PURPOSE: Modafinil is a wake-promoting agent that has been proposed to improve cognitive performance at the preclinical and clinical levels. Since there is insufficient evidence for modafinil to be regarded as a cognitive enhancer, the aim of this study was to investigate the effects of chronic modafinil administration on behavioral learning in healthy adult rats. METHODS: Y-maze training was used to assess learning performance, and the whole-cell patch clamp technique was used to assess synaptic transmission in pyramidal neurons of the hippocampal CA1 region of rats. RESULTS: Intraperitoneal administration of modafinil at 200 mg/kg or 300 mg/kg significantly improved learning performance. Furthermore, perfusion with 1mM modafinil enhanced the frequency and amplitude of spontaneous postsynaptic currents and spontaneous excitatory postsynaptic currents in CA1 pyramidal neurons in hippocampal slices. However, the frequency and amplitude of spontaneous inhibitory postsynaptic currents in CA1 pyramidal neurons were inhibited by treatment with 1mM modafinil. CONCLUSIONS: These results indicate that modafinil improves learning and memory in rats possibly by enhancing glutamatergic excitatory synaptic transmission and inhibiting GABAergic (gamma-aminobutyric acid-ergic) inhibitory synaptic transmission.
Adult ; Animals ; CA1 Region, Hippocampal ; Excitatory Postsynaptic Potentials ; Humans ; Inhibitory Postsynaptic Potentials ; Learning* ; Memory ; Neurons ; Perfusion ; Rats* ; Synaptic Potentials ; Synaptic Transmission*

Neurotransmission begins with neurotransmitter being released from synaptic vesicles. To achieve this function, synaptic vesicles endure the dynamic "release-recycle" process to maintain the function and structure of presynaptic terminal. Synaptic transmission starts with a single action potential that depolarizes axonal bouton, followed by an increase in the cytosolic calcium concentration that triggers the synaptic vesicle membrane fusion with presynaptic membrane to release neurotransmitter; then the vesicle membrane can be endocytosed for reusing afterwards. This process requires delicate regulation, intermediate steps and dynamic balances. Accumulating evidence showed that the release ability and mobility of synapses varies under different stimulations. Synaptic vesicle heterogeneity has been studied at molecular and cellular levels, hopefully leading to the identification of the relationships between structure and function and understanding how vesicle regulation affects synaptic transmission and plasticity. People are beginning to realize that different types of synapses show diverse presynaptic activities. The steady advances of technology studying synaptic vesicle recycling promote people's understanding of this field. In this review, we discuss the following three aspects of the research progresses on synaptic vesicle recycling: 1) presynaptic vesicle pools and recycling; 2) research progresses on the differences of glutamatergic and GABAergic presynaptic vesicle recycling mechanism and 3) comparison of the technologies used in studying presyanptic vesicle recycling and the latest progress in the technology development in this field.
Action Potentials ; Axons ; physiology ; Calcium ; physiology ; Endocytosis ; Humans ; Presynaptic Terminals ; physiology ; Synapses ; physiology ; Synaptic Transmission ; Synaptic Vesicles ; physiology

BACKGROUND: Although there have been reports showing the changes of the auditory brainstem response (ABR) waves by propofol, no detailed studies have been done at the level of brainstem auditory circuit. So, we studied the effects of propofol on the postsynaptic currents of the medial nucleus of the trapezoid body (MNTB)-lateral superior olive (LSO) synapses by using the whole cell voltage clamp technique and we compared this data with that obtained by the ABR. METHODS: 5 rats at postnatal (P) 15 days were used for the study of the ABR. After inducing deep anesthesia using xylazine 6 mg/kg and ketamine 25 mg/kg, the ABRs were recorded before and after intraperitoneal propofol injection (10 mg/kg) and the effects of propofol on the latencies of the I, III, and V waves and the I-III and III-V interwave intervals were evaluated. Rats that were aged under P11 were used in the voltage clamp experiments. After making brainstem slices, the postsynaptic currents (PSCs) elicited by MNTB stimulation were recorded at the LSO, and the changes of the PSCs by the bath application of propofol (100 microM) were monitored. RESULTS: We found small, but statistically significant increases in the latencies of ABR waves III and V and the interwave intervals of I-III and III-V by propofol. However, no significant changes were observed in the glycinergic or glutamatergic PSCs of the MNTB-LSO synpases by the application of propofol (100 microM). CONCLUSIONS: Glycinergic or glutamatergic transmission of the MNTB-LSO synapses might not contribute to the propofol-induced changes of the ABR.
Aged ; Anesthesia ; Animals ; Baths ; Brain Stem ; Evoked Potentials, Auditory, Brain Stem ; Humans ; Ketamine ; Olea ; Propofol ; Rats ; Synapses ; Synaptic Potentials ; Xylazine

