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PubMed2000

Apoptotic and anti-apoptotic synaptic signaling mechanisms.

Although several prominent morphological features of apoptosis are evident in the cell body (e.g., cell shrinkage, membrane blebbing, and nuclear DNA condensation and fragmentation) the biochemical and molecular cascades that constitute the cell death machinery can be engaged in synaptic terminals and neurites. Initiating events such as oxyradical production and calcium influx, and effector processes such as Par-4 production, mitochondrial alterations and caspase activation, can be induced in synapses and neurites. Several prominent signal transduction pathways in synaptic terminals play important roles in either promoting or preventing neuronal death in physiological and pathological conditions. For example, activation of glutamate receptors in postsynaptic spines can induce neuronal apoptosis, whereas local activation of neurotrophic factor receptors in presynaptic terminals can prevent neuronal death. Factors capable of inducing nuclear chromatin condensation and fragmentation can be produced locally in synaptic terminals and neurites, and may propogate to the cell body. Recent findings suggest that, beyond their roles in inducing or preventing cell death, apoptotic and anti-apoptotic cascades play roles in synaptic plasticity (structural remodelling and long-term functional changes). For example, caspase activation results in proteolysis of glutamate receptor (AMPA) subunits, which results in altered neuronal responsivity to glutamate. Activation of neurotrophic factor receptors in synaptic terminals can result in local changes in energy metabolism and calcium homeostasis, and can induce long-term changes in synaptic transmission. The emerging data therefore suggest that synapses can be considered as autonomous compartments in which both pro- and anti-apoptotic signaling pathways are activated resulting in structural and functional changes in neuronal circuits. A better understanding of such synaptic signaling mechanisms may reveal novel approaches for preventing and treating an array of neurodegenerative conditions that are initiated by perturbed synaptic homeostasis.

Animals↗
PubMed1988

Long-term facilitation in Aplysia involves increase in transmitter release.

In a variety of vertebrates and invertebrates, long-lasting enhancement of synaptic transmission contributes to the storage of memory lasting one or more days. However, it has not been demonstrated directly whether this increase in synaptic transmission is caused by an enhancement of transmitter release or an increase in the sensitivity of the postsynaptic receptors. These possibilities can be distinguished by a quantal analysis in which the size of the miniature excitatory postsynaptic potential released spontaneously from the presynaptic terminal is used as a reference. By means of microcultures, in which single sensory and motor neurons of Aplysia were plated together, miniature excitatory postsynaptic potentials attributable to the spontaneous release of single transmitter quanta from individual presynaptic neurons were recorded and used to analyze long-term facilitation induced by repeated applications of 5-hydroxytryptamine. The results indicate that the facilitation is caused by an increase in the number of transmitter quanta released by the presynaptic neuron.

Animals↗
PubMed1976

Modulation of synaptic transmitter release by repetitive postsynaptic action potentials.

The effect of repetitive action potentials in the postsynaptic axon on the release of synaptic transmitter from the presynaptic terminal was investigated at the squid giant synapse. Repetitive antidromic stimulation of the postsynaptic axon resulted in a reduction in the excitatory postsynaptic potential (EPSP). The reduction in transmitter release was accompanied by a decrease in the presynaptic spike after-hyperpolarization (AH). Increasing the concentration of extracellular potassium ions also reduced the EPSP and decreased the amplitude of the presynaptic spike AH. The reduction in transmitter release resulting from repetitive postsynaptic impulses is attributed to the accumulation of extracellular potassium ions. It is proposed that the accumulation of extracellular potassium ions resulting from repetitive postsynaptic activity may modulate synaptic transmission and function as an integrative mechanism in the nervous system.

Action Potentials↗
PubMed1999

Alterations of muscarinic acetylcholine receptor subtypes in diffuse lewy body disease: relation to Alzheimer's disease.

