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PubMed2004

Background synaptic activity in rat entorhinal cortical neurones: differential control of transmitter release by presynaptic receptors.

The entorhinal cortex (EC) is a key brain area controlling both hippocampal input and output via neurones in layer II and layer V, respectively. It is also a pivotal area in the generation and propagation of epilepsies involving the temporal lobe. We have previously shown that within the network of the EC, neurones in layer V are subject to powerful synaptic excitation but weak inhibition, whereas the reverse is true in layer II. The deep layers are also highly susceptible to acutely provoked epileptogenesis. Considerable evidence now points to a role of spontaneous background synaptic activity in control of neuronal, and hence network, excitability. In the present article we describe results of studies where we have compared background release of the excitatory transmitter, glutamate, and the inhibitory transmitter, GABA, in the two layers, the role of this background release in the balance of excitability, and its control by presynaptic auto- and heteroreceptors on presynaptic terminals.

Animals↗
PubMed2001

Effects of long-term hormone therapy on cholinergic synaptic concentrations in healthy postmenopausal women.

Experimental evidence suggests that gonadal steroids regulate brain neurochemical systems associated with cognitive function, such as the cholinergic system. This study examines the effect of long-term postmenopausal hormone therapy on the brain concentrations of cholinergic synaptic terminals in women using single photon emission computed tomography and the radiotracer [(123)I]iodobenzovesamicol ([(123)I]IBVM). [(123)I]IBVM labels the vesicular acetylcholine transporter (VAChT) located in the presynaptic terminals of these neurons. Sixteen healthy women treated with hormone therapy since the menopause and 12 women not treated with hormones were studied. There were no significant differences in regional IBVM binding indexes between the 2 groups. The length of hormone replacement therapy correlated positively with VAChT binding indexes in multiple cortical areas (P < 0.05): frontal cortex (Spearman rank correlation: rho = 0.79), parietal cortex (rho = 0.62), temporal cortex (rho = 0.80), anterior cingulate (rho = 0.71), and posterior cingulate (rho = 0.63), but not in the basal ganglia (rho = 0.35; P = 0.2). An earlier onset of menopause in hormone-treated women was associated with higher VAChT indexes in the anterior cingulate (rho = -0.56; P = 0.02) and posterior cingulate (rho = -0.63; P = 0.01). The opposite was found in the posterior cingulate of women not treated with hormones (rho = 0.58; P = 0.04). Women treated with estrogen alone also showed higher VAChT indexes than women treated with estrogen and progestin in the posterior cingulate cortex (by Mann-Whitney U test: z = 2.42; P = 0.015). Although an overall effect of postmenopausal hormone therapy was not found, associations between an index of cortical cholinergic terminal concentrations and the length of hormonal replacement suggest that hormone therapy may influence the survival or plasticity of these cells in postmenopausal women. The data also suggest possible differential effects of estrogen and estrogen with progestin treatments in brain areas critical for cognitive processing.

Aged↗
PubMed1994

Response of striatal astrocytes to neuronal deafferentation: an immunocytochemical and ultrastructural study.

