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PubMed2000

Influence of the target on distribution and functioning of the varicosities of Helix pomatia metacerebral cell C1 in dissociated cell culture.

The serotonergic metacerebral giant cell (C1) of Helix pomatia was isolated with its bifurcate axon and plated in culture under five conditions: (i) with no target; (ii) with the appropriate target B2 near the stump of the bigger branch (CBC); (iii) with B2 near the stump of the smaller branch (CC); (iv) with a wrong target (C3) near the stump of the CBC branch and (v) with B2 and C3 positioned near the CBC and CC stump, respectively. The counting of anti-serotonin antibody-labelled varicosities of the C1 neuron showed that the presence of the appropriate target in either axonal domain both down-regulated the number of varicosities of the contralateral neuritic field, and increased their average size, whereas the wrong target induced an overall reduction of the number of C1 neuron varicosities, and inhibited the evoked transmitter release. The action potential-evoked calcium concentration increase in the neuritic terminals of the C1 neuron cultured alone, or in presence of the appropriate target, reached a value significantly higher than that reached in presence of the wrong target. These results provide evidence that the postsynaptic neuron regulates both morphological and functional development of presynaptic terminals.

Action Potentials↗
PubMed1992

Autoradiographic localization of dopamine D1 and D2 receptors in rat cerebral cortex following unilateral neurotoxic lesions.

Relative to dopaminergic innervation of cortex, dopamine D1 and D2 receptors may be located on presynaptic terminals and/or postsynaptically on cortical neurons. To assess the relative distribution of these sites, quantitative in vitro receptor autoradiography was performed following injection of 6-hydroxydopamine (6-OHDA) into the median forebrain bundle (MFB; which lesions presynaptic DA terminals) and ibotenic acid into the prefrontal and anterior cingulate cortices (which lesions neurons whose cell bodies are intrinsic to cortex). Receptor autoradiography was performed ten days after injection of neurotoxins with [3H]SCH 23390 (a D1 probe) and [125I]epidepride (a D2 probe). Both DA receptor subtypes were found in all layers of anterior cingulate and prefrontal cortices but were concentrated in deeper layers V and VI. Ibotenic acid lesion of cortex reduced D1 and D2 receptors by 55-80%, although the concentrations of DA and its major metabolite dihydroxyphenylacetic acid (DOPAC) were unchanged. Lesion of MFB produced no significant change in D1 and D2 receptors, but was associated with a 49-52% decrease in DA and DOPAC levels relative to the contralateral side. These results suggest that the majority of D1 and D2 receptors in prefrontal and anterior cingulate cortices are located postsynaptically on neurons intrinsic to the cortex.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Frequency modulation of transmitter release.

In 1952 Fatt and Katz recorded at a frog neuromuscular junction while stimulating the nerve and found "... that successive endplate potential responses varied in a step-like manner, corresponding to units of miniature endplate potentials" (J Physiol 117, 109-128). This led them to propose that fast neuromuscular transmission is 'quantal'. Quantal release is now commonly ascribed to a vesicular form of neurosecretion since vesicles have routinely been visualized in presynaptic terminals. The vesicular hypothesis (Del Castillo and Katz, 1955) assumes that quanta, or 'transmitter packets of standard size', are assembled and stored in the numerous vesicles routinely identified in micrographs of virtually all central and peripheral presynaptic nerve terminals. Simply stated, this model predicts that each one of the miniature synaptic signals (MSSs) follows from the exocytosis of one vesicle's contents. However, the time required for membrane fusion preceding exocytosis (Almers and Tse, 1990) and the variability in MSS amplitude and time course (Vautrin et al, 1992a,b) cannot readily be reconciled by a simple, exocytotic model of quantal release from preloaded vesicles. These difficulties with the original model have led us to re-evaluate MSSs generated at the classical peripheral synapse, the cholinergic neuromuscular junction of the mouse diaphragm, as well as at central synapses between embryonic hippocampal neurons mediated by gamma-aminobutyric acid (GABA). At these synapses, the release of GABA is also assumed to have classical quantal properties like peripheral acetylcholine release (Edwards et al, 1990). Our results show that at both synapses, progressive alterations in elementary signal properties can be induced in a remarkably rapid manner. The original report of preferred amplitudes and intervals in the spontaneous miniature signals (Fatt and Katz, 1952) has repeatedly been confirmed and is here incorporated into a dynamic model of fast synaptic transmission. Although MSSs exhibit variable rise-times and peak amplitudes, they can both be described in terms of synchronization of transmitter release. We have reviewed many experimental findings, which together strongly suggest that the original interpretation of Fatt and Katz (1952) regarding MSSs as reflecting the non-propagated 'neurogenic' activity of 'terminal spots' may be a useful concept to pursue since it may help to explain part of the underlying molecular basis of quantal release.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMedDate not supplied

