-
Journal of Neurophysiology Apr 19891. The membrane properties and synaptic responses of guinea pig nucleus accumbens neurons in vitro were studied with intracellular recording methods. 2. The population...
1. The membrane properties and synaptic responses of guinea pig nucleus accumbens neurons in vitro were studied with intracellular recording methods. 2. The population of neurons could be divided into groups of low (20-60 M omega, average 46.5 M omega) and high (60-180 M omega, average 96.5 M omega) input resistance. The resting membrane potential in both groups was approximately -70 mV. 3. Other membrane properties were quite similar in both groups. Inward rectification occurred at potentials more negative than -80 mV; this was blocked by Cs+ (2 mM). Membrane potential oscillations were observed at potentials between -65 and -55 mV; these were blocked by tetrodotoxin (TTX, 0.5 microM). Outward rectification occurred at potentials less negative than -45 mV; this was depressed by tetraethylammonium (TEA, 10 mM). 4. Action potentials elicited by small depolarizing current pulses (2-5 ms, 0.3-0.5 nA) were approximately 95 mV in amplitude and 1.0 ms in duration. The afterhyperpolarization following each action potential was less than 30 ms in duration, and no accommodation of action-potential discharge was seen at frequencies up to 40 Hz. The action potentials were reversibly blocked by TTX (0.3 microM). In addition, TTX-insensitive, Ca2+-dependent spikes were evoked by passing larger and more prolonged current pulses (greater than 40 ms, greater than 0.5 nA) across the membrane. 5. Focal electrical stimulation of the slice surface with low intensity (1 ms, less than 10 V) elicited excitatory postsynaptic potentials (EPSPs) in neurons of both high- and low-resistance groups. The reversal potential (+10.2 mV) for the EPSPs was close to the reversal potential (+7.7 mV) of the responses to glutamate applied in the superfusing solution. The N-methyl-D-aspartic acid (NMDA) receptor antagonists, D-alpha-aminoadipic acid (1 mM) and DL-2-amino-5-phosphonovaleric acid (DL-APV, 250 microM), reversibly depressed the EPSP; the glutamate uptake inhibitor, L-aspartic acid-beta-hydroxamate (50 microM), or removal of Mg2+ from the superfusate, augmented the EPSP. 6. When the intensity of the focal stimulus was increased (1 ms, greater than or equal to 10 V), a second larger depolarizing response (duration, 800 ms to 2 s) could be evoked in addition to the smoothly graded EPSP. This was seen only in cells of the high-resistance group (90-130 M omega).(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Action Potentials; Animals; Electric Stimulation; Electrophysiology; Glutamates; Guinea Pigs; In Vitro Techniques; Male; Membrane Potentials; Membranes; Nucleus Accumbens; Septal Nuclei; Synapses; gamma-Aminobutyric Acid
PubMed: 2723719
DOI: 10.1152/jn.1989.61.4.769 -
GABAergic mechanisms that shape the temporal response to odors in moth olfactory projection neurons.Annals of the New York Academy of... Nov 1998Mitral/tufted cells in the olfactory bulb and projection neurons (PNs) in the insect antennal lobe are involved in complex synaptic interactions with inhibitory... (Review)
Review
Mitral/tufted cells in the olfactory bulb and projection neurons (PNs) in the insect antennal lobe are involved in complex synaptic interactions with inhibitory interneurons to help shape their odor-evoked responses. In the moth Manduca sexta, both gamma-aminobutyric acid (GABA) and the GABAA receptor agonist muscimol hyperpolarize and lower input resistance in many PNs, often blocking ongoing spike traffic. The GABA response mimics a short-latency, chloride-mediated inhibitory postsynaptic potential (IPSP) evoked in PNs by electrical or odor stimulation of afferent inputs, and the classical GABAA receptor antagonist bicuculline methiodide (BMI) quickly and reversibly blocks this IPSP. Focal injection of BMI (100 microM) immediately preceding a GABA pulse blocks the hyperpolarization evoked by GABA, but a similar injection of BMI preceding an acetylcholine (ACh) pulse fails to block the depolarization evoked by ACh. Moreover, the temporal pattern of odor-evoked activity in moth PNs is also strongly and reversibly altered by BMI. Importantly, the temporal pattern of the response depends on the temporal characteristics of the stimulus: continuous stimulation evokes more complex, rhythmic responses, whereas a pulsatile stimulus can be copied with a discrete burst of spikes for each pulse. Collectively our results indicate that PNs in the moth antennal lobe possess GABA receptors that share certain characteristics in common with vertebrate GABAA receptors. These receptors are largely responsible for helping PNs integrate information about both the molecular features and the timing of olfactory input to the brain.
