45 and Cx 46 as well as for beta-actin and GAPDH in rat neocortex during the first 6 postnatal weeks. The time courses for mRNA expression for GAPDH, Cx 30, Cx 36 and Cx 43 were also investigated by northern blotting. Cx 30 and Cx 45 mRNA abundance showed no time-dependent changes during the early postnatal period. The relative abundance of Cx 32, Cx 43 and Cx 46 mRNA increased significantly during the first 2-3 weeks and then remained relatively constant during weeks 3-6. The relative abundance of Cx 26, Cx 36, Cx 37 and Cx 40 mRNA also increased significantly during the first 10-15 postnatal days but then declined significantly from their peak values during weeks 3-6. beta-actin mRNA expression showed no time-related changes but GAPDH mRNA expression increased significantly during the first postnatal week, then remained constant. The time-dependent changes in mRNA relative abundance for GAPDH, Cx 36 and Cx 43 determined by northern blotting corroborate the results from the RT-PCR study. None of the Cx exhibited time-dependent changes in mRNA expression in homogenates of rat neocortex which parallel the changes in neuronal dye-coupling during postnatal development.

Actins↗

Reelin immunoreactivity in the adult neocortex: a comparative study in rodents, carnivores, and non-human primates.

Recent evidence indicates that, in addition to playing a crucial role in early cortical development, intercellular signaling mediated by the protein Reelin may be widely active in the adult neocortex. The extent of Reelin distribution and its functional role in the adult are not clear yet. Here, we have examined Reelin immunoreactivity in the neocortex of an adult rodent (rat, Rattus norvegicus), a carnivore (ferret, Mustela putorius), and a primate (macaque monkeys Macaca nemestrina, Macaca mulatta) at the optic microscope level. Our data show that the neocortex of all three species contains several morphologically distinct populations of interneurons whose perikaryon and proximal dendritic processes are heavily immunoreactive for Reelin. The laminar distribution of these cells is species-specific. In addition, discrete reelin-immunoreactive pericellular structures are present in virtually all neocortical neurons of macaques.

Animals↗

High potassium-induced activation of choline-acetyltransferase in human neocortex: implications and species differences.

The role of electrical and potassium (K(+))-induced depolarisation on choline-acetyltransferase (ChAT) activity in human and mouse neocortical slices was studied. When [3H]-ACh release was evoked by two K(+) stimulations in human neocortex, the mean S(2)/S(1) ratio was significantly below unity. ChAT inhibitors, like bromo-acetylcholine and ocadaic acid, raised this ratio by 79 and 63%, respectively, suggesting that the diminished S(2)/S(1) value in the absence of ChAT inhibitors reflected an increased ChAT activity at S(2) following K(+) depolarisation at S(1). When stimulated electrically, however, the S(2)/S(1) ratio in human neocortex was near unity and ocadaic acid remained without effect. In parallel experiments on mouse neocortical slices, the S(2)/S(1) ratio was near unity in both electrically or K(+)-evoked [3H]-ACh release and was not altered by ChAT inhibition. ChAT activity following K(+) depolarisation was also determined directly. ChAT activation in human neocortical slices was highest at 10 and 20mM K(+). ChAT activity in mouse neocortical tissue was not altered by K(+) depolarisation. These results suggest that in human, but not in mouse, neocortex ChAT activity may be increased due to ongoing K(+) depolarisation. This increase of ChAT activity supports a cholinergic degeneration hypothesis which has been entitled "autocannibalism" by Wurtman [TINS 15 (1992) 177].

Acetylcholine↗

Aging and the human neocortex.

Neurostereology has been applied to quantitative anatomical study of the human brain. Such studies have included the total neocortical number of neurons and glial cells, the estimated size distribution of neocortical neurons, the total myelinated fiber length in the brain white matter, the total number of synapses in the neocortex, and the effect of normal aging on these structural elements. The difference in total number of neurons was found to be less than 10% over the age range from 20 to 90 years, while the glial cell number in six elderly individuals, mean age 89.2 years, showed an average number of 36 billion glial cells, which was not statistically significantly different from the 39 billion glial cells in the neocortex of six young individuals with a mean age of 26.2 years. The total myelinated fiber length varied from 150,000 to 180,000 km in young individuals and showed a large reduction as a function of age. The total number of synapses in the human neocortex is approximately 0.15 x 10(15) (0.15 quadrillion). Although the effect of aging is seen in all estimated structural elements, the effect of sex is actually higher. The functional relevance of these differences in neuron numbers in both age and gender is not known.