BACKGROUND AND OBJECTIVES: We are developing an in vitro preparation of the mouse inner ear so as to study morphophysiologic character of primary vestibular afferents and synaptic transmission within the vestibular epithelium. MATERIALS AND METHOD: We have intra-axonally recorded from over 300 ampullary fibers, close to the base of their respective anterior and lateral crista (<500 micrometer from hair cell/afferent nerve synapse), and labelled as a sub-set of these with biocytin (n=71). Discharge activity can be classified as regular or irregular based on the variation of the interspike interval (coefficient of variation). Using a micropusher to indent exposed windows of membranous labyrinth, we have characterized the response properties of both anterior and horizontal canal afferents. We studied afferent activity in response to sinusoidal indentations of anterior and horizontal membranous canal. RESULTS: The majority of labelled units were dimorphic (56 out of 71), having both calyx and bouton terminals and there was no labelled bouton terminal. Whether action potentials (Aps) were spontaneous or elicited with current, a heterogeneity of discharge activity was observed and these were similar to those previously reported in in vivo recordings from other mammalian species. In recordings over a range of frequencies from 0.01 to 10.0Hz, afferents responded with sinusoidal changes at discharge rates and modulation of membrane potential in a predictable manner. The phase response of the afferent discharge was characterized by frequency-dependent shifts in peak activity. The peak activity of anterior canal was in advance of the maximum indentation (180dgrees out of phase), with largest phase leads at 0.01 Hz (59.2+/-14.1dgrees) and the smallest phase leads occurring at 1.0 Hz (13.4+/-9.3dgrees), while maximum indentation was in advance of the peak activity at 10.0 Hz (-17.6+/-9.1dgrees). These phase shifts were similar to those reported in in vivo recordings from mammals, despite our use of artificial rather than natural rotational stimuli. CONCLUSION: We developed an in-vitro mouse model to study morphophysiologic characteristics of primary vestibular afferent nerve and synaptic transmission.
Action Potentials ; Animals ; Ear, Inner* ; Electrophysiology ; Epithelium ; Hair ; Mammals ; Membrane Potentials ; Mice* ; Population Characteristics ; Semicircular Canals ; Synaptic Transmission

The biological effect on the organism generated by magnetic field is widely studied. The present study was aimed to observe the change of sodium channel under magnetic field in neurons. Cortical neurons of Kunming mice were isolated, subjected to 15 Hz, 1 mT pulse magnetic stimulation, and then the currents of neurons were recorded by whole-cell patch clamp. The results showed that, under magnetic stimulation, the activation process of Na(+) channel was delayed, and the inactivation process was accelerated. Given the classic three-layer model, the polarization diagram of cell membrane potential distribution under pulse magnetic field was simulated, and it was found that the membrane potential induced was associated with the frequency and intensity of magnetic field. Also the effect of magnetic field-induced current on action potential was simulated by Hodgkin-Huxley (H-H) model. The result showed that the generation of action potential was delayed, and frequency and the amplitudes were decreased when working current was between -1.32 μA and 0 μA. When the working current was higher than 0 μA, the generation frequency of action potential was increased, and the change of amplitudes was not obvious, and when the working current was lower than -1.32 μA, the time of rising edge and amplitudes of action potential were decreased drastically, and the action potential was unable to generate. These results suggest that the magnetic field simulation can affect the distribution frequency and amplitude of action potential of neuron via sodium channel mediation.
Action Potentials ; Animals ; Magnetic Fields ; Membrane Potentials ; Mice ; Neurons ; cytology ; Patch-Clamp Techniques ; Sodium Channels ; physiology ; Synaptic Transmission

We report here a patient with major depressive disorder who experienced severe adverse effects after the administration of SSRIs (serotonin selective reuptake inhibitors) without improvement of his depressive symptoms. These adverse effects disappeared and his depressive symptoms improved after discontinuation of the SSRIs and the administration of tianeptine. The patient exhibited a low value for the loudness dependent of auditory evoked potentials (LDAEP) -0.14 at baseline, which means that his central serotonergic neurotransmission was already highly active. We assumed that it was this high serotonergic activity that rendered him unresponsive to SSRIs, and brought on him the adverse effects, and that the tianeptine was effective due to the lack of serotonin reuptake inhibitory action. Thus, we suggest that LDAEP can be used to predict an individual patient's tolerability and clinical response to SSRIs in major depression.
Depression ; Depressive Disorder, Major ; Evoked Potentials, Auditory ; Humans ; Serotonin ; Synaptic Transmission ; Thiazepines