Factors controlling the dendritic arborization of retinal ganglion cells.

The effects of changing retinal ganglion cell (RGC) density and availability of presynaptic sites on the development of RGC dendritic arbor in the developing chick retina were contrasted. Visual form deprivation was used to induce ocular enlargement and expanded retinal area resulting in a 20-30% decrease in RGC density. In these retinas, RGC dendritic arbors increased in a compensatory manner to maintain the inner nuclear layer to RGC convergence ratio in a way that is consistent with simple stretching; RGC dendritic arbors become larger with increased branch lengths, but without change in the total number of branches. In the second manipulation, partial optic nerve section was used to produce areas of RGC depletion of approximately 60% in the central retina. This reduction in density is comparable to the density of locations in the normal peripheral retina. In RGC depleted retinas, dendritic arbor areas of RGCs in the central retina grow to match the size of normal peripheral arbors. In contrast to the expanded case, two measures of intrinsic arbor structure are changed in RGC-depleted retinas; the branch density of RGC dendrites is greater, and the relative areas of the two arbors of bistratified cells are altered. We discuss the potential roles of retinal growth, local RGC density, and availability of presynaptic terminals in the developmental control of RGC dendritic arbor.

Animals↗
PubMed1997

Disruption of syntaxin-mediated protein interactions blocks neurotransmitter secretion.

The membrane protein syntaxin participates in several protein-protein interactions that have been implicated in neurotransmitter release. To probe the physiological importance of these interactions, we microinjected into the squid giant presynaptic terminal botulinum toxin C1, which cleaves syntaxin, and the H3 domain of syntaxin, which mediates binding to other proteins. Both reagents inhibited synaptic transmission yet did not affect the number or distribution of synaptic vesicles at the presynaptic active zone. Recombinant H3 domain inhibited the interactions between syntaxin and SNAP-25 that underlie the formation of stable SNARE complexes in vitro. These data support the notion that syntaxin-mediated SNARE complexes are necessary for docked synaptic vesicles to fuse.

Amino Acid Sequence↗
PubMed2003

NO enhances presynaptic currents during cerebellar mossy fiber-granule cell LTP.

Nitric oxide (NO) is a candidate retrograde messenger in long-term potentiation (LTP). The NO metabolic pathway is expressed in the cerebellar granule cell layer but its physiological role remained unknown. In this paper we have investigated the role of NO in cerebellar mossy fiber-granule cell LTP, which has postsynaptic N-methyl-d-aspartate (NMDA) receptor-dependent induction. Pre- and postsynaptic current changes were simultaneously measured by using extracellular focal recordings, and NO release was monitored with an electrochemical probe in P21 rat cerebellar slices. High-frequency mossy fiber stimulation induced LTP and caused a significant NO release (6.2 +/- 2.8 nM; n = 5) in the granular layer that was dependent on NMDA receptor as well as on nitric oxide synthase (NOS) activation. Preventing NO production by perfusing the NOS inhibitor 100 microM NG-nitro-l-arginine (L-NNA), blocking extracellular NO diffusion by 10 microM MbO2, or inhibiting the NO target guanylyl cyclase (sGC) with 10 microM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-dione (ODQ) prevented LTP. Moreover, the NO donor 10 microM 2-(N,N-diethylamino)-diazenolate-2-oxide.Na (DEA-NO) induced LTP, which was mutually occlusive with LTP generated by high-frequency stimulation, prevented by ODQ, and insensitive to NMDA channel blockade (50 microM APV + 25 microM 7-Cl-kyn) or interruption of mossy fiber stimulation. Thus NO is critical for LTP induction at the cerebellar mossy fiber-granule cell relay. Interestingly, LTP manipulations were accompanied by consensual changes in the presynaptic current, suggesting that NO acts as a retrograde signal-enhancing presynaptic terminal excitability.