Topics: Animals; Manduca; Odorants; Olfactory Receptor Neurons; Receptors, GABA; Synaptic Transmission; gamma-Aminobutyric Acid
PubMed: 9929641
DOI: 10.1111/j.1749-6632.1998.tb10608.x -
BMC Neuroscience Feb 2020Synaptic degeneration and accumulation of amyloid β-peptides (Aβ) are hallmarks of the Alzheimer diseased brain. Aβ is synaptotoxic and produced by sequential...
BACKGROUND
Synaptic degeneration and accumulation of amyloid β-peptides (Aβ) are hallmarks of the Alzheimer diseased brain. Aβ is synaptotoxic and produced by sequential cleavage of the amyloid precursor protein (APP) by the β-secretase BACE1 and by γ-secretase. If APP is instead cleaved by the α-secretase ADAM10, Aβ will not be generated. Although BACE1 is considered to be a presynaptic protein and ADAM10 has been reported to mainly localize to the postsynaptic density, we have previously shown that both ADAM10 and BACE1 are highly enriched in synaptic vesicles of rat brain and mouse primary hippocampal neurons.
RESULTS
Here, using brightfield proximity ligation assay, we expanded our previous result in primary neurons and investigated the in situ synaptic localization of ADAM10 and BACE1 in rat and human adult brain using both pre- and postsynaptic markers. We found that ADAM10 and BACE1 were in close proximity with both the presynaptic marker synaptophysin and the postsynaptic marker PSD-95. The substrate APP was also detected both pre- and postsynaptically. Subcellular fractionation confirmed that ADAM10 and BACE1 are enriched to a similar degree in synaptic vesicles and as well as in the postsynaptic density.
CONCLUSIONS
We show that the α-secretase ADAM10 and the β-secretase BACE1 are located in both the pre- and postsynaptic compartments in intact brain sections. These findings increase our understanding of the regulation of APP processing, thereby facilitating development of more specific treatment strategies.
Topics: ADAM10 Protein; Aged; Aged, 80 and over; Amyloid Precursor Protein Secretases; Amyloid beta-Protein Precursor; Animals; Aspartic Acid Endopeptidases; Brain; Female; Humans; Male; Membrane Proteins; Neurons; Rats, Wistar; Synapses; Synaptophysin
PubMed: 32019490
DOI: 10.1186/s12868-020-0554-0 -
Neuron Dec 1988Long-term potentiation (LTP) is a long-lasting enhancement of synaptic transmission that can be induced by brief repetitive stimulation of excitatory pathways in the...
Long-term potentiation (LTP) is a long-lasting enhancement of synaptic transmission that can be induced by brief repetitive stimulation of excitatory pathways in the hippocampus. One of the most controversial points is whether the process underlying the enhanced synaptic transmission occurs pre- or postsynaptically. To examine this question, we have taken advantage of the novel physiological properties of excitatory synaptic transmission in the CA1 region of the hippocampus. Synaptically released glutamate activates both NMDA and non-NMDA receptors on pyramidal cells, resulting in an excitatory postsynaptic potential (EPSP) with two distinct components. A selective increase in the non-NMDA component of the EPSP was observed with LTP. This result suggests that the enhancement of synaptic transmission during LTP is caused by an increased sensitivity of the postsynaptic neuron to synaptically released glutamate.
Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Aspartic Acid; Glutamates; Hippocampus; Membrane Potentials; N-Methylaspartate; Quinoxalines; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Synapses; Synaptic Transmission
PubMed: 2908443
DOI: 10.1016/0896-6273(88)90148-1 -
Metabotropic glutamate receptors in the cerebellum with a focus on their function in Purkinje cells.Cerebellum (London, England) 2002Metabotropic glutamate receptors (mGluRs) are a family of proteins that have seven transmembrane segments and that couple to G proteins. They differ from ionotropic... (Review)
Review
Metabotropic glutamate receptors (mGluRs) are a family of proteins that have seven transmembrane segments and that couple to G proteins. They differ from ionotropic glutamate receptors in that they do not form ion channels but instead affect intracellular chemical messenger systems. Eight genes coding for different subtypes of mGluRs have been identified to date and numbered accordingly in the order in which the cDNAs were cloned. Based on their principal signal-transduction capabilities in recombinant expression systems and sequence similarities, the family of mGluR subtypes is subdivided into three groups. Group 1 mGluRs (consisting of mGluR1 and 5) functionally couple to phospholipase C and affect the IP3/Ca2+ signaling pathway. The subtypes of group 2 (mGluR2 and 3) and group 3 (mGluR4, 6 7 and 8) inhibit adenylate cyclase and, thereby, mediate a decrease in cAMP concentration. All mGluR subtypes are found in the cerebellar cortex with the exception of mGluR6 which is exclusively expressed in the retina. At the parallel fiber-Purkinje cell synapses mGluR1 is localized in the peri- and extra-synaptic membrane of Purkinje cells. The main focus of this review deals with the functions of this postsynaptically localized mGluR1. These functions include (i) mediation of an inward current and a slow excitatory postsynaptic potential, and (ii) a role in induction of parallel fiber-Purkinje cell long-term depression. We discuss the mechanism underlying the mGluR1-mediated postsynaptic current as well as current theories on the role of mGluR1 in parallel fiber-Purkinje cell long-term depression.