This ultrastructural and light microscopic immunocytochemical study describes the time course of anatomical changes that occur in striatal astrocytes in response to neuronal deafferentation in young adult rats and the coordinate distribution of two astrocytic proteins involved in reactive synaptogenesis, glial fibrillary acidic protein and clusterin. We found that following a unilateral lesion of the cerebral cortex, striatal astrocytes undergo a rapid ultrastructural transformation from a protoplasmic to a reactive type of astroglia and are the primary cells involved in the removal of degenerating axon terminals, but not axons of passage, from the neuropil. In addition, at 10 and 27 days postlesion, processes of reactive astrocytes are also seen to occupy vacant postsynaptic spines after degenerating presynaptic terminals are removed, suggesting that they may also participate in the reinnervation of the deafferented neurons. By immunocytochemistry, reactive astrocytes were characterized by a significant increase in the intensity of glial fibrillary acidic protein staining beginning at three days postlesion and lasting for at least 27 days postlesion. Reactive astrocytes were characterized by cellular hypertrophy and an increase in the density of immunoreactive processes distributed throughout the deafferented striatum. However, our analysis of astrocyte cell number found no evidence of astrocyte proliferation in response to the deafferentation lesion. Although previous in situ hybridization studies have reported elevated clusterin messenger RNA in reactive astrocytes after decortication, clusterin immunoreactivity was not seen in the cell soma of reactive astrocytes but was distributed as punctate deposits, ranging from 1 to 2 microns in diameter, within the neuropil of the deafferented striatum. At 10 days postlesion, the distribution of clusterin staining appeared as large aggregates of immunoreactive deposits adjacent to neurons. However, by 27 days postlesion, the aggregates of clusterin reaction product were replaced by a fine scattering of individual punctate deposits distributed evenly over the dorsal part of the deafferented striatum. These data support the notion that reactive astrocytes serve multiple, time-dependent roles in response to brain injury and are involved in both the removal of degenerative debris from the lesion site as well as in reforming the synaptic circuitry of the damaged brain. Our data suggest that, in response to decortication, reactive astrocytes are the primary cells responsible for removing degenerating axon terminals, but not axons of passage, from the deafferented striatum and that the coordinate increase in glial fibrillary acidic protein may serve to stabilize the extension of reactive astrocytic processes during phagocytosis.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗
PubMed1988

Membrane potential has no direct role in evoking neurotransmitter release.

Neurons communicate by secreting a transmitter that excites or inhibits other neurons at synapses. The role of presynaptic membrane potential in triggering transmitter release is still controversial. In one view, presynaptic action potentials trigger the release by the entry of calcium ions into presynaptic terminals through voltage-dependent calcium channels. Calcium acts at high local concentrations at release sites near channel mouths to cause neurosecretion. An opposing view is that, in addition to elevating presynaptic calcium, presynaptic potential stimulates transmitter release by a distinct direct action. The relative importance of depolarization and calcium entry in neurosecretion cannot be determined because the two events are tightly linked. To delineate the roles of presynaptic potential and calcium entry in transmitter release, we have used nitr-5, a photolabile calcium chelator, and a voltage-clamp technique to control intracellular calcium and membrane potential independently at a synapse formed between cell bodies of cultured neurons of the fresh water snail Helisoma trivolvis. We found transmitter release occurred when presynaptic calcium levels were elevated to concentrations of a few micromolar, and that presynaptic voltage had no direct effect on neurosecretion.

Animals↗
PubMed1999

Cellular localization of adenosine A1 receptors in rat forebrain: immunohistochemical analysis using adenosine A1 receptor-specific monoclonal antibody.