Animals↗
PubMed1997

Pharmacologically distinct presynaptic calcium channels in cerebellar excitatory and inhibitory synapses.

We have used whole-cell patch clamp recordings and pharmacological blockers of Ca channels to compare the pharmacology of Ca channels that mediate synaptic transmission at the three types of synapses innervating Purkinje cells in rat cerebellar slices. Both parallel fiber and climbing fiber excitatory synapses were sensitive to the P-type Ca channel blocker, omega-AgaIVA and the P/Q/N-type channel blocker, omega-conotoxin MVIIC. Transmission at inhibitory interneuronal synapses was not suppressed by these toxins, or by the N-type (omega-conotoxins GVIA and MVIIA) or L-type (nimodipine) channel blockers. Inhibitory transmission could be inhibited by Ni2+ and amiloride, but only at concentrations (IC50 approximately 300 microM) that affect other types of Ca channels. These results indicate that excitatory and inhibitory presynaptic terminals of the cerebellar cortex possess different types of voltage-gated Ca channels. The excitatory terminals contain P-type, Q-type and N-type Ca channels, with P-type channels playing the most prominent role. The inhibitory terminals possess quite different type(s) of Ca channel. The heterogeneous distribution of Ca channel types should impart unique properties to transmitter release from the excitatory and inhibitory terminals.

Animals↗
PubMed1998

Alzheimer amyloid protein precursor in the rat hippocampus: transport and processing through the perforant path.

Amyloid deposition is a neuropathological hallmark of Alzheimer's disease. The principal component of amyloid deposits is beta amyloid peptide (Abeta), a peptide derived by proteolytic processing of the amyloid precursor protein (APP). APP is axonally transported by the fast anterograde component. Several studies have indicated that Abeta deposits occur in proximity to neuritic and synaptic profiles. Taken together, these latter observations have suggested that APP, axonally transported to nerve terminals, may be processed to Abeta at those sites. To examine the fate of APP in the CNS, we injected [35S]methionine into the rat entorhinal cortex and examined the trafficking and processing of de novo synthesized APP in the perforant pathway and at presynaptic sites in the hippocampal formation. We report that both full-length and processed APP accumulate at presynaptic terminals of entorhinal neurons. Finally, we demonstrate that at these synaptic sites, C-terminal fragments of APP containing the entire Abeta domain accumulate, suggesting that these species may represent the penultimate precursors of synaptic Abeta.

Amyloid beta-Peptides↗
PubMed1998

Reduced glutamate immunolabeling in the nucleus accumbens following extended withdrawal from self-administered cocaine.

Alterations in the density of GABA and glutamate immunolabeling within nerve terminals in the shell region of the nucleus accumbens were assessed in rats withdrawn from intravenous cocaine exposure. Four groups of rats were used: one group self-administered cocaine (0.42 mg/kg/infusion) in daily 3-h sessions for approximately 2 weeks, two additional groups received either saline or cocaine in a noncontingent fashion, and a fourth comprised a drug-naive, age-matched control group. Immunogold electron microscopy was used to quantify presynaptic terminal GABA and glutamate density within the vesicular and mitochondrial pools approximately 18 days following the last drug or saline exposure in the treatment groups. A significant 27.7% decrease in vesicular glutamate density within asymmetrical nerve terminals was observed in animals that self-administered cocaine as compared to controls. This group also showed an 18.6% decrease in vesicular nerve terminal glutamate immunolabeling as compared to animals that were administered a similar total dose of cocaine in a response-independent fashion. No significant changes in the density of nerve terminal GABA vesicular immunolabeling were observed in any groups. For both transmitters, no differences were detected in the density of immunolabeling within the presynaptic mitochondrial (i.e., metabolic) pool. These results demonstrate that glutamate density is suppressed in the shell region of the nucleus accumbens following withdrawal from 2 weeks of cocaine exposure. The findings also suggest that the motivational aspects that accompany self-administration may participate in this reduction.