Topics: Animals; Humans; Long-Term Synaptic Depression; Models, Neurological; Presynaptic Terminals; Purkinje Cells; Receptors, Metabotropic Glutamate; Second Messenger Systems; Synaptic Membranes; Synaptic Transmission
PubMed: 12879970
DOI: 10.1007/BF02941886 -
Journal of Controlled Release :... Feb 2024Conventional transnasal brain-targeted drug delivery strategies are limited by nasal cilia clearance and the nasal mucosal barrier. To address this challenge, we...
Conventional transnasal brain-targeted drug delivery strategies are limited by nasal cilia clearance and the nasal mucosal barrier. To address this challenge, we designed dissolving microneedles combined with nanocarriers for enhanced nose-to-brain drug delivery. To facilitate transnasal administration, a toothbrush-like microneedle patch was fabricated with hyaluronic acid-formed microneedles and tannic acid-crosslinked gelatin as the base, which completely dissolved in the nasal mucosa within seconds leaving only the base, thereby releasing the loaded cyclodextrin-based metal-organic frameworks (CD-MOFs) without affecting the nasal cilia and nasal microbial communities. As nanocarriers for high loading of huperzine A, these potassium-structured CD-MOFs, reinforced with stigmasterol and functionalized with lactoferrin, possessed improved physical stability and excellent biocompatibility, enabling efficient brain-targeted drug delivery. This delivery system substantially attenuated HO- and scopolamine-induced neurocyte damage. The efficacy of huperzine A on scopolamine- and D-galactose & AlCl-induced memory deficits in rats was significantly improved, as evidenced by inhibiting acetylcholinesterase activity, alleviating oxidative stress damage in the brain, and improving learning function, meanwhile activating extracellular regulated protein kinases-cyclic AMP responsive element binding protein-brain derived neurotrophic factor pathway. Moreover, postsynaptic density protein PSD-95, which interacts with two important therapeutic targets Tau and β-amyloid in Alzheimer's disease, was upregulated. This fruitful treatment was further shown to significantly ameliorate Tau hyperphosphorylation and decrease β-amyloid by ways including modulating beta-site amyloid precursor protein cleaving enzyme 1 and a disintegrin and metalloproteinase 10. Collectively, such a newly developed strategy breaks the impasse for efficient drug delivery to the brain, and the potential therapeutic role of huperzine A for Alzheimer's disease is further illustrated.
Topics: Animals; Rats; Alzheimer Disease; Acetylcholinesterase; Hydrogen Peroxide; Brain; Nasal Mucosa; Amyloid beta-Peptides; Scopolamine; Cyclodextrins; Alkaloids; Sesquiterpenes; Polyphenols
PubMed: 38219911
DOI: 10.1016/j.jconrel.2024.01.013 -
Journal of Neurocytology Jun 1975The ultrastructure of synaptic junctions in whole brain tissue and isolated synaptic membranes has been compared. Type 1 junctions are present in the isolated... (Comparative Study)
Comparative Study
The ultrastructure of synaptic junctions in whole brain tissue and isolated synaptic membranes has been compared. Type 1 junctions are present in the isolated membranes,readily identified by the presence of dense-staining material associated with the postsynaptic membrane, but the dense projections present at the presynaptic membrane in intact tissue are absent. Type 2 junctions are not easily recognized because of the absence of prominent junctional densities, but apposed membranes with the appearance of type 2 junctions are seen in isolated membrane preparations. Junctions without dense-staining material are also seen among SYNAPtosomes and survive the hypotonic conditions used during isolation of the membranes. It thus seems probable that both type 1 and 2 junctions are present in isolated synaptic membrane preparations. In type 1 junctions after isolation,the postsynaptic thickening and cleft substance are together seen to be composed of an array of 200 A dense-staining subunits spanning the postsynaptic unit membrane. The relationship of this structure to the ultrastructure of the cleft substance and postsynapticthickening in intact tissue is discussed.
