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PubMed1997

Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia. Regional and diagnostic specificity.

BACKGROUND: Multiple lines of evidence indicate that the prefrontal cortex is a site of dysfunction in schizophrenia. However, the apparent absence of gross structural abnormalities in this area suggests that the pathophysiological characteristics of schizophrenia may involve more subtle disturbances in prefrontal cortical circuitry, such as alterations in synaptic connectivity and transmission. In this study, immunoreactivity for synaptophysin, an integral membrane protein of small synaptic vesicles, was used to assess the integrity of cortical synaptic circuitry in schizophrenia. METHODS: Using immunocytochemical techniques and adjusted optical density measurements, we examined synaptophysin immunoreactivity in prefrontal cortical areas 9 and 46 and in area 17 (the primary visual cortex) from 10 pairs of case subjects with schizophrenia and control subjects. matched on a pairwise basis for age, sex, race, and postmortem interval, and in 5 matched pairs of nonschizophrenic psychiatric case subjects and normal control subjects. RESULTS: Compared with levels found in matched control subjects, synaptophysin immunoreactivity in areas 46 and 9 was significantly decreased (P < .001 and P < .008, respectively) across all cortical layers in the case subjects with schizophrenia. In contrast, no differences were observed in area 17. In addition, levels of synaptophysin immunoreactivity in areas 46, 9, and 17 did not differ between 5 nonschizophrenic psychiatric case subjects and their matched controls, suggesting that decreased synaptophysin levels in the prefrontal cortex of patients with schizophrenia may be specific to that disorder. CONCLUSION: Additional studies are required to determine if the decrease in levels of synaptophysin immunoreactivity is caused by a decrease in the number or size of presynaptic terminals, a decrease in the number of synaptic vesicle per terminal, or a decrease in the expression of synaptophysin. However, all of these potential explanations are consistent with a disturbance in synaptic transmission in the prefrontal cortex of patients with schizophrenia.

Adult↗
PubMed1997

Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia. Regional and diagnostic specificity.

BACKGROUND: Multiple lines of evidence indicate that the prefrontal cortex is a site of dysfunction in schizophrenia. However, the apparent absence of gross structural abnormalities in this area suggests that the pathophysiological characteristics of schizophrenia may involve more subtle disturbances in prefrontal cortical circuitry, such as alterations in synaptic connectivity and transmission. In this study, immunoreactivity for synaptophysin, an integral membrane protein of small synaptic vesicles, was used to assess the integrity of cortical synaptic circuitry in schizophrenia. METHODS: Using immunocytochemical techniques and adjusted optical density measurements, we examined synaptophysin immunoreactivity in prefrontal cortical areas 9 and 46 and in area 17 (the primary visual cortex) from 10 pairs of case subjects with schizophrenia and control subjects matched on a pairwise basis for age, sex, race, and postmortem interval, and in 5 matched pairs of nonschizophrenic psychiatric case subjects and normal control subjects. RESULTS: Compared with levels found in matched control subjects, synaptophysin immunoreactivity in areas 46 and 9 was significantly decreased (P < .001 and P < .008, respectively) across all cortical layers in the case subjects with schizophrenia. In contrast, no differences were observed in area 17. In addition, levels of synaptophysin immunoreactivity in areas 46, 9, and 17 did not differ between 5 nonschizophrenic psychiatric case subjects and their matched controls, suggesting that decreased synaptophysin levels in the prefrontal cortex of patients with schizophrenia may be specific to that disorder. CONCLUSIONS: Additional studies are required to determine if the decrease in levels of synaptophysin immunoreactivity is caused by a decrease in the number or size of presynaptic terminals, a decrease in the number of synaptic vesicles per terminal, or a decrease in the expression of synaptophysin. However, all of these potential explanations are consistent with a disturbance in synaptic transmission in the prefrontal cortex of patients with schizophrenia.

Adult↗
PubMed1997

Human dopamine transporter gene polymorphism (VNTR) and alcoholism.

The dopamine transporter (DAT1) is responsible for taking released dopamine back up into presynaptic terminals and terminating dopaminergic activity. It has been shown that cocaine binds to the dopamine transporter and blocks dopamine reuptake in a fashion that correlates with cocaine reward and reinforcement. To determine the role of this gene in the development of alcoholism, we have used two approaches, relative risk and haplotype relative risk. The relative risk approach involved 162 alcoholic probands who were categorized into type I and type II, and 89 unrelated normal controls. In the haplotype relative risk approach, 29 trios (father, mother, and proband) were genotyped with dopamine transporter gene polymorphism. Comparison of allele frequencies between total alcoholics, subtypes of alcoholics, and normal controls were negative. The results of haplotype relative risk, differences between alleles transmitted and nontransmitted, were also negative. However, both approaches produced similar results. Therefore, we concluded that the VNTR polymorphism in DAT1 gene is not associated with alcoholism susceptibility genes in our samples.