Monoclonal antibodies were generated against the adenosine A1 receptor (A1R) purified from rat brain. In immunoblot analyses of purified or partially purified A1R preparations from rat brain, these antibodies recognized a solitary band, the size of which corresponded to that expected for A1R. These antibodies recognized not only the native form of A1R but also the deglycosylated form of A1R. Immunocytochemical analysis of Chinese hamster ovarian cells that were transfected stably with rat A1R cDNA showed that their cell bodies were stained intensely by these antibodies, whereas nontransfected Chinese hamster ovarian cells were not. These antibodies detected the A1R naturally present in the DDT(1)( )MF-2 smooth muscle cells. One of these antibodies (the 511CA antibody) was then used to examine the immunohistochemical distribution of A1Rs in rat forebrain. On light microscopy, A1R immunoreactivity was observed in the cerebral cortex, septum, basal ganglia, hippocampal formation, and thalamus. However, in some regions of the forebrain, regional differences in staining intensity were found as follows: In the cerebral cortex, the strongest immunoreactivity was found in the large pyramidal neurons of layer V. This immunoreactivity was detected in the pyramidal cell bodies, dendrites, and axon initial segments. In the hippocampus, A1R immunoreactivity was detected mainly in the stratum pyramidale. The pyramidal cells in fields CA2-CA3 of the hippocampus were stained more intensely or more clearly than those in field CA1 or the dentate gyrus. More intense A1R immunoreactivity of the apical dendrites was detected in field CA2 compared with other hippocampal fields and the dentate gyrus. Many interneurons of the hippocampus were stained by the 511CA antibody. The subcellular distribution of A1Rs in the forebrain was examined by using a digital deconvolution system and electron microscopy. In the cerebral cortex, the view obtained by removing the background haze by deconvolution revealed that the immunofluoresence-labeled A1Rs were distributed on the surfaces of the cell bodies and dendrites and in the cytoplasm of layer V neurons as small spots. In field CA1, immunoreactivity was detected in the areas surrounding pyramidal cells. Electron microscopy revealed the presence of A1R-immunoreactive products in both the presynaptic terminals and the postsynaptic structures. The specific cellular distribution of A1Rs is consistent with the physiological premise that endogeneously released adenosine exerts control over the excitability of forebrain neurons at both presynaptic and postsynaptic sites through A1Rs.

Animals↗
PubMed1997

Preferential termination of corticorubral axons on spine-like dendritic protrusions in developing cat.

The formation of synaptic contacts is a crucial event during neural development and is thought to be achieved by complex interactions between incoming axons and the neurons in the target. We have focused on spine-like dendritic protrusions (SLDPs), which are transient pleomorphic protrusive structures seen in developing brains. Although the functional significance of SLDPs remains unknown, accumulating in vitro evidence suggests that the SLDP plays an important role in synaptogenetic interactions with axons. As a test of this idea, the present study was performed to examine whether the SLDPs are the preferential sites of synapse formation in vivo. The ultrastructure of biocytin-labeled corticorubral (CR) terminals was examined in serial thin sections during the period of synaptogenesis in newborn cats. We found that a major proportion (86%) of the CR synapses was formed on SLDPs. The presynaptic terminals were often invaginated by fine processes extending from the tips of SLDPs. Synaptic structures presumably of cortical origin were also found on SLDPs of HRP-labeled rubrospinal cells, suggesting that SLDPs postsynaptic to labeled CR terminals originate at least in part from rubrospinal cells. Taken together, these results indicate that SLDPs may represent preferred sites of synapse formation and support the notion that SLDPs play a role in synaptogenic interactions during brain development.

Animals↗
PubMed1994

Neurotransmitter release at fast synapses.

As stated at the beginning of this review, the mechanism of neurotransmitter release is not yet known. Keeping this in mind, we shall, nevertheless, attempt to speculate and outline a possible scenario of events as it emerges from the foregoing discussion. At resting membrane potentials, the release machinery is in a blocked state produced by the constant presence in the synaptic cleft of neurotransmitter at low concentrations. At resting potentials, Ca2+ channels are closed, but this is probably not associated with the presence of low levels of neurotransmitter. Upon arrival of the action potential at the nerve terminal, (as suggested by the Ca-voltage hypothesis) two things happen independently: The release machinery is relieved of its block, being activated and readied to trigger release. Concurrently, Ca2+ enters the presynaptic terminal, and together with specific Ca2+ binding proteins, it abolishes the hydration repulsive forces without which the intimate contact between the vesicle and the plasmatic release machinery is not possible. The biophysical meaning of triggering release is at present not known. There are several suggestions, the one most consistent with the arguments of this review being the mechanism discussed and modeled by Nanavati et al. (1992; see also review: Monck & Fernandez, 1992). According to that hypothesis, an activated scaffold of proteins forms a dimple in the plasma membrane upon stimulation. This dimple, which exhibits high tension--perhaps together with Ca(2+)--overcomes the repulsive forces of hydration, permitting the two membranes to "jump" into intimate contact. As a result, a single hemifused bilayer is formed. In this hemifused bilayer, a lipidic fusion pore opens. In the context of the lipidic fusion pore hypothesis, the role of the depolarization-dependent triggering could be to start those manipulations in the plasmatic membrane that result in increased lateral bilayer tension and formation of the dimple. Ca2+ could then, in view of reduced repulsive forces and increased attractive forces, be responsible for the intimate docking of the vesicle at the release site. Under such conditions, hemifusion could take place with the final formation of the lipidic fusion pore. Finally, once the fusion pore opens, discharge of the vesicular content takes place immediately and lasts for up to 50-70 microseconds. To be so fast, discharge must occur by a mechanism other than diffusion, possibly by ion-exchange (R. Khanin, H. Parnas and L. Segel, in preparation).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Effects of differential rearing on the structure of perforated synapses in the granule cell layer of the rat's accessory olfactory bulb.