OBJECTIVES: Dementia associated with Lewy bodies in cortical and subcortical areas is classified as dementia of the non-Alzheimer type and termed diffuse Lewy body disease (DLBD). The generic term "dementia with Lewy bodies (DLB)" was proposed in the international workshop on Lewy body dementia to include the similar disorders presenting Lewy bodies. In DLB, a lower level of choline acetyltransferase (ChAT) activity in the neocortex was found compared with that in Alzheimer's disease. The purpose of the present study was to determine the total amount of muscarinic acetylcholine receptors (mAChRs) and relative proportion of each subtype (m1-m4) of mAChRs in the frontal and temporal cortex of seven DLBD and 11 Alzheimer's disease necropsied brains. METHODS: A [(3)H]quinuclidinyl benzilate (QNB) binding assay and an immunoprecipitation assay using subtype-specific antibodies were performed. Each antibody was raised against fusion proteins containing peptides corresponding to the third intracellular (i3) loops of the respective mAChR subtype. RESULTS: The total amounts of mAChRs were significantly lower in the preparations of temporal cortices from DLBD and Alzheimer's disease than in those from dead controls (seven cases). In both diseases, the proportion of the m3 receptor in the frontal cortex was significantly increased and that of the m4 receptor in the temporal cortex was significantly decreased compared with the control specimens. The proportions of the m1 and m2 subtypes were significantly different in the temporal cortex. The proportion of the m1 receptor was significantly greater in the DLBD brains, whereas that of the m2 receptor was significantly greater in the Alzheimer's disease brains than in the controls. CONCLUSIONS: The m1 receptor is the major subtype in the cerebral cortex, and m2 is known to be present at presynaptic terminals. The higher proportions of m1 in DLBD and m2 in Alzheimer's disease suggest that the manner of degeneration in the cholinergic system is different between the diseases. It is hypothesised that a severe depletion of presynaptic cholinergic projective neurons causes the upregulation of m1 receptor in the temporal cortex in DLBD.

Aged↗
PubMed2001

Neuroprotective agent riluzole dramatically slows inactivation of Kv1.4 potassium channels by a voltage-dependent oxidative mechanism.

The modulation of Kv1.4 K+ channels by the neuroprotective agent riluzole was studied in bovine adrenal zona fasciculata cells by using whole-cell patch clamp. At concentrations ranging from 1 to 100 microM, riluzole reversibly inhibited Kv1.4 channels (IC50 = 70 microM) and irreversibly slowed Kv1.4 inactivation. Riluzole (100 microM) increased the inactivation time constant (tau(i)) from a control value of 28.9 +/- 3.9 to 623 +/- 47.6 ms (n = 13). The slowing of bKv1.4 inactivation was not affected by substituting poorly hydrolyzable nucleotides for ATP in the pipette solution, or by the addition of cAMP. Riluzole-induced slowing of bKv1.4 inactivation was nearly eliminated by the presence of the antioxidant reduced glutathione (3 mM) or dithiothreitol (3-5 mM) in the recording pipette, or when cells were superfused with riluzole at a holding potential of -40 mV rather than -80 mV. These results are consistent with a model in which riluzole inhibits bKv1.4 currents and slows inactivation by separate mechanisms. Slowing of inactivation is independent of protein kinases, but probably involves oxidation of a cysteine in the N-terminal inactivation domain. Failure of riluzole to slow inactivation when applied to a depolarized cell suggests that this cysteine is protected in an inactivated Kv1.4 channel. The neuroprotective action of riluzole involves inhibition of glutamate release from presynaptic terminals within the central nervous system. Kv1.4 K+ channels are distributed throughout the brain in axons and nerve terminals, including those from which glutamate is released. The pronounced slowing of Kv1.4 inactivation by riluzole in these neurons could be an important mechanism underlying the inhibition of glutamate release and the therapeutic actions of this drug.

Animals↗
PubMed2004

Regulation of HCN channel surface expression by a novel C-terminal protein-protein interaction.