Animals↗
PubMed2000

Temporal regularity of neurotransmitter release at single terminal in cultured hippocampal neurons.

The whole-cell GABA-mediated inhibitory postsynaptic currents were studied using the patch-clamp technique on synaptically connected cultured hippocampal neurons. The stimulus-evoked inhibitory postsynaptic currents were recorded in the tetrodotoxin-containing solution in response to the low-amplitude long (10-20ms) extracellular depolarization of a single presynaptic terminal. During each depolarization the postsynaptic response in a form of several superimposed independent events was recorded. The amplitudes of these responses fluctuated randomly, irrespective of the number of the event. In all the investigated neurons the distributions of delays revealed regularly spaced multiple peaks. The number of peaks increased with the duration of stimulus. The distance between the peaks was on average 2.97+/-0.86ms (n=58). The mean intervals between successive releases were distributed exponentially indicating the independence of the release sites. Thus neurotransmitter release might occur with maximal probability at the most probable times irrespective of the presence or failure of the previous event. The increase in stimulating pulse amplitude led to a decrease in the number of clearly detectable peaks in distributions. The decrease in the number of peaks in the distribution of delays was not accompanied with a decrease in the distance between peaks within the range of reliable resolution of the peaks. The amplitude distribution also revealed regularly spaced multiple peaks. The absence of significant correlation between the amplitude of the first and the second event demonstrated the independence of the succeeding release on the preceding release during long stimulation. Results of statistical analysis of our experimental data supports the hypothesis of multiquantal neurotransmitter release in a single inhibitory hippocampal synapse. Neurotransmitter release during long stimulation may occur at certain times with maximal probability, keeping the mean inter-release interval constant. Thus the interval is not determined directly by the depletion of vesicles and the number of vesicles which may be released at the most probable time is random.

Animals↗
PubMed2000

Differential localization of septins in the mouse brain.

We have carried out a comparative immunohistochemical study on four members of the septin family, CDCrel-1, Septin6, CDC10, and H5, which are abundantly expressed in the adult mouse brain. We found that each septin showed overlapping but distinct distribution at the levels of light and electron microscopy. CDCrel-1 was abundant in inhibitory presynaptic terminals and associated with GABAergic vesicles in the thalamus, globus pallidus, and cerebellar nuclei. Septin6 was associated with synaptic vesicles in various brain regions, including glomeruli of the olfactory bulb. CDC10 was diffusely expressed in the brain and was localized beneath presynaptic membrane and astroglial processes. H5 was localized in the astroglial processes in some specific brain regions. The differential expression and subcellular localization of these septins indicates that a given neuron or glial cell expresses a specific set of septin monomers and that the resulting septin complexes with distinct compositions may play distinct roles in the brain.

Animals↗
PubMed2004

Distinct roles of different neural cell adhesion molecule (NCAM) isoforms in synaptic maturation revealed by analysis of NCAM 180 kDa isoform-deficient mice.

Mice that lack all three major isoforms of neural cell adhesion molecule (NCAM) (180 and 140 kDa transmembrane, and 120 kDa glycosylphosphatidylinositol linked) were previously shown to exhibit major alterations in the maturation of their neuromuscular junctions (NMJs). Specifically, even by postnatal day 30, they failed to downregulate from along their axons and terminals an immature, brefeldin A-sensitive, synaptic vesicle-cycling mechanism that used L-type Ca2+ channels. In addition, these NCAM null NMJs were unable to maintain effective transmitter output with high-frequency repetitive stimulation, exhibiting both severe initial depression and subsequent cyclical periods of total transmission failures that were of presynaptic origin. As reported here, mice that lack only the 180 kDa isoform of NCAM downregulated the immature vesicle-cycling mechanism on schedule, implicating either the 140 or 120 kDa NCAM isoforms in this important maturational event. However, 180 NCAM-deficient mice still exhibited many functional transmission defects. Although 180 NCAM null NMJs did not show the severe initial depression of NCAM null NMJs, they still had cyclical periods of complete transmission failure. In addition, several presynaptic molecules were expressed at lower levels or were more diffusely localized. Thus, the 180 kDa isoform of NCAM appears to play an important role in the molecular organization of the presynaptic terminal and in ensuring effective transmitter output with repetitive stimulation. Our results also suggest that PKC and MLCK (myosin light chain kinase) may be downstream effectors of NCAM in these processes. Together, these results indicate that different isoforms of NCAM mediate distinct and important events in presynaptic maturation.