The effects of differential rearing on synaptic morphology in the granule cell layer of the accessory olfactory bulb (AOB) were examined in adult rats. Forty-day-old male rats were housed in one of three ways: individually (isolated condition, IC); with four males per cage (unisexual condition, UC); or with two males and two females per cage (social condition, SC). After 2 months, the animals were killed for electron microscopy. Two types of synapses were classified: (1) perforated synapses, which are characterized by discontinuities in their postsynaptic thickenings, and (2) non-perforated synapses. The length of the synaptic contact zone as well as the area and the length of the perimeter of both the pre- and postsynaptic terminals were measured in each observed synapse. For perforated synapses, the length of the synaptic contact zone was significantly greater in the UC and the SC than in the IC. For the presynaptic terminals of perforated synapses, the area was greater in the UC and the SC than in the IC, and the length of the perimeter was greater in the UC than in the IC. In contrast, there was no difference in the area and the length of the perimeter among the three groups for postsynaptic terminals. For non-perforated synapses, there was no statistically significant difference in either the area or the length of the perimeter of pre- and postsynaptic terminals among the three experimental groups, although the length of the synaptic contact zone was greater in the SC than in the IC.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed2000

Presynaptic signalling mediated by mono- and dinucleotides in the central nervous system.

Synaptosomal preparations from rat midbrain exhibit specific responses to both ATP and Ap(5)A, which elicit a Ca(2+) entrance to the presynaptic terminals. Studies of isolated single terminals showed that not all the terminals contain ionotropic receptors for nucleotides, in fact only 46% of them do. Of these, 12% responded only to the dinucleotide Ap(5)A, and 20% to the mononucleotide ATP. At the presynaptic level, diinosine pentaphosphate, Ip(5)I, is a good tool to specifically block dinucleotide responses, which are inhibited at low nM concentration, versus the high microM concentrations required to block ATP responses. There is evidence for a presynaptic control of mononucleotide and dinucleotide responses, mediated by metabotropic and ionotropic receptors. Stimulation of adenosine A1 receptors increases the affinity of dinucleotide receptors by five orders of magnitude, from 30 microM to 680 pM for control and in the presence of A1 agonist, respectively.

Animals↗
PubMed1996

Timing of neurotransmission at fast synapses in the mammalian brain.

Understanding the factors controlling synaptic delays has broad implications. On a systems level, the speed of synaptic transmission limits the communication rate between neurons and strongly influences local circuit dynamics. On a molecular level, the delay from presynaptic calcium entry to postsynaptic responses constrains the molecular mechanism of vesicle fusion. Previously it has not been possible to elucidate the determinants of synaptic delays in the mammalian central nervous system, where presynaptic terminals are small and difficult to study. We have developed a new approach to study timing at rat cerebellar synapses: we used optical techniques to measure voltage and calcium current simultaneously from presynaptic boutons while monitoring postsynaptic currents electrically. Here we report that the classic view that vesicle release is driven by calcium entry during action-potential repolarization holds for these synapses at room temperature, but not at physiological temperatures, where postsynaptic responses commence just 150 micros after the start of the presynaptic action potential. This brisk communication is a consequence of rapid calcium-channel kinetics, which allow significant calcium entry during the upstroke of the presynaptic action potential, and extremely fast calcium-driven vesicle fusion, which lags behind calcium influx by 60 micros.