Alcoholism↗
PubMed1996

Distribution of omega-Conotoxin GVIA binding sites in teleost cerebellar and electrosensory neurons.

The distribution of omega-Conotoxin GVIA (CgTx) binding sites was used to localize putative N-type Ca2+ channels in an electrosensory cerebellar lobule, the eminentia granularis pars posterior, and in the electrosensory lateral line lobe of a gymnotiform teleost (Apteronotus leptorhynchus). The binding sites for CgTx revealed by an anti-CgTx antibody had a consistent distribution on somatic and dendritic membranes of specific cell types in both structures. The distribution of CgTx binding was unaffected by co-incubation with nifedipine or AgaToxin IVA, blocking agents for L- and P-type Ca2+ channels, respectively. Incubation with CgTx in the presence of varying levels of extracellular Ca2+ altered the number but not the cell types exhibiting immunolabel. A punctate immunolabel was detected on somatic membranes of granule and stellate cell interneurons in both the eminentia granularis pars posterior and the electrosensory lateral line lobe. Punctate CgTx binding sites were also present on spherical cell somata and on the large presynaptic terminals of primary afferents that terminate on spherical cells in the electrosensory lateral line lobe. No label was detected in association with distal dendritic membranes of any cell class, or with parallel fibers in the respective molecular layers. Binding sites for CgTx in the eminentia granularis are consistent with the established role for N-type Ca2+ channels in cell migrations, an activity which is known to persist in this layer in adult Apteronotus. The distribution of labeled stellate cells with respect to topographic maps in the electrosensory lateral line lobe further suggest that N-type Ca2+ channels are expressed in relation to functional activity across these sensory maps.

Animals↗
PubMed1996

Dendrites of locus coeruleus neurons extend preferentially into two pericoerulear zones.

The intrinsic cytoarchitecture and neurochemical organization of the nucleus locus coeruleus have been characterized extensively, but there is little information about the organization of locus coeruleus neuronal processes extending outside of the nucleus proper. Light and electron microscopic immunocytochemical techniques were used to investigate the distribution of dopamine-beta-hydroxylase- or tyrosine-hydroxylase-labeled extranuclear processes in the rat pericoerulear region. The vast majority of these processes extended preferentially into two zones: (1) the pontine tegmentum medial and rostral to locus coeruleus, here termed the rostromedial pericoerulear region; and (2) a narrow region adjacent to the IVth ventricle caudomedial to locus coeruleus, designated here as the caudal juxtaependymal pericoerulear region. Far fewer labeled processes extended into the lateral and ventral pericoerulear regions. Seventy-seven percent of the labeled profiles in the pericoerulear region were dendrites. All labeled profiles in the rostromedial pericoerulear region and 94% of the labeled profiles in the caudal juxtaependymal zone were dendrites. By contrast, in the rostroventral pericoerulear region, 25% of the labeled profiles were axons. Locus coeruleus extranuclear dendrites were never presynaptic to other structures but were often contacted by several unlabeled presynaptic terminals. These results indicate that the dendrites of locus coeruleus neurons extend preferentially into two pericoerulear zones. Extranuclear dendrites in all pericoerulear regions receive extensive, nonnoradrenergic synaptic contacts. Thus, pericoerulear dendrites, particularly in the rostromedial and caudal juxtaependymal zones, are important sites for the integration of inputs to locus coeruleus neurons.

Animals↗
PubMed1997

Postnatal development of GAP-43 immunoreactivity in the auditory brainstem of the rat.

Extensive data link the growth associated protein GAP-43 to axonal elongation and synapse formation during development and in plastic responses of nervous tissue. We have studied the changing levels of GAP-43 expression in the auditory brainstem nuclei of the developing rat by applying immunocytochemical techniques. By the first postnatal day (P1), GAP-43 was expressed at high concentrations in all subdivisions of the cochlear nuclear complex and the superior olivary complex. At this stage, neuropil structures recognized by the antibody did not show any varicosities on cellular processes in all these regions. By P8, the texture of the stain has turned markedly more granular, a pattern likely to reflect the formation of presynaptic endings. A predominantly granular distribution of GAP-43 has developed by P12. At that time, the staining intensity is markedly reduced compared to the levels of the newborn. By P16, the auditory brainstem nuclei have lost most of their GAP-43 immunoreactivity, but a distinct level of staining persisted into adulthood in all of them. This staining was restricted to boutons, which are thought to be presynaptic terminals. We conclude that a moderate but apparently relevant potential for plasticity is retained in these auditory structures. Should the patterns of neural signals, mediated by the inner ear, change during adulthood, the central structures appear to be able to respond with the formation of altered synaptic connectivity.