Animals↗
PubMed1995

Analysis of synaptic transmission at single identified boutons on rat spinal neurons in culture.

The spatial organization of receptor channels has a major influence on the speed and possible plasticity of synaptic signal transmission. We have studies glutamatergic synapses on neurons in organotypic cultures of rat spinal cord. In order to avoid the problems related to the analysis of currents of unknown origin within a neuron, we chose to examine the functional properties of single identified synapses. Iontophoretic mapping of the cell surface revealed hot spots of high glutamate sensitivity coincident with presynaptic boutons stained with the dye FM 1-43. Local application of KCl to these sites caused bursts of synaptic release. Hot spots typically consisted of 330 receptors with an average single-channel conductance of 8.3 pS. Evoked synaptic currents involved only about 40-50 receptors and nevertheless showed characteristics of saturation. This suggests that glutamate receptor clusters at sites of presynaptic terminals are organized into well separated subclusters opposite release sites.

Animals↗
PubMed1999

Role of presynaptic L-type Ca2+ channels in GABAergic synaptic transmission in cultured hippocampal neurons.

Using dual whole cell patch-clamp recordings of monosynaptic GABAergic inhibitory postsynaptic currents (IPSCs) in cultured rat hippocampal neurons, we have previously demonstrated posttetanic potentiation (PTP) of IPSCs. Tetanic stimulation of the GABAergic neuron leads to accumulation of Ca2+ in the presynaptic terminals. This enhances the probability of GABA-vesicle release for up to 1 min, which underlies PTP. In the present study, we have examined the effect of altering the probability of release on PTP of IPSCs. Baclofen (10 microM), which depresses presynaptic Ca2+ entry through N- and P/Q-type voltage-dependent Ca2+ channels (VDCCs), caused a threefold greater enhancement of PTP than did reducing [Ca2+]o to 1.2 mM, which causes a nonspecific reduction in Ca2+ entry. This finding prompted us to investigate whether presynaptic L-type VDCCs contribute to the Ca2+ accumulation in the boutons during spike activity. The L-type VDCC antagonist, nifedipine (10 microM), had no effect on single IPSCs evoked at 0.2 Hz but reduced the PTP evoked by a train of 40 Hz for 2 s by 60%. Another L-type VDCC antagonist, isradipine (5 microM), similarly inhibited PTP by 65%. Both L-type VDCC blockers also depressed IPSCs during the stimulation (i.e., they increased tetanic depression). The L-type VDCC "agonist" (-)BayK 8644 (4 microM) had no effect on PTP evoked by a train of 40 Hz for 2 s, which probably saturated the PTP process, but enhanced PTP evoked by a train of 1 s by 91%. In conclusion, the results indicate that L-type VDCCs do not participate in low-frequency synchronous transmitter release, but contribute to presynaptic Ca2+ accumulation during high-frequency activity. This helps maintain vesicle release during tetanic stimulation and also enhances the probability of transmitter release during the posttetanic period, which is manifest as PTP. Involvement of L-type channels in these processes represents a novel presynaptic regulatory mechanism at fast CNS synapses.

Animals↗
PubMed2000

Action potentials reliably invade axonal arbors of rat neocortical neurons.