Action Potentials↗
PubMed2003

Mitochondrial regulation of synaptic plasticity in the hippocampus.

Synaptic mechanisms of plasticity are calcium-dependent processes that are affected by dysfunction of mitochondrial calcium buffering. Recently, we observed that mice deficient in mitochondrial voltage-dependent anion channels, the outer component of the mitochondrial permeability transition pore, have impairments in learning and hippocampal synaptic plasticity, suggesting that the mitochondrial permeability transition pore is involved in hippocampal synaptic plasticity. In this study, we examined the effect on synaptic transmission and plasticity of blocking the permeability transition pore with low doses of cyclosporin A and found a deficit in synaptic plasticity and an increase in base-line synaptic transmission. Calcium imaging of presynaptic terminals revealed a transient increase in the resting calcium concentration immediately upon incubation with cyclosporin A that correlated with the changes in synaptic transmission and plasticity. The effect of cyclosporin A on presynaptic calcium was abolished when mitochondria were depolarized prior to cyclosporin A exposure, and the effects of cyclosporin A and mitochondrial depolarization on presynaptic resting calcium were similar, suggesting a mitochondrial locus of action of cyclosporin A. To further characterize the calcium dynamics of the mitochondrial permeability transition pore, we used an in vitro assay of calcium handling by isolated brain mitochondria. Cyclosporin A-exposed mitochondria buffered calcium more rapidly and subsequently triggered a more rapid mitochondrial depolarization. Similarly, mitochondria lacking the voltage-dependent anion channel 1 isoform depolarized more readily than littermate controls. The data suggest a role for the mitochondrial permeability transition pore and voltage-dependent anion channels in mitochondrial synaptic calcium buffering and in hippocampal synaptic plasticity.

Animals↗
PubMed1984

Electron microscopic localization of neuron-specific enolase in rat and mouse brain.

The cellular distribution and intracellular localization of neuron-specific enolase (NSE) has been studied by electron microscopic immunocytochemistry in the brain of the rat and of the mouse. Although the intensity of staining was less in the mouse, the same structures were positive in both species. In the cerebrum, the neuronal perikarya and dendrites were intensely stained, but staining was almost entirely absent in the presynaptic terminals. The deep neurons of the brain stem were also positive. In the cerebellum, perikarya, axons, and parallel fibers of the granule cell neurons were stained as were the synaptic vesicles and presynaptic membranes of the synapses between the parallel fibers and the Purkinje cell dendrites. Golgi cell dendrites, basket cells and their axons, and mossy fibers were also positive. In contrast, the Purkinje cells including their dendrites, and the climbing fibers that formed synapses with the Purkinje cell dendrites were not stained. The majority of the myelinated axons in both the cerebrum and the cerebellum did not stain, but the fibrillary astrocytic processes between myelinated axons in the white matter did. Oligodendroglia, protoplasmic astrocytes, Bergmann glia, astrocytes investing capillaries, and vascular endothelial cells were negative for reaction product. In the positively staining cells and their processes, the positivity was dispersed throughout the cytoplasm and corresponded most closely to the distribution of ribosomes, the granular endoplasmic reticulum, and microtubules. Nuclei, mitochondria, the cisternae of the Golgi complex, myelin lamellae, and most membranes were not stained.

Animals↗
PubMed1999

L-type calcium channels in the photoreceptor ribbon synapse: localization and role in plasticity.