Hyperpolarization-activated cation currents (I(h)) are carried by channels encoded by a family of four genes (HCN1-4) that are differentially expressed within the brain in specific cellular and subcellular compartments. HCN1 shows a high level of expression in apical dendrites of cortical pyramidal neurons and in presynaptic terminals of cerebellar basket cells, structures with a high density of I(h). Expression of I(h) is also regulated by neuronal activity. To isolate proteins that may control HCN channel expression or function, we performed yeast two-hybrid screens using the C-terminal cytoplasmic tails of the HCN proteins as bait. We identified a brain-specific protein, which has been previously termed TRIP8b (for TPR-containing Rab8b interacting protein) and PEX5Rp (for Pex5p-related protein), that specifically interacts with all four HCN channels through a conserved sequence in their C-terminal tails. In situ hybridization and immunohistochemistry show that TRIP8b and HCN1 are colocalized, particularly within dendritic arbors of hippocampal CA1 and neocortical layer V pyramidal neurons. The dendritic expression of TRIP8b in layer V pyramidal neurons is disrupted after deletion of HCN1 through homologous recombination, demonstrating a key in vivo interaction between HCN1 and TRIP8b. TRIP8b dramatically alters the trafficking of HCN channels heterologously expressed in Xenopus oocytes and human embryonic kidney 293 cells, causing a specific decrease in surface expression of HCN protein and I(h) density, with a pronounced intracellular accumulation of HCN protein that is colocalized in discrete cytoplasmic clusters with TRIP8b. Finally, TRIP8b expression in cultured pyramidal neurons markedly decreases native I(h) density. These data suggest a possible role for TRIP8b in regulating HCN channel density in the plasma membrane.

Action Potentials↗
PubMed1990

Inhibition of phosphorylation of rat synaptosomal proteins by snake venom phospholipase A2 neurotoxins (beta-bungarotoxin, notexin) and enzymes (Naja naja atra, Naja nigricollis).

Some snake venom neurotoxins, such as beta-bungarotoxin (beta-BuTX) and notexin, which inhibit the release of neurotransmitter at both peripheral and central presynaptic terminals possess phospholipase A2 activity. In contrast, most snake venom phospholipase A2 enzymes such as those isolated from Naja naja atra and Naja nigricollis are structurally homologous to these neutrotoxins but do not have any specific or potent presynaptic action although they have higher enzymatic activities than the neurotoxins. In order to investigate the mechanisms of presynaptic action of the snake venom neurotoxins, we studied their effects on phosphorylation of rat brain synaptosomal proteins. It is known that phosphorylation of synapsin I, a neuron specific and synaptic vesicle associated phosphoprotein, increases neurotransmitter release. Incubation of cerebral cortical synaptosomes with 32P-orthophosphate at 37 degrees C for 30 min, caused significant phosphorylation of a wide mol. wt range of proteins including most markedly those proteins in the mol. wt range (81,000-86,000) of synapsin I. Both snake venom phospholipase A2 neurotoxins and enzymes (5, 15 and 50 nM) inhibited phosphorylation in a Ca2(+)-dependent manner with the following order of potencies: beta-BuTX greater than N.n. atra phospholipase A2 greater than or equal to notexin greater than N. nigricollis phospholipase A2. Five nanomoles of beta-BuTX, which has the lowest phospholipase A2 activity, inhibited phosphorylation of a wide range of mol. wt proteins (51,000-188,000) by 42-58%. At the same concentration, N.n. atra phospholipase A2 (which possesses the highest enzymatic activity), notexin and N. nigricollis phospholipase A2 caused less inhibition than beta-BuTX, ranging from 0-40% depending on the agent used. These results indicate that there is no correlation between their potencies in inhibiting phosphorylation and the levels of their phospholipase A2 activities. An inhibitory activity on phosphorylation may be at least partially responsible for a presynaptically-induced block of neurotransmitter release.

Animals↗
PubMed1990

Plasticity of GABA- and glutamate-containing terminals in the mouse thalamic ventrobasal complex deprived of vibrissal afferents: an immunogold-electron microscopic study.