Aging↗
PubMed1998

Localization of the clustering protein gephyrin at GABAergic synapses in the main olfactory bulb of the rat.

The tubulin-binding protein gephyrin is essential for the formation of postsynaptic glycine-receptor clusters in cultured spinal neurons. In addition, there is increasing evidence that gephyrin can also be present at nonglycinergic synapses. Here we analyzed immunocytochemically the subcellular localization of gephyrin in the main olfactory bulb of the rat and compared its distribution with that of gamma-aminobutyric acid (GABA) and of two major GABA(A)-receptor subunits. Gephyrin was selectively localized to the postsynaptic side of symmetric synaptic junctions, where the presynaptic terminals contained GABA. Moreover, gephyrin colocalized extensively with the alpha1 and gamma2 subunits of the GABA(A) receptor. In contrast, gephyrin was not detected at presumed glutamatergic synapses. These results indicate that gephyrin is not uniquely associated with glycine receptors, but can also be found at distinct GABAergic synapses. Thus, they raise the possibility that gephyrin is involved in anchoring certain GABA(A)-receptor subtypes in the postsynaptic membrane.

Animals↗
PubMed1998

Altered expression of glutamate transporter GLAST mRNA in rat brain after photochemically induced focal ischemia.

BACKGROUND: The neurotransmitter glutamate is involved in fast excitatory synaptic transmission in the mammalian brain. Glutamate released from presynaptic terminals must be removed rapidly from the synaptic cleft by high affinity, sodium-dependent glutamate transporters to keep the extracellular glutamate concentration low to protect neuron from glutamate excitotoxicity, which is the major pathological mechanism of brain ischemia. GLAST is one of the identified four subtypes of the glutamate transporter system and has been suggested to play an important role in some pathological conditions. But until recently, very little information existed the concerning relationship between GLAST expression and cerebral ischemia. METHODS: Nonradioactive in situ hybridization was employed to evaluate the changes of glutamate transporter GLAST mRNA expression in rat cerebral cortex and hippocampus following photochemically induced focal cortical ischemia. RESULTS: GLAST mRNA expression in cerebral pyramid cells below the infarcted area did not change at 3 h, significantly decreased at 12 h, recovered to the control level at 24 h, and significantly increased at 72 h following the ischemic lesion. No changes in GLAST mRNA expression were observed in all subfields of the hippocampal complex. CONCLUSIONS: The present findings suggest that the time-course changes of GLAST mRNA expression after ischemia may be correlated with the pathogenesis of photosensitive ischemic brain damage.

ATP-Binding Cassette Transporters↗
PubMed1996

Dopamine receptors mediate differential morphological effects on cerebral cortical neurons in vitro.

A morphogenic role of neurotransmitters during cellular differentiation in vitro has been demonstrated in recent years. Using in situ hybridization, we confirm the presence of the D1 receptor at E16 and show additionally that the transcript is relatively widespread and present in both proliferative and differentiating areas of the cerebral wall. Because DA receptor expression precedes the arrival of presynaptic terminals during forebrain development, we examined the role of DA in cerebral cortical neuron differentiation in vitro, using immunohistochemical markers of dendrites, microtubule-associated-membrane protein 2 (MAP2) and axons, neurofilament protein (NF-H). Neurite length, cell size, and cell viability in response to D1 and D2 receptor agonists SKF38393 and quinpirole, respectively, and to DA were analyzed in neurons obtained from embryonic (E) day 16 rats. We have shown that 1) paradoxically, DA at different concentrations can either stimulate or inhibit neurite outgrowth; 2) there is a bimodal pattern of DA-induced axonal outgrowth, i.e., at low and high doses; 3) D2 receptor activation induces neurite outgrowth while D1 receptor activation is inhibitory; 4) D2-mediated neurite elongation is preferentially axonal while D1 receptor activation reduces both axonal and dendritic outgrowth; 5) low doses of DA promote the expression of cytoskeletal components of axonal maturation; and 6) D1 receptor activation decreases neuronal size. We suggest that DA may influence cellular differentiation and circuitry formation early in development of the cerebral cortex through receptor-mediated effects on process outgrowth, which could lead to effects on circuit formation.