Calcium (Ca(2+)) influx through voltage-gated Ca(2+)channels stimulates a variety of neural activities, including process outgrowth, neurotransmission, and synaptic plasticity. In general, L-type channels control Ca(2+) influx into the soma and dendrites, whereas other Ca(2+) channel types control presynaptic activities. Neurons that make ribbon synapses, however, are among a select group of nerve cells whose presynaptic Ca(2+)-dependent secretion is linked to L-type channels. Recently, photoreceptor ribbon synapses have been shown to be capable of dramatic structural remodeling and neuritic outgrowth. Here, we have examined 1) the distribution of dihydropyridine (DHP)-sensitive (L-type) Ca(2+) channels in photoreceptor presynaptic structures and 2) the role of these channels in axonal plasticity and process outgrowth in culture. Using anti-alpha(1C) and the fluorescent dihydropyridine, (-)-DM-BODIPY DHP, L-type channels were localized in the outer plexiform layer of retinal sections and in presynaptic terminals of freshly isolated photoreceptors. In the rod terminal, dense patches of label were present; their distribution and number matched that of synaptic ribbons. After 1-7 days in vitro, punctate alpha(1C) staining occurred along newly formed neurites and presynaptic varicosities. Functional channels were present throughout the culture period, as determined by fura-2 imaging. Channel blockage by nicardipine, a DHP antagonist, inhibited axonal remodeling. Specifically, it prevented axon retraction and lamellipodium formation, reduced neurite growth, and produced long, thin processes on some, primarily cone, photoreceptors. L-type Ca(2+) channel activity, therefore, not only stimulates neurotransmission but contributes to presynaptic structural plasticity at the ribbon synapse.

Ambystoma↗
PubMed1972

The role of post-synaptic neurones in the biochemical maturation of presynaptic cholinergic nerve terminals in a mouse sympathetic ganglion.

1. The role of post-synaptic adrenergic neurones in the biochemical maturation of presynaptic cholinergic nerve terminals has been investigated in mouse superior cervical ganglion in vivo.2. Selective destruction of ganglion adrenergic neurones chemically, with 6-hydroxydopamine (6-OH-DA), or immunologically, with nerve growth factor antiserum (NGF-antiserum) prevented the normal maturation of choline acetyl transferase (ChAc) activity in presynaptic endings during development. Enzyme activity remained depressed for at least 2 months.3. 6-OH-DA treatment failed to alter ChAc activity in the developing duodenum or diaphragm, organs in which cholinergic fibres do not synapse with adrenergic neurones, suggesting that destruction of post-synaptic neurones per se inhibited presynaptic maturation.4. Similarly, NGF-antiserum, which does not destroy adrenergic neurones in the adult did not alter ChAc activity in adult mouse ganglia.5. These observations suggest that post-synaptic adrenergic neurones regulate the biochemical development of presynaptic cholinergic nerve terminals.

Acyltransferases↗
PubMed1991

GABA-like immunoreactivity in the tuberomammillary nucleus: an electron microscopic study in the rat.

The organization of GABAergic elements in the histaminergic tuberomammillary nucleus has been examined by using antibodies against gamma-aminobutyric acid (GABA) and light and electron microscopy. Most neuronal perikarya of the ventral subgroup of the tuberomammillary nucleus were GABA immunoreactive (GABA-i). The morphology of the GABA-i perikarya was similar to the morphology of histaminergic perikarya described by Hayashi et al. ('84: J. Comp. Neurol. 229: 223-241) and Wouterlood et al. ('86: J. Comp. Neurol. 252:227-243). The GABA-i perikarya were contacted by relatively few terminals. The mean bouton covering ratio of GABA-i perikarya was 6.1%, whereas the mean bouton covering ratio for GABA-i dendrites in the tuberomammillary nucleus was 31%. Some of the presynaptic terminals were GABA-i. In addition, GABA-i perikarya and dendrites formed close contacts that never presented synaptic specializations. These results suggest that neurons of the histaminergic tuberomammillary nucleus contain the neurotransmitter GABA. Furthermore, GABA may act as a modulator of cellular processes within the tuberomammillary nucleus.