GABA and glutamate immunogold staining demonstrated that nerve cells of the thalamic ventrobasal complex (VB) of mice were positive exclusively for glutamate. None of the neuronal perikarya reacted the GABA antibody. By using alternate thin sections of the normal VB, it was also shown that large "specific" somatosensory and small corticothalamic terminals, both of which contained spherical synaptic vesicles, exhibited only glutamate-like immunoreactivity. A third axonal type, containing flat-ovoid synaptic vesicles, stained only for GABA. Seventy-five days after coagulation of the vibrissal follicles in newborn mice, a characteristic multiplication of GABA positive axon terminals was observed. In addition, it was demonstrated that, similarly to modified cortical endings (Hámori et al., J. Comp. Neurol. 254:166-183, '86), many GABA positive terminals appeared as specific afferent endings, replacing the missing "specific" vibrissal afferents. This finding shows a remarkable plasticity of inhibitory GABA axons during developmental synaptogenesis and provides further evidence that the size, location, and the type of attachment of presynaptic terminals are dependent on their postsynaptic target.

Afferent Pathways↗
PubMed1988

Long-term sensitization in Aplysia increases the number of presynaptic contacts onto the identified gill motor neuron L7.

We have used the gill and siphon withdrawal reflex of Aplysia to study the morphological basis of the persistent synaptic plasticity that underlies long-term sensitization. One critical locus for storage of the memory for sensitization is the set of monosynaptic connections between identified siphon sensory neurons and gill and siphon motor neurons. To complement previous morphological studies of the presynaptic terminals of identified sensory neurons, we examined the effects of long-term sensitization on the structure of an identified postsynaptic target--the gill motor neuron L7. We found an increase in the frequency, size, and vesicle complement of presynaptic contacts onto L7 processes in sensitized compared to control animals. Combined, these data indicate a striking increase in the percentage of the surface area of L7 that is occupied by synaptic contacts after long-term training. These results are consistent with our observations that sensitization produces an increase in the synapses that the sensory neurons make on their target cells and provide additional support for the hypothesis that changes in synapse number may represent a mechanism underlying long-term memory.

Animals↗
PubMed1975

A note of the mechanism by which inhibitors of the sodium pump accelerate spontaneous release of transmitter from motor nerve terminals.

1. The actions of 0-1 mM ouabain and of K-free Ringer have been examined at the frog neuromuscular junction. 2. After a delay of more than 30 min, ouabain produces an increase in the miniature end-plate potential (m.e.p.p.) frequency. This increase occurs unchanged in Ca-free Ringer containing 1 mM-EGTA and is therefore unlikely to be due to an entry of Ca into the motor nerve terminals. 3. If the nerve to the preparation is stimulated repetitively in Ca-free Ringer containing 0-1 mM ouabain and 1 mM-EGTA the response of the m.e.p.p. frequency depends on the timing of the tetanus relative to the beginning of the ouabain treatment. 4. During the first 30 min of exposure to ouabain, the tetanus produces a small, transient increase in the m.e.p.p. frequency similar to that which occurs before ouabain is present. After about 30 min the same tetanus produces large, irreversible increases in the m.e.p.p. frequency. 5. Superfusion of an end-plate with K-free Ringer causes an immediate exponential rise in the m.e.p.p. frequency that is unaffected by the presence of external Ca ions. On replacing the normal K of the Ringer (2 mM) the m.e.p.p. frequency recovers quickly to its original value. 6. Late in an exposure to 0-1 mM ouabain the m.e.p.p. frequency becomes extremely sensitive to changes in the external Na concentration, [Na]o. Reducing [Na]o increases the m.e.p.p. frequency. The sensitivity to [Na]o is independent of external Ca ions or whether the isotonic substitute for NaCl is LiCl or sucrose. 7. It is suggested that the spontaneous release of transmitter is facilitated, in some way, by the changes in the monovalent cation content of the nerve terminals that result from blocking the Na-K exchange pump. The Na sensitivity of the m.e.p.p. frequency that develops simultaneously can be explained if a Na-dependent Ca efflux system is present in the membrane of the presynaptic terminals.

Animals↗
PubMed2002

The cannabinoid CB1 receptor mediates retrograde signals for depolarization-induced suppression of inhibition in cerebellar Purkinje cells.