Animals↗
PubMed1999

Long-term survival of fetal porcine lateral ganglionic eminence cells in the hippocampus of rats.

Embryonic porcine brain tissue from the lateral ganglionic eminence was transplanted into the adult rat hippocampus to determine whether fetal striatal cells could survive, differentiate, and integrate in a heterotopic site. The hippocampus, a common site of epileptic seizure activity, was chosen to determine if fetal striatal cells could supply inhibitory GABAergic neurons that may serve to block seizures. Cells were either implanted with a single deposit using a standard metal cannula or by five smaller disseminated deposits with a glass micropipette. At 20-24 weeks, animals immunosuppressed with cyclosporin showed long-term survival of porcine cells in the adult hippocampus. Analysis by immunohistochemistry and in situ hybridization showed that the grafts contained glial and neuronal cell types, including GABAergic neurons within graft core and networks of porcine neuronal fibers extending from the graft into the host parenchyma. In addition, a marker of porcine presynaptic terminals, synaptobrevin, was abundant within the grafts and was found associated with hippocampal structures and cell layers suggesting functional integration of grafted cells within the host. The survival of xenografts in the hippocampus and potential integration of inhibitory components provides evidence that these grafts may serve as an internal negative feedback mechanism to quench epileptiform activity.

Animals↗
PubMed1996

Neuropeptide localization in varicosities of Aplysia sensory neurons is regulated by target and neuromodulators evoking long-term synaptic plasticity.

The synapses between the sensory neuron (SN) and motor neuron of Aplysia undergo long-term functional and structural modulation with appropriate behavioral training or with applications of specific neuromodulators. Expression of molecules within the presynaptic terminals may be regulated in parallel with the changes evoked by the neuromodulators. We examined with immunocytochemical methods whether the level of sensorin, the SN-specific neuropeptide, is modulated in SN varicosities by the location of interaction with the target motor cell L7 and by applications of either 5-HT that evoke long-term facilitation or FMRFamide that evoke long-term depression of Aplysia sensorimotor connections in vitro. A significantly higher proportion of SN varicosities are sensorin positive when they are in contact with the proximal axons of L7 compared to varicosities of the same SNs in contact with distal L7 neurites. Both 5-HT and FMRFamide evoked changes in the efficacy and structure of sensorimotor connections that are accompanied by changes in the frequency of sensorin-positive varicosities contacting the axons of L7. More preexisting SN varicosities are stained after 5-HT, and fewer preexisting SN varicosities are stained after FMRFamide. These results suggest that the postsynaptic target and the neuromodulators not only regulate overall structure but also regulate the level of SN neuropeptide at synaptic sites.

Animals↗
PubMed1998

Glutamate antagonism during secondary deafferentation enhances cognition and axo-dendritic integrity after traumatic brain injury.

The combination of central fluid percussion traumatic brain injury (TBI) followed 24 h later by a bilateral entorhinal cortical deafferentation (BEC) produces profound cognitive morbidity. We recently showed that MK-801 given prior to TBI in this insult improved spatial memory for up to 15 days. In the present study we examine whether MK-801 treatment of the BEC component in the combined insult model affects cognitive recovery. Two strategies for drug treatment were tested. Fifteen minutes prior to the BEC lesion in the combined insult, rats were given i.p. doses of either 3 mg/kg (acute group) or 1 mg/kg (chronic group) MK-801. The acute group received no further injections, whereas the chronic group received 1 mg/kg MK-801 i.p. twice a day for 2 days post-BEC lesion. Two additional groups of animals received BEC lesion alone and either acute or chronic MK-801 treatment identical with the combined insult cases. Each group was then assessed for spatial memory deficits with the Morris water maze at days 11-15 and 60-64 postinjury. Both acute and chronic MK-801 treatment in the combined insult group significantly reduced spatial memory deficits at 15 days postinjury relative to untreated injured cases (P < .01). This reduction appeared more robust at 15 days and persisted for up to 64 days in the chronically treated group (P < .05). By contrast, neither acute nor chronic MK-801 treatment affected memory performance with the BEC insult alone. Immunocytochemical localization of parvalbumin showed that chronic administration of MK-801 in the combined insult cases attenuated the injury-induced dendritic atrophy of inhibitory neurons in the dentate gyrus and area CA1. Synaptophysin immunobinding revealed that chronic MK-801 treatment of the BEC component of the combined insult normalized the distribution of presynaptic terminals within the dentate gyrus. These results suggest that cognitive deficits produced by head trauma involving both neuroexcitation and deafferentation can be attenuated with chronic application of glutamatergic antagonists during the period of deafferentation injury and that this attenuation is correlated with axo-dendritic integrity.