Isoliquiritigenin (ILTG) is a chalcone compound and shows various pharmacological properties, including antioxidant and anti-inflammatory activities. In recent study, we have reported a novel role of ILTG in sleep through a positive allosteric modulation of gamma-aminobutyric acid type A (GABA(A))-benzodiazepine (BZD) receptors. However, the effect of ILTG in GABA(A)R-mediated synaptic response in brain has not been tested yet. Here we report that ILTG significantly prolonged the decay of spontaneous inhibitory postsynaptic currents (sIPSCs) mediated by GABA(A)R in mouse hippocampal CA1 pyramidal neurons without affecting amplitude and frequency of sIPSCs. This enhancement was fully inhibited by flumazenil (FLU), a specific GABA(A)-BZD receptor antagonist. These results suggest a potential role of ILTG as a modulator of GABAergic synaptic transmission.
Animals ; Brain ; Chalcone* ; Flumazenil ; gamma-Aminobutyric Acid ; Inhibitory Postsynaptic Potentials ; Mice ; Neurons ; Synaptic Transmission

Previous studies have suggested that brain stem noradrenergic inputs differentially modulate neurons in the paraventricular nucleus (PVN). Here, we compared the effects of norepinephrine (NE) on spontaneous GABAergic inhibitory postsynaptic currents (sIPSCs) in identified PVN neurons using slice patch technique. In 17 of 18 type I neurons, NE (30-100microM) reversibly decreased sIPSC frequency to 41+/-7% of the baseline value (4.4+/-0.8 Hz, p<0.001). This effect was blocked by yohimbine (2-20microM), an alpha2-adrenoceptor antagonist and mimicked by clonidine (50 microM), an alpha2-adrenoceptor agonist. In contrast, NE increased sIPSC frequency to 248+/-32% of the control (3.06+/-0.37 Hz, p<0.001) in 31 of 54 type II neurons, but decreased the frequency to 41+/-7% of the control (5.5+/-1.3 Hz) in the rest of type II neurons (p<0.001). In both types of PVN neurons, NE did not affect the mean amplitude and decay time constant of sIPSCs. In addition, membrane input resistance and amplitude of sIPSC of type I neurons were larger than those of type II neurons tested (1209 vs. 736 M omega, p<0.001; 110 vs. 81 pS, p<0.001). The results suggest that noradrenergic modulation of inhibitory synaptic transmission in the PVN decreases the neuronal excitability in most type I neurons via alpha2-adrenoceptor, however, either increases in about 60% or decreases in 40% of type II neurons.
Brain Stem ; Clonidine ; Inhibitory Postsynaptic Potentials* ; Membranes ; Neurons ; Norepinephrine ; Paraventricular Hypothalamic Nucleus* ; Synaptic Transmission ; Yohimbine

Because synaptic refinement of medial nucleus of trapezoid body (MNTB) - lateral superior olive (LSO) synapses is most active during the first postnatal week and the long term depression (LTD) has been suggested as one of its mechanisms, LTD of MNTB-LSO synapses was investigated in neonatal rat brain stem slices with the whole cell voltage clamp technique. In Mg2+ free condition, tetanus (10 stimuli at 10 Hz for 2 min) in the current clamp mode induced a robust LTD of isolated D, L-APV-sensitive postsynaptic currents (PSCs) for more than 30 min (n=6, 2.4+/-0.4% of the control), while isolated CNQX-sensitive PSCs were not suppressed (n=6, 95.3+/-1.6%). Tetanus also elicited similar LTD in the isolated GABAergic/glycinergic PSCs (n=5, 3.6+/-0.5%) and mixed PSCs (GABAergic/glycinergic/glutamatergic) (n=4, 2.2+/-0.7%). However, such a strong LTD was not observed in the mixed PSCs when 10 mM EGTA was added in the internal solution (n=10), indicating that postsynaptic Ca2+ rise is needed for the strong LTD. This robust LTD might contribute to the active synaptic refinement occurring during the first postnatal week.
Animals ; Brain Stem ; Depression ; Egtazic Acid ; Olea ; Rats* ; Synapses* ; Synaptic Potentials ; Tetanus

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in vertebrate are reverse voltage-dependent, and its activation depends on the hyperpolarization of cell and may be directly or indirectly regulated by the cyclic adenosine monophosphate (cAMP) or other signal transduction cascades. The distribution, quantity, and activation states of HCN channels differ in tissues throughout the body. By modulating If/If current, HCN channels may influence the resting membrane potential, and thus importantly regulate neuronal excitability, dendritic integration of synaptic potentials, and synaptic transmission. Evidence exhibits that HCN channels participate in pain and other physiological and pathological process. Pharmacological treatment targeting HCN channels is of benefit to relieve pain and other related diseases.
Humans ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ; physiology ; Membrane Potentials ; Pain ; physiopathology ; Potassium Channels ; Synaptic Transmission