Adult↗

delta 1-Opioid receptor-mediated control of acetylcholine (ACh) release in human neocortex slices.

In slices of human neocortex, prelabelled with [3H]-choline, the release of [3H]-acetylcholine reflects the evoked release of endogenous acetylcholine which was elicited by the same electrical stimulation paradigm. [3H]-Acetylcholine release was depressed by the delta-opioid receptor agonist D-Pen2-D-Pen5-enkephalin. When the nerve endings were depolarized by elevating extracellular potassium the evoked [3H]-acetylcholine release was similarly depressed by D-Pen2-D-Pen5-enkephalin in the absence, but not in the presence, of tetrodotoxin which blocks action potential propagation. Therefore, the delta-opioid receptor inhibiting [3H]-acetylcholine release should not be located to cholinergic nerve terminals, but rather to interneurons. The somatostatin2 receptor partial agonist octreotide per se did not influence action potential-evoked [3H]-acetylcholine release, but prevented the inhibition of release of [3H]-acetylcholine by D-Pen2-D-Pen5-enkephalin. Similarly, the delta 1-opioid receptor antagonist 7-benzylidenenaltrexon per se did not influence [3H]-acetylcholine release, but prevented of the inhibition of release by D-Pen2-D-Pen5-enkephalin. From the present findings we conclude: (1) The evoked release of [3H]-acetylcholine from human neocortex slices reflects the release of endogenous acetylcholine. (2) It is inhibited in an indirect manner by opioid receptors of the delta 1-subtype, which (3) are not localized on cholinergic axon terminals but on soma and dendrites of somatostatin-containing interneurons, where they inhibit somatostatin release. (4) These interneurons innervate cholinergic nerve endings in the human neocortex and appear to facilitate acetylcholine release via somatostatin2 receptors.

Acetylcholine↗

Cellular distribution of the calcium-binding proteins parvalbumin, calbindin, and calretinin in the neocortex of mammals: phylogenetic and developmental patterns.

The three calcium-binding proteins parvalbumin, calbindin, and calretinin are found in morphologically distinct classes of inhibitory interneurons as well as in some pyramidal neurons in the mammalian neocortex. Although there is a wide variability in the qualitative and quantitative characteristics of the neocortical subpopulations of calcium-binding protein-immunoreactive neurons in mammals, most of the available data show that there is a fundamental similarity among the mammalian species investigated so far, in terms of the distribution of parvalbumin, calbindin, and calretinin across the depth of the neocortex. Thus, calbindin- and calretinin-immunoreactive neurons are predominant in layers II and III, but are present across all cortical layers, whereas parvalbumin-immunoreactive neurons are more prevalent in the middle and lower cortical layers. These different neuronal populations have well defined regional and laminar distribution, neurochemical characteristics and synaptic connections, and each of these cell types displays a particular developmental sequence. Most of the available data on the development, distribution and morphological characteristics of these calcium-binding proteins are from studies in common laboratory animals such as the rat, mouse, cat, macaque monkey, as well as from postmortem analyses in humans, but there are virtually no data on other species aside of a few incidental reports. In the context of the evolution of mammalian neocortex, the distribution and morphological characteristics of calcium-binding protein-immunoreactive neurons may help defining taxon-specific patterns that may be used as reliable phylogenetic traits. It would be interesting to extend such neurochemical analyses of neuronal subpopulations to other species to assess the degree to which neurochemical specialization of particular neuronal subtypes, as well as their regional and laminar distribution in the cerebral cortex, may represent sets of derived features in any given mammalian order. This could be particularly interesting in view of the consistent differences in neurochemical typology observed in considerably divergent orders such as cetaceans and certain families of insectivores and metatherians, as well as in monotremes. The present article provides an overview of calcium-binding protein distribution across a large number of representative mammalian species and a review of their developmental patterns in the species where data are available. This analysis demonstrates that while it is likely that the developmental patterns are quite consistent across species, at least based on the limited number of species for which ontogenetic data exist, the distribution and morphology of calcium-binding protein-containingneurons varies substantially among mammalian orders and that certain species show highly divergent patterns compared to closely related taxa. Interestingly, primates, carnivores, rodents and tree shrews appear closely related on the basis of the observed patterns, marsupials show some affinities with that group, whereas prototherians have unique patterns. Our findings also support the relationships of cetaceans and ungulates, and demonstrates possible affinities between carnivores and ungulates, as well as the existence of common, probably primitive, traits in cetaceans and insectivores.