Action potential firing or depolarization of the postsynaptic neuron can induce a transient suppression of inhibitory synaptic inputs to the depolarized neuron in the cerebellum and hippocampus. This phenomenon, termed depolarization-induced suppression of inhibition (DSI), is initiated postsynaptically by an elevation of intracellular Ca2+ concentration ([Ca2+]i) and is expressed presynaptically as a suppression of the transmitter release. It is, therefore, thought that some retrograde signal must exist from the depolarized postsynaptic neurons to the presynaptic terminals. Recent studies on hippocampal neurons have revealed that endogenous cannabinoids (endocannabinoids) play a key role as a retrograde messenger. There are, however, conflicting reports that glutamate may be a candidate retrograde messenger for cerebellar DSI that acts on presynaptic group II metabotropic glutamate receptors (mGluRs). In this study, we examined whether endocannabinoids mediate retrograde signal for cerebellar DSI. We recorded IPSCs from Purkinje cells by stimulating putative basket cell axons in mouse cerebellar slices. DSI was readily induced in evoked IPSCs by a depolarizing pulse train. We found that DSI was completely occluded by a cannabinoid agonist, WIN55,212-2, was totally eliminated by a specific antagonist of the type 1 cannabinoid (CB1) receptor, SR141716A, and was deficient in the CB1 knock-out mouse. In contrast, a group II mGluR-specific agonist, (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine, did not completely occlude DSI, and an mGluR antagonist, (RS)-alpha-methyl-4-carboxyphenylglycine, had no depressant effect on DSI. These results clearly indicate that the CB1 receptor mediates retrograde signal for DSI in cerebellar Purkinje cells.

Animals↗
PubMed1994

Haloperidol-induced morphological alterations are associated with changes in calcium/calmodulin kinase II activity and glutamate immunoreactivity.

Administration of haloperidol for 2 weeks causes an increase within the caudate nucleus of asymmetrical synapses associated with a discontinuous or perforated, postsynaptic density (PSD) [Meshul et al. (1992), Psychopharmacology, 106:45-52; Meshul et al. (1992), Neuropsychopharmacology, 7:285-293]. Coadministration of the N-methyl-D-aspartate noncompetitive antagonist, MK-801, with haloperidol blocked the increase in striatal synapses containing a perforated PSD [Meshul et al. (1994), Brain Res., 648:181-195]. Examination of the caudate using immuno-gold electron microscopy revealed the vast majority (90%) of asymmetrical synapses were labelled with a glutamate antibody [Meshul et al. (1994), Brain Res., 648:181-195]. The purpose of this study was to determine if there were any changes in the density of glutamate immunoreactivity within presynaptic terminals of asymmetric synapses within the striatum following treatment with haloperidol for 1 month that would correlate with the previously observed increase in synapses with perforated PSDs. We also determined the activity of striatal calcium/calmodulin kinase II (CaMK II), an enzyme known to be localized within the synaptic region, after administration of haloperidol. We report here that haloperidol causes an increase in the activity of CaMK II and a decrease in the density of immuno-gold labelling for glutamate within the nerve terminals of asymmetrical synapses containing a perforated or nonperforated PSD. These results are consistent with the hypothesis that the haloperidol-induced increase in activity of CaMK II and the increase in glutamate release, as suggested by the decrease in presynaptic glutamate immunoreactivity, may ultimately lead to an increase in the number of synapses displaying a perforated PSD. These results support the speculation that the haloperidol-induced increase in synapses containing a perforated PSD may be associated with enhanced activity at excitatory synapses.

Animals↗
PubMed1988

The binding of a monoclonal antibody reactive with pp60v-src to the rat CNS both in vitro and in vivo: evidence that the epitope is present intracellularly as well as being associated with a number of antigenically related polypeptides located externally in the plasma membrane only in the synaptic region.