Afferent Pathways↗
PubMed1996

Activation of corticostriatal pathway leads to similar morphological changes observed following haloperidol treatment.

Treatment with haloperidol, a dopamine receptor D-2 antagonist, for one month resulted in an increase in the mean percentage of asymmetric synapses containing a discontinuous, or perforated, postsynaptic density (PSD) [Meshul et al. (1994) Brain Res., 648:181-195] and a change in the density of striatal glutamate immunoreactivity within those presynaptic terminals [Meshul and Tan (1994) Synapse, 18:205-217]. We speculated that this haloperidol-induced change in glutamate density might be due to an activation of the corticostriatal pathway. To determine if activation of this pathway leads to similar morphological changes previously described following haloperidol treatment, GABA (10(-5) M, 0.5 microliters) was injected into the thalamic motor (VL/VM) nuclei daily for 3 weeks. This treatment resulted in an increase in the mean percentage of striatal asymmetric synapses containing a perforated PSD and an increase in the density of glutamate immunoreactivity within nerve terminals of asymmetric synapses containing a perforated or non-perforated PSD. Subchronic injections of GABA into the thalamic somatosensory nuclei (VPM/VPL) had no effect on the mean percentage of synapses with perforated PSDs but resulted in a small, but significant, increase in density of glutamate immunoreactivity. Using in vivo microdialysis, an acute injection of GABA (10(-5) M, 15 microliters) into VL/VM resulted in a prolonged rise in the extracellular level of striatal glutamate. The increase in asymmetric synapses with perforated PSDs and in glutamate immunoreactivity within nerve terminals of the striatum following either subchronic haloperidol treatment or GABA injections into VL/VM suggest that an increase in glutamate release may be a common factor in these two experiments. It is possible that the extrapyramidal side effects associated with haloperidol treatment may be due, in part, to an increase in release of glutamate within the corticostriatal pathway.

Animals↗
PubMed1998

Repeated treatment with the selective kappa opioid agonist U-69593 produces a marked depletion of dopamine D2 receptors.

U-69593, the selective K-opioid agonist, was repeatedly administered in single daily injections (0.32 mg/kg) to male, Sprague-Dawley rats. Two or ten days later, the rats were euthanized and dopamine D1 and D2 receptors were measured using (3H]SCH 23390 or [3H]sulpiride, respectively, in caudate putamen and nucleus accumbens. Two days after the last of three injections, dopamine D2 receptors in the caudate putamen were decreased by approximately 40%, with no change in D1 receptors. Dopamine D2 receptor number had returned to normal by 10 days posttreatment. In contrast, in the nucleus accumbens there was a small, nonsignificant decrease in dopamine D2 receptors 2 days after treatment, but a large increase (65%) after 10 days. In agreement with the changes in D2 receptors, there was a significant downward shift in the locomotor activity curve for the D2 agonist quinpirole after a 2-day withdrawal. There were no differences in either the total amount of dopamine taken up or in the IC50 for cocaine to inhibit dopamine uptake following this treatment, suggesting that the dopamine transporter and presynaptic terminals were intact. The results of these studies demonstrate that repeated administration of a selective K-opioid agonist induces long-term alterations in dopamine D2 receptors. Furthermore, the finding that these changes in receptor number require both repeated injections and a withdrawal time greater than 1 day suggests that these alterations are compensatory in nature.

Animals↗
PubMed2000

The mechanism of the neurotransmitter release in growth cones.

The growth cone is considered the precursor of the presynaptic terminal. To elucidate the minimal molecular machinery required for exocytosis, we examined the characteristics of alpha-latrotoxin-induced exocytosis in growth cones. In isolated growth cones (IGC), neurotransmitters were released in a SNARE-dependent manner, but rab3A cycling was blocked. By supplying rabphilin, a rab3A acceptor found in low levels in IGC, the IGC obtained as high an exocytotic efficiency as adult synaptosomes, and the complete GDP-GTP conversion of rab3A occurred on growth cone vesicles (GCV). GCVs bound SNAREs but not NSF or alpha-SNAP; whereas in the rabphilin-supplied IGC, GCVs recruited both NSF and alpha-SNAP, to form the SNARE-NSF-SNAP complex. These results suggest that rab3A cycling is dependent upon the accumulation of rabphilin and is completed later than the SNARE mechanism, and that rabphilin is involved in determining the efficiency of exocytosis by modifying the SNARE mechanism.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Protein synthesis in entorhinal cortex and long-term potentiation in dentate gyrus.