Animals↗

Long-term changes in hippocampus and neocortex EEG spectra in response to pharmacological treatments affecting the cholinergic system.

Statistical analysis of EEG spectra averaged over 10-min intervals showed that in rats performing free behavior, peripheral administration of the acetylcholinesterase inhibitor physostigmine induced long-lasting characteristic changes (lasting tens of minutes) in the electrical activity of the dorsal hippocampus (field CAI) and the somatosensory cortex. An increase in the physostigmine dose from 0.05 to 1 mg/kg shifted the peak of the theta rhythm to lower frequencies (3.6-4.9 Hz) without a change in power at this frequency, though there was a decrease in power at 5.7-11.9 Hz. The power of the beta-1 rhythm (13.8-16.4 Hz) was also strongly suppressed. In contrast, the power of the beta-2 rhythm (20.3-26.5 Hz) increased several-fold in a non-linear fashion. Scopolamine suppressed all the changes induced by physostigmine, demonstrating the important role of m-cholinoceptors in changes in EEG spectra. The high dose of physostigmine caused inversion of the power of the beta-2 rhythm: unlike the situation obtaining in controls, the beta-2 power in the hippocampus became significantly greater than that in the neocortex. These data suggest the conclusion that overall significant increases in endogenous acetylcholine levels lead to decreases in the functional activity of the hippocampus and neocortex and that the mechanisms of cholinergic modulation of the theta and beta rhythms are significantly different. It is suggested that conditioned reflex switching, contextual learning, and dissociated sates of memory and consciousness are to a significant extent dependent on long-term changes in the oscillatory activity of the hippocampus and neocortex.

Animals↗

A light and electron microscopic study of the iron transporter protein DMT-1 in the monkey cerebral neocortex and hippocampus.

We have studied by immunocytochemistry, the distribution of DMT-1, a cellular iron transporter responsible for transport of metal irons from the plasma membrane to endosomes, in the normal monkey cerebral neocortex and hippocampus. Light to moderate DMT-1 staining was observed in glial cell bodies in the neocortex, the subcortical white matter, and the hippocampus. Despite light labeling of cell bodies, glial end feet around cortical and subcortical blood vessels were heavily labeled. In the neocortex, the glial cell bodies displayed the morphological features of protoplasmic astrocytes. Labeled glial cells in the subcortical white matter contained dense bundles of glial filaments and were identified as fibrous astrocytes. The observation that DMT-1 was present on astrocytic endfeet suggests that these cells are involved in uptake of iron from endothelial cells. It is possible that the iron could then be redistributed into the extracellular space in the brain parenchyma.

Animals↗

Release of dopamine from human neocortex nerve terminals evoked by different stimuli involving extra- and intraterminal calcium.

The release of [(3)H]-dopamine ([(3)H]-DA) from human neocortex nerve terminals was studied in synaptosomes prepared from brain specimens removed in neurosurgery and exposed during superfusion to different releasing stimuli. Treatment with 15 mM KCl, 100 microM 4-aminopyridine, 1 microM ionomycin or 30 mM caffeine elicited almost identical overflows of tritium. Removal of external Ca(2+) ions abolished the overflow evoked by K(+) or ionomycin and largely prevented that caused by 4-aminopyridine; the overflow evoked by caffeine was completely independent of external Ca(2+). Exposure of synaptosomes to 25 microM of the broad spectrum calcium channel blocker CdCl(2) strongly inhibited the 4-aminopyridine-induced tritium overflow while that evoked by ionomycin remained unaffected. The Ca(2+) chelator, 1,2-bis-(2-aminophenoxy)ethane-N,N,N',N' tetraacetic acid (BAPTA), reduced significantly the K(+)- and the caffeine-induced tritium overflow. The effect of caffeine was attenuated by exposure to the ryanodine receptor blocker dantrolene or when the membrane-impermeant inositol trisphosphate receptor antagonist, heparin, was entrapped into synaptosomes; the combined treatment with dantrolene and heparin abolished the release elicited by caffeine. Tetanus toxin, entrapped into human neocortex synaptosomes to avoid prolonged incubation, inhibited in a concentration-dependent manner the K(+)- or the 4-aminopyridine-evoked tritium overflow; in contrast, the release stimulated by ionomycin and by caffeine were both totally insensitive to the same concentrations of tetanus toxin. Western blot analysis showed about 50% reduction of the content of the vesicular protein, synaptobrevin, in synaptosomes poisoned with tetanus toxin. In conclusion, the release of dopamine from human neocortex nerve terminals can be triggered by Ca(2+) ions originating from various sources. It seems that stimuli not leading to activation of voltage-sensitive Ca(2+) channels elicit Ca(2+)-dependent, probably exocytotic, release that is insensitive to tetanus toxin.