A monoclonal antibody, F4, has been produced which reacts with an epitope possessing an unusual subcellular distribution. It binds to the external surface of the neuronal plasma membrane only in the region of the synapse. This is evidenced by binding of F4 to presynaptic terminals in unfixed cultures of rat cerebellum and to preparations of unfixed synaptosomes. In addition, much larger amounts of the epitope are present intracellularly. In fixed nervous tissue, the epitope is found in many neurons, and is associated mainly with presynaptic plasma membranes, synaptic vesicles, postsynaptic densities (cerebral cortex and hippocampus, but not cerebellum), rough endoplasmic reticulum, and the Golgi apparatus. The epitope is especially abundant in large neurons (e.g. pyramidal cells). Similar amounts of epitope are present in the chromaffin cells of the adrenal medulla. It is also expressed in ependymal cells in the brain, and in epithelial cells present in ducts of the medulla, but not cortex, of the kidney. However, the epitope is not found in glial cells in the brain, or in either liver, spleen, skeletal muscle, or testes. F4 is not species specific, as it binds to postmortem adult human cerebral cortex and neonatal cerebellum in a manner as described for the rat. It also binds to homogenates of brains of fish, chicken and mouse. The appearance of the epitope during development of the cerebellum in vivo and in vitro occurs in parallel with the differentiation of neurons and formation of synapses, though small amounts are also present in neuronal precursor cells. The F4 antibody can detect nanogram amounts of pp60v-src on immunodots. The strength of this reaction is high enough that F4 can be used to demonstrate pp60v-src-like immunoreactivity in Rous Sarcoma virus-transformed chick embryo fibroblasts. However, present evidence suggests that it may be premature to assign the immunocytochemical reactivity of F4 in the brain exclusively to pp60c-src. This conclusion is based on the fact that F4 reacts with several polypeptides from synaptic plasma membranes on Western blots of renaturing, two-dimensional gels that are dissimilar in size to pp60c-src, and from the fact that it can cross-react, albeit weakly, with several other serine protein kinases in an immunodot assay. Appreciation of this cross-reactivity, and of the evolutionary conservation of the epitope, as well as its sensitivity to denaturation, has led to our working hypothesis that F4 binds to a conformational epitope present on several polypeptides that may be most perfectly represented by some aspect of the catalytic domain of tyrosine protein kinases.

Animals↗
PubMed2005

MAPK activation in cerebellar basket cell terminals after harmaline treatment.

The mitogen-activated protein kinases (MAPKs) are a family of signal transduction mediators that regulate a number of cellular activities, including cell growth and proliferation, differentiation and survival, via phosphorylation (activation) of protein kinases. MAPKs are also recruited during synaptic plasticity and remodeling. In the present study we used Western blotting and immunohistochemistry to examine the effects of harmaline administration on the phosphorylation state of three MAPKs: the extracellular signal-regulated kinase (ERK1/2), c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK), and p38 MAPK. Harmaline is a tremorigenic drug known to induce enhanced and rhythmic firing of the inferior olive. In rats, synchronous activity of the inferior olive cells induced by harmaline administered for four days from postnatal day 9 to 12 resulted in prolonged maintenance of polyinnervation of Purkinje cells by climbing fibers (axons of olivary cells). Immunohistochemistry showed small but sustained cytoplasmic positivity to phospho-ERK in Purkinje cells and a strong signal for phospho-ERK in the "pinceaux," terminals of the interneuronal basket cells onto Purkinje cells. A similar pattern was observed for JNK/SAPK, while no changes in p38 were noticed. Thus, it was revealed that the activation of two members of the MAPK family in these inhibitory presynaptic terminals is also one consequence of synchronous olivary input to Purkinje cells known to affect developmental plasticity.

Animals↗
PubMed2001

Calcium channel isoforms underlying synaptic transmission at embryonic Xenopus neuromuscular junctions.

Studies on the amphibian neuromuscular junction have indicated that N-type calcium channels are the sole mediators of stimulus-evoked neurotransmitter release. We show, via both presynaptic and postsynaptic voltage-clamp measurements, that dihydropyridine (DHP)-sensitive calcium channels also contribute to stimulus-evoked release at developing Xenopus neuromuscular junctions. Whereas inhibition of postsynaptic responses by omega-conotoxin (omega-Ctx) GVIA has been taken previously as evidence that only N-type channels mediate transmitter release, we find that both N-type and DHP-sensitive calcium currents are sensitive to this toxin. The unusual sensitivity of DHP-sensitive calcium channels to omega-Ctx GVIA in presynaptic terminals raises the possibility that this channel type may have escaped detection in previous physiological studies on adult frog neuromuscular junctions. Alternatively, the additional channel isoforms may be present only during early development, when they may serve to strengthen collectively presynaptic release during critical periods of synaptogenesis.