Despite the concentration of effort in recent years, the mechanisms underlying the expression of long-term potentiation (LTP) in the hippocampus remain elusive, but amidst the uncertainty and sometimes controversy, one consistent finding is emerging; this is that late-phase LTP requires synthesis of proteins. This hypothesis was first proposed by a number of groups who reported that the more persistent components of LTP were blocked by protein synthesis inhibitors, and was supported by a significant literature which indicated that morphological changes accompanied LTP. Recent evidence indicated that the increase in protein synthesis may be cAMP-dependent and that subsequent activation of the transcription factor, CREB, represented one step in the cascade of events leading to protein synthesis. Whether protein synthesis occurs in presynaptic or postsynaptic neurons, or both, is still a subject of debate. Here we present evidence which suggests that LTP in perforant path-granule cell synapses is accompanied by protein synthesis, specifically synthesis of synaptic vesicle proteins, in the entorhinal cortex. We also show that protein synthesis is decreased in the entorhinal cortex of aged rats and a strain of rat which is genetically hypertensive, both of which exhibited impaired LTP. We propose that that the observed increase in protein synthesis in the entorhinal cortex, which accompanied LTP in the dentate gyrus, contributes to the reported changes in morphology in the presynaptic terminal.

Aging↗
PubMed1992

Persistent signalling and changes in presynaptic function in long-term potentiation.

Long-term potentiation (LTP) is an example of a persistent change in synaptic function in the mammalian brain, thought to be essential for learning and memory. At the synapse between hippocampal CA3 and CA1 neurons LTP is induced by a Ca2+ influx through glutamate receptors of the NMDA (N-methyl-D-aspartate) type (see Collingridge et al 1992, this volume). How does a rise in [Ca2+]i lead to enhancement of synaptic function? We have tested the popular hypothesis that Ca2+ acts via a Ca(2+)-dependent protein kinase. We found that long-lasting synaptic enhancement was prevented by prior intracellular injection of potent and selective inhibitory peptide blockers of either protein kinase C (PKC) or Ca2+/calmodulin-dependent protein kinase II (CaMKII), such as PKC(19-31) or CaMKII(273-302), but not by control peptides. Evidently, activity of both PKC and CaMKII is somehow necessary for the postsynaptic induction of LTP. To determine if these kinases are also involved in the expression of LTP, we impaled cells with microelectrodes containing protein kinase inhibitors after LTP had already been induced. Strikingly, established LTP was not suppressed by a combination of PKC and CaMKII blocking peptides, or by intracellular postsynaptic H-7. However, established LTP remained sensitive to bath application of H-7. Thus, the persistent signal may be a persistent kinase, but if so, the kinase cannot be accessed within the postsynaptic cell. Evidence for a presynaptic locus of expression comes from our studies of quantal synaptic transmission under whole-cell voltage clamp. We find changes in synaptic variability expected to result from enhanced presynaptic transmitter release, but little or no increase in quantal size. Furthermore, miniature synaptic currents in hippocampal cultures are increased in frequency but not amplitude as a result of a glutamate-driven postsynaptic induction. The combination of postsynaptic induction and presynaptic expression necessitates a retrograde signal from the postsynaptic cell to the presynaptic terminal.

Animals↗
PubMed1995

No association between schizophrenia and polymorphisms within the genes for debrisoquine 4-hydroxylase (CYP2D6) and the dopamine transporter (DAT).

It has been suggested that the cytochrome P450 mono-oxygenase, debrisoquine 4-hydroxylase, is involved in the catabolism and processing of neurotransmitters subsequent to their reuptake into target cells. It is also thought to be related to the dopamine transporter that acts to take released dopamine back up into presynaptic terminals. The present study used the association approach to test the hypothesis that mutations in the genes for debrisoquine 4-hydroxylase (CYP2D6) and the dopamine transporter (DAT) confer susceptibility to schizophrenia. There were no differences in allele or genotype frequencies between patients and controls in the mutations causing the poor metaboliser phenotype in CYP2D6. In addition there was no association found between schizophrenia and a 48bp repeat within the 3' untranslated region of DAT.

Adolescent↗