Adult↗

Presynaptic opioid receptors on noradrenergic and serotonergic neurons in the human as compared to the rat neocortex.

1. Electrically evoked release of [3H]-noradrenaline ([3H]-NA) or [3H]-5-hydroxytryptamine ([3H]-5-HT) in slices of human and the rat neocortex was used to characterize presynaptic opioid receptors. 2. Release of [3H]-NA in rat neocortical slices was reduced only by the mu-receptor agonist DAMGO (pIC50: 7.27, CI95: [7.22, 7.32]; Imax: 77.6+/-1.6%; antagonized by naloxone: pA2: 8.88, CI95: [8.78, 8.98]). 3. Release of [3H]-NA in human neocortical slices was unaffected by DAMGO, but inhibited by the delta-receptor agonist DPDPE (Imax: 25.7+/-2.2%) and the kappa-receptor agonist U-50,488H (19.7+/-2.7% inhibition at 1 microM). Both effects were antagonized by naltrindole (1 microM). 4. Release of [3H]-5-HT in rat neocortical slices, was inhibited by DAMGO (10 microM) and U-50,488H (1 and 10 microM) only in the presence of the 5-HT receptor antagonist methiotepin (1 microM). 5. Release of [3H]-5-HT in human neocortical slices was unaffected by DPDPE, but U-50,488H (Imax: 40.8+/-8.3%; antagonized by 0.1 microM norbinaltorphimine) and DAMGO (16.4+/-3.9% inhibition at 1 microM; antagonized by 0.1 microM naloxone) acted inhibitory. 6. Release of [3H]-5-HT in human neocortical slices was reduced by nociceptin/orphanin (0.1 and 1 microM). These effects were antagonized by the ORL1 antagonist J-113397 (1-[(3R,4R)-1-cyclo-octylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one; 0.1 microM). 7. This study provides evidence for significant species differences in opioid receptor-mediated modulation of NA and 5-HT-release in human vs rat neocortex. In rats, mu-opioid receptors modulate NA release, but 5-HT release is only weakly affected by mu- and kappa-opioids. In contrast, NA release in human neocortex is modulated via delta-opioid receptors, but 5-HT release mainly via kappa-opioid receptors. In addition also the ORL1 receptor seems to be involved in 5-HT release modulation.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

The occ1 gene is preferentially expressed in the primary visual cortex in an activity-dependent manner: a pattern of gene expression related to the cytoarchitectonic area in adult macaque neocortex.

Marker molecules to visualize specific subsets of neurons are useful for studying the functional organization of the neocortex. One approach to identify such molecular markers is to examine the differences in molecular properties among morphologically and physiologically distinct neuronal cell types. We used differential display to compare mRNA expression in the anatomically and functionally distinct areas of the adult macaque neocortex. We found that a gene, designated occ1, was preferentially transcribed in the posterior region of the neocortex, especially in area 17. Complete sequence analysis revealed that occ1 encodes a macaque homolog of a secretable protein, TSC-36/follistatin-related protein (FRP). In situ hybridization histochemistry confirmed the characteristic neocortical expression pattern of occ1 and showed that occ1 transcription is high in layers II, III, IVA and IVC of area 17. In addition, occ1 transcription was observed selectively in cells of the magnocellular layers in the lateral geniculate nucleus (LGN). Dual labeling immunohistochemistry showed that the occ1-positive neurons in area 17 include both gamma-aminobutyric acid (GABA)-positive aspiny inhibitory cells and the alpha-subunit of type II calcium/calmodulin-dependent protein kinase (CaMKII alpha)-positive spiny excitatory cells. With brief periods of monocular deprivation, the occ1 mRNA level decreased markedly in deprived ocular dominance columns of area 17. From this we conclude that the expression of occ1 mRNA is present in a subset of neurons that are preferentially localized in particular laminae of area 17 and consist of various morphological and physiological neuronal types, and, furthermore, occ1 transcription is subject to visually driven activity-dependent regulation.

Age Factors↗