Neocortical pyramidal neurons have extensive axonal arborizations that make thousands of synapses. Action potentials can invade these arbors and cause calcium influx that is required for neurotransmitter release and excitation of postsynaptic targets. Thus, the regulation of action potential invasion in axonal branches might shape the spread of excitation in cortical neural networks. To measure the reliability and extent of action potential invasion into axonal arbors, we have used two-photon excitation laser scanning microscopy to directly image action-potential-mediated calcium influx in single varicosities of layer 2/3 pyramidal neurons in acute brain slices. Our data show that single action potentials or bursts of action potentials reliably invade axonal arbors over a range of developmental ages (postnatal 10-24 days) and temperatures (24 degrees C-30 degrees C). Hyperpolarizing current steps preceding action potential initiation, protocols that had previously been observed to produce failures of action potential propagation in cultured preparations, were ineffective in modulating the spread of action potentials in acute slices. Our data show that action potentials reliably invade the axonal arbors of neocortical pyramidal neurons. Failures in synaptic transmission must therefore originate downstream of action potential invasion. We also explored the function of modulators that inhibit presynaptic calcium influx. Consistent with previous studies, we find that adenosine reduces action-potential-mediated calcium influx in presynaptic terminals. This reduction was observed in all terminals tested, suggesting that some modulatory systems are expressed homogeneously in most terminals of the same neuron.

Action Potentials↗
PubMed2005

Presynaptic calcium stores and synaptic transmission.

Following the gradual recognition of the importance of intracellular calcium stores for somatodendritic signaling in the mammalian brain, recent reports have also indicated a significant role of presynaptic calcium stores. Ryanodine-sensitive stores generate local, random calcium signals that shape spontaneous transmitter release. They amplify spike-driven calcium signals in presynaptic terminals, and consequently enhance the efficacy of transmitter release. They appear to be recruited by an association with certain types of calcium-permeant ion channels, and they induce specific forms of synaptic plasticity. Recent research also indicates a role of inositoltrisphosphate-sensitive presynaptic calcium stores in synaptic plasticity.

Animals↗
PubMed2005

Gephyrin regulates the cell surface dynamics of synaptic GABAA receptors.

The efficacy of fast synaptic inhibition is critically dependent on the accumulation of GABAA receptors at inhibitory synapses, a process that remains poorly understood. Here, we examined the dynamics of cell surface GABAA receptors using receptor subunits modified with N-terminal extracellular ecliptic pHluorin reporters. In hippocampal neurons, GABAA receptors incorporating pHluorin-tagged subunits were found to be clustered at synaptic sites and also expressed as diffuse extrasynaptic staining. By combining FRAP (fluorescence recovery after photobleaching) measurements with live imaging of FM4-64-labeled active presynaptic terminals, it was evident that clustered synaptic receptors exhibit significantly lower rates of mobility at the cell surface compared with their extrasynaptic counterparts. To examine the basis of this confinement, we used RNAi to inhibit the expression of gephyrin, a protein shown to regulate the accumulation of GABAA receptors at synaptic sites. However, whether gephyrin acts to control the actual formation of receptor clusters, their stability, or is simply a global regulator of receptor cell surface number remains unknown. Inhibiting gephyrin expression did not modify the total number of GABAA receptors expressed on the neuronal cell surface but significantly decreased the number of receptor clusters. Live imaging revealed that clusters that formed in the absence of gephyrin were significantly more mobile compared with those in control neurons. Together, our results demonstrate that synaptic GABAA receptors have lower levels of lateral mobility compared with their extrasynaptic counterparts, and suggest a specific role for gephyrin in reducing the diffusion of GABAA receptors, facilitating their accumulation at inhibitory synapses.

Animals↗
PubMed2000

Long-term potentiation of excitatory inputs to brain reward areas by nicotine.

Nicotine reinforces smoking behavior by activating nicotinic acetylcholine receptors (nAChRs) in the midbrain dopaminergic (DA) reward centers, including the ventral tegmental area (VTA). Although nicotine induces prolonged excitation of the VTA in vivo, the nAChRs on the DA neurons desensitize in seconds. Here, we show that activation of nAChRs on presynaptic terminals in the VTA enhances glutamatergic inputs to DA neurons. Under conditions where the released glutamate can activate NMDA receptors, long-term potentiation (LTP) of the excitatory inputs is induced. Both the short- and the long-term effects of nicotine required activation of presynaptic alpha7 subunit-containing nAChRs. These results can explain the long-term excitation of brain reward areas induced by a brief nicotine exposure. They also show that nicotine alters synaptic function through mechanisms that are linked to learning and memory.

Animals↗