Animals↗
PubMed1992

Postsynaptic then presynaptic protein kinase C activity may be necessary for long-term potentiation.

Protein kinase C inhibitor was injected intracellularly by iontophoresis into CA1 somata either before or after long-term potentiation in the hippocampal slice preparation. Two different protein kinase C inhibitors, polymyxin B (PMXB) or 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), injected 10 min before long-term potentiation induction caused potentiated responses to return to baseline 15-35 min after induction without significantly affecting the initial magnitude of potentiation. There was no effect on long-term potentiation persistence when H-7 or PMXB was injected intracellularly 5 min after long-term potentiation induction. In contrast, focal extracellular micro-pressure ejection of protein kinase C inhibitor in the stratum radiatum, 15 or 30 min, but not 60 min after long-term potentiation induction caused decay of long-term potentiation to baseline. This is probably a presynaptic action since intracellular inhibitors injected postsynaptically were ineffective 5 min after long-term potentiation induction. Focal application to stratum pyramidale produced a weaker decay than to stratum radiatum suggesting a Schaffer collateral presynaptic terminal site of action. We propose that activation of postsynaptic protein kinase C activity is necessary for long-term potentiation persistence but this activity persists for less than 5 min after induction. Presynaptic protein kinase C activity is also necessary for persistence and is time-limited to less than 60 min. It is attractive to think that these two events are sequentially activated and employ different protein kinase C subtypes differentially localized to presynaptic or postsynaptic elements.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2006

Amphetamine depresses excitatory synaptic transmission at prefrontal cortical layer V synapses.

Dopamine modulates the function of glutamatergic synapses in prefrontal cortex, modifying synaptic strength and influencing synaptic plasticity. Here we have explored the ability of endogenous dopamine, present in slices containing the prefrontal cortex, to influence excitatory synaptic transmission. We found that 10 microM amphetamine, which releases and blocks the reuptake of dopamine from dopaminergic nerve terminals, significantly depressed excitatory field potentials recorded in layer V during stimulation of layer II/III. The depression was reversible, dose dependent and correlated with increased paired pulse facilitation, suggesting that amphetamine inhibits the presynaptic release of glutamate. Pharmacological dissection of this response showed that dopamine D1 receptors are likely to mediate the effects of endogenous dopamine on excitatory synaptic transmission, with little effect of alpha2 adrenergic receptors, serotonin receptors, or D2 dopamine receptors. The time to peak amphetamine effect was longer than expected based on diffusion, suggesting that to raise dopamine levels in brain slices amphetamine may need to be transported into the presynaptic terminals. These results provide evidence that D1/D5 receptors depress glutamate release at this cortical synapse, and suggest that amphetamine will have profound and persistent effects on PFC functioning in vivo. Dysregulation of this mechanism could contribute to the impairment in cognitive performance associated with abnormal PFC dopamine receptor activation.

Adrenergic alpha-Antagonists↗
PubMed1971

The effect of prolonged depolarization on synaptic transfer in the stellate ganglion of the squid.

1. Depolarization of the giant axon terminal of the squid causes local calcium influx which gives rise to transmitter release and post-synaptic response, and which under certain experimental conditions leads to a regenerative action potential in the presynaptic terminal itself.2. There has been conflicting evidence in the literature on the question whether the calcium permeability change in the terminal is rapidly inactivated, or whether it can persist with little diminution for hundreds of milliseconds during a depolarizing voltage step.3. Results are presented which show that there is little ;calcium inactivation', even when very large depolarizing steps are imposed on the terminal and maintained for periods of 1-2 sec.4. Contrary indications are examined and found to be attributable to an increase of potassium conductance, rather than direct inactivation of calcium conductance.

Action Potentials↗