Topics: Animals; Brain; Cell Fractionation; Microscopy, Electron; Rats; Synapses; Synaptic Membranes; Synaptosomes
PubMed: 1133593
DOI: 10.1007/BF01102118 -
Progress in Neurobiology Jul 1995The inhibitory neurotransmitter GABA acts in the mammalian brain through two different receptor classes: GABAA and GABAB receptors. GABAB receptors differ fundamentally... (Review)
Review
The inhibitory neurotransmitter GABA acts in the mammalian brain through two different receptor classes: GABAA and GABAB receptors. GABAB receptors differ fundamentally from GABAA receptors in that they require a G-protein. GABAB receptors are located pre- and/or post-synaptically, and are coupled to various K+ and Ca2+ channels presumably through both a membrane delimited pathway and a pathway involving second messengers. Baclofen, a selective GABAB receptor agonist, as well as GABA itself have pre- and post-synaptic effects. Pre-synaptic effects comprise the reduction of the release of excitatory and inhibitory transmitters. GABAergic receptors on GABAergic terminals may regulate GABA release, however, in most instances spontaneous inhibitory synaptic activity is not modulated by endogenous GABA. Post-synaptic GABAB receptor-mediated inhibition is likely to occur through a membrane delimited pathway activating K+ channels, while baclofen, in some neurons, may activate K+ channels through a second messenger pathway involving arachidonic acid. Some, but not all GABAB receptor-gated K+ channels have the typical properties of those G-protein-activated K+ channels which are also gated by other endogenous ligands of the brain. New, high affinity GABAB antagonists are now available, and some pharmacological evidence points to a receptor heterogeneity. The pharmacological distinction of receptor subtypes, however, has to await final support from a characterization of the molecular structure. The function importance of post-synaptic GABAB receptors is highlighted by a segregation of GABAA and GABAB synapses in the mammalian brain.
Topics: Animals; Autoreceptors; Baclofen; Central Nervous System; Potassium Channels; Receptors, GABA-B
PubMed: 8532848
DOI: 10.1016/0301-0082(95)00012-k -
The Journal of Comparative Neurology Feb 1977Receptoneural junctions and synapses in the organ of Corti of the chinchilla have been examined with the freeze-fracture technique. The presynaptic membranes at the...
Receptoneural junctions and synapses in the organ of Corti of the chinchilla have been examined with the freeze-fracture technique. The presynaptic membranes at the receptoneural junctions of inner and outer hair cells have many structural features in common with membranes found at chemical synapses outside the organ of Corti. However, the membranes of the postsynaptic afferent terminals are quite different depending on whether they are part of an inner or outer hair cell synapse. These differences in the distribution of intramembrane particles suggest that the transmitters, or transmitter actions, may be different at these two synapses. The distribution of particles in the postsynaptic membrane at efferent synapses with outer hair cell differs from that in the postsynaptic membrane at efferent synapses with afferent terminals or fibers, suggesting that transmitter actions at these locations could also differ.
Topics: Animals; Chinchilla; Female; Freeze Fracturing; Male; Microscopy, Electron; Organ of Corti; Rabbits; Synapses; Synaptic Membranes
PubMed: 833356
DOI: 10.1002/cne.901710407 -
Annals of the New York Academy of... Jun 1999Radioligand binding experiments carried out in cell membranes from rat and human stomach revealed the existence of non-adrenoceptor [3H]clonidine and [3H]idazoxan... (Review)
Review
Radioligand binding experiments carried out in cell membranes from rat and human stomach revealed the existence of non-adrenoceptor [3H]clonidine and [3H]idazoxan binding sites and of [3H]DTG (1,2-di-(2-tolyl)guanidine) binding sites. In rat stomach, specific binding was inhibited by imidazolines and guanidines and by non-imidazoline sigma-site ligands, respectively, at different rank orders of affinity, suggesting the existence of non-I1/non-I2 [3H]clonidine binding sites, I2-imidazoline binding sites as well as sigma 2-like-sites. These sites are not directly related to a postsynaptic contractile effect on rat gastric smooth muscle or to acid release from isolated gastric glands. Finally, we demonstrated that the gastric pathogen Helicobacter pylori is able to form and to release the endogenous imidazoline receptor ligand agmatine and that considerable amounts of agmatine are present in human gastric juice. The quantities of agmatine were higher in gastric juice from H. pylori-positive than H. pylori-negative patients.
Topics: Animals; Binding Sites; Gastric Acid; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Imidazoles; Imidazoline Receptors; Rats; Receptors, Drug; Stomach
PubMed: 10415933
DOI: 10.1111/j.1749-6632.1999.tb09377.x