Action Potentials↗
PubMed2002

Evidence that synaptically released beta-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice.

A neuropathological hallmark of Alzheimer's disease is the deposition of amyloid-beta (Abeta) peptides in senile plaques in the hippocampus and cerebral cortex. Abeta is derived from larger integral membrane proteins termed amyloid precursor proteins (APP). We demonstrated previously that APP, synthesized by neurons in the entorhinal cortex, is transported via the perforant pathway to presynaptic terminals in the dentate gyrus. We reported that, although full-length APP and membrane-tethered, C-terminal APP derivatives (APP-CTFs) accumulate at terminal fields, the production of Abeta peptides at these sites was indeterminate. To test the hypothesis that APP-CTFs, generated from axonally transported APP, are further metabolized to Abeta peptides that are subsequently released and deposited proximal to nerve terminals, we created unilateral knife lesions of the perforant pathway of transgenic mice that exhibit hippocampal amyloid deposits. We observed pronounced reductions in amyloid burden in the ipsilateral dentate gyrus, findings that lead us to conclude that axonally transported APP gives rise to Abeta peptides that are released from presynaptic sites in the dentate gyrus and deposited in extracellular plaques. Moreover, our findings are consistent with the view that Abeta deposits are dynamic structures and that the perforant path lesion alters the equilibrium between Abeta production-deposition toward clearance as a consequence of blocked axonal transport of APP from the entorhinal cortex to terminal fields in the hippocampus.

Alzheimer Disease↗
PubMed1999

Ultrastructural change of synapses of Betz cells in patients with amyotrophic lateral sclerosis.

This report concerns an ultrastructural study of the synapses present on the surface of somata of normal-looking Betz cells in the fifth layer of motor cortex of seven patients with amyotrophic lateral sclerosis (ALS). Specimens from 12 age-matched, neurologically normal control individuals were included for comparison. Presynaptic terminals on the somata of normal-appearing Betz cells showed a wide range of changes including increased mitochondria, and the dark type of degenerative change of synapses such as dense conglomerates of dark mitochondria with dense cristae and densely aggregated presynaptic vesicles. These alterations were significantly more common in ALS patients than in controls, suggesting that a substantial synaptic change occurs in Betz cells even in the early stage of ALS.

Aged↗
PubMed1990

Phorbol ester enhances synaptic transmission at crustacean neuromuscular junctions.

Effects of phorbol ester (PE) (4 beta-phorbol-12,13-dibutyrate) on transmitter release were studied in the deep extensor neuromuscular system of the prawn, Macrobrachium rosenbergii. Our findings show that PE enhances transmitter release as indicated by an increase in the quantal content. PE had no post-synaptic effects. The increase in release is accompanied by a slight decline in twin pulse facilitation, suggesting a minor increase in Ca2+ entry. The fact that the increase in Ca2+ entry has a minor contribution to the PE effect is supported by the following observations: the duration of facilitation was not affected by PE, and 3,4-diaminopyridine (3,4-DAP), which by itself increased release, did not reduce the effect of PE. The time course of release was measured from synaptic delay histograms, upon which PE had no effect. This finding indicates that protein kinase C (PKC) is probably not involved in the rate limiting step of the process of secretion. The log/log plot of the initial part of the delay histogram is not affected by PE, suggesting a lack of effect on cooperativity of the release process. Increased release by loading the presynaptic terminal with Ca2+ either by pretreatment with Ca2+ ionophore or by frequent stimulation prevented further increase in release by PE. We conclude that the main effect of PE is confined to stages of release that are secondary to the first elevation in presynaptic Ca2+. PKC in this system probably plays a role in long term modulation of release, and it can be activated in processes leading to presynaptic Ca2+ accumulation.

Animals↗