P3-169: OPTOGENETIC QUANTAL ANALYSIS OF BASAL FOREBRAIN SYNAPTIC TRANSMISSION WITH PHARMACOLOGICAL TESTING OF SYNAPTIC ACTIVITY WITH GLUTAMATE AND CALCIUM MODULATORS

It has been proposed that the small volume of a dendritic spine can amplify Ca2+ signals during synaptic transmission. Accordingly, we have performed calculations to determine whether the activation of N-methyl-D-aspartate (NMDA) type glutamate receptors during synaptic transmission results in significant elevation in intracellular Ca2+ levels, permitting optical detection of synaptic signals within a single spine. Simple calculations suggest that the opening of even a single NMDA receptor would result in the influx of ~ 310 000 Ca2+ ions into the small volume of a spine, producing changes in Ca2+ levels that are readily detectable using high affinity Ca2+ indicators such as fura-2 or fluo-3. Using fluorescent Ca2+ indicators, we have imaged local Ca2+ transients mediated by NMDA receptors in spines and dendritic shafts attributed to spontaneous miniature synaptic activity. Detailed analysis of these quantal events suggests that the current triggering these transients is attributed to the activation of <10 NMDA receptors. The frequency of these miniature synaptic Ca2+ transients is not randomly distributed across synapses, as some synapses can display a >10-fold higher frequency of transients than others. As expected for events mediated by NMDA receptors, miniature synaptic Ca2+ transients were suppressed by extracellular Mg2+ at negative membrane potentials; however, the Mg2+ block could be removed by depolarization.Key words: miniature release, N-methyl-D-aspartate (NMDA), calcium, glutamate, spine.

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GPI-1046 Increases Presenilin-1 Expression and Restores NMDA Channel Activity

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100010465 ◽

2010 ◽

Vol 37 (4) ◽

pp. 457-467 ◽

Cited By ~ 3

Author(s):

Joseph P. Steiner ◽

Kathryn B. Payne ◽

Christopher Drummond Main ◽

Sabrina D'Alfonso ◽

Kirsten X. Jacobsen ◽

...

Keyword(s):

Nmda Receptor ◽

Synaptic Transmission ◽

Brain Slices ◽

Synaptic Activity ◽

Presenilin 1 ◽

Receptor Function ◽

Channel Function ◽

Nmda Channel ◽

Nmda Receptor Function ◽

6 Hydroxydopamine

Background:Previously we showed that 6-hydroxydopamine lesions of the substantia nigra eliminate corticostriatal LTP and that the neuroimmunolophilin ligand (NIL), GPI-1046, restores LTP.Methods:We used cDNA microarrays to determine what mRNAs may be over- or under-expressed in response to lesioning and/or GPI-1046 treatment. Patch clamp recordings were performed to investigate changes in NMDA channel function before and after treatments.Results:We found that 51 gene products were differentially expressed. Among these we found that GPI-1046 treatment up-regulated presenilin-1 (PS-1) mRNA abundance. This finding was confirmed using QPCR. PS-1 protein was also shown to be over-expressed in the striatum of lesioned/GPI-1046-treated rats. As PS-1 has been implicated in controlling NMDA-receptor function and LTP is reduced by lesioning we assayed NMDA mediated synaptic activity in striatal brain slices. The lesion-induced reduction of dopaminergic innervation was accompanied by the near complete loss of NDMA receptor-mediated synaptic transmission between the cortex and striatum. GPI-1046 treatment of the lesioned rats restored NMDA-mediated synaptic transmission but not the dopaminergic innervation. Restoration of NDMA channel function was apparently specific as the sodium channel current density was also reduced due to lesioning but GPI-1046 did not reverse this effect. We also found that restoration of NMDA receptor function was also not associated with either an increase in NMDA receptor mRNA or protein expression.Conclusion:As it has been previously shown that PS-1 is critical for normal NMDA receptor function, our data suggest that the improvement of excitatory neurotransmission occurs through the GPI-1046-induced up-regulation of PS-1.

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NMDA Receptor-Dependent Synaptic Activity in Dorsal Motor Nucleus of Vagus Mediates the Enhancement of Gastric Motility by Stimulating ST36

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/438460 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 9

Author(s):

Xinyan Gao ◽

Yongfa Qiao ◽

Baohui Jia ◽

Xianghong Jing ◽

Bin Cheng ◽

...

Keyword(s):

Synaptic Transmission ◽

Gastric Motility ◽

Low Frequency ◽

Synaptic Activity ◽

Motor Nucleus ◽

Dorsal Motor Nucleus ◽

Vagal Reflex ◽

Precise Molecular Mechanism ◽

Lines Of Evidence

Previous studies have demonstrated the efficacy of electroacupuncture at ST36 for patients with gastrointestinal motility disorders. While several lines of evidence suggest that the effect may involve vagal reflex, the precise molecular mechanism underlying this process still remains unclear. Here we report that the intragastric pressure increase induced by low frequency electric stimulation at ST36 was blocked by AP-5, an antagonist of N-methyl-D-aspartate receptors (NMDARs). Indeed, stimulating ST36 enhanced NMDAR-mediated, but not 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic-acid-(AMPA-) receptor-(AMPAR-) mediated synaptic transmission in gastric-projecting neurons of the dorsal motor nucleus of the vagus (DMV). We also identified that suppression of presynapticμ-opioid receptors may contribute to upregulation of NMDAR-mediated synaptic transmission induced by electroacupuncture at ST36. Furthermore, we determined that the glutamate-receptor-2a-(NR2A-) containing NMDARs are essential for NMDAR-mediated enhancement of gastric motility caused by stimulating ST36. Taken together, our results reveal an important role of NMDA receptors in mediating enhancement of gastric motility induced by stimulating ST36.

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Late-onset, short-term intermittent fasting reverses age-related changes in calcium buffering and inhibitory synaptic transmission in mouse basal forebrain neurons

Journal of Neuroscience ◽

10.1523/jneurosci.1442-21.2021 ◽

2021 ◽

pp. JN-RM-1442-21

Author(s):

Eunyoung Bang ◽

Annette S. Fincher ◽

Sophie Nader ◽

David A. Murchison ◽

William H. Griffith

Keyword(s):

Synaptic Transmission ◽

Basal Forebrain ◽

Late Onset ◽

Intermittent Fasting ◽

Short Term ◽

Inhibitory Synaptic Transmission ◽

Age Related ◽

Calcium Buffering ◽

Mouse Basal Forebrain ◽

Age Related Changes

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The Cellular Prion Protein Prevents Copper-Induced Inhibition of P2X4Receptors

International Journal of Alzheimer s Disease ◽

10.4061/2011/706576 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6

Author(s):

Ramón A. Lorca ◽

Lorena Varela-Nallar ◽

Nibaldo C. Inestrosa ◽

J. Pablo Huidobro-Toro

Keyword(s):

Amino Acids ◽

Synaptic Transmission ◽

Prion Protein ◽

Adenosine Triphosphate ◽

Response Curve ◽

Physiological Function ◽

Cellular Prion Protein ◽

Synaptic Activity ◽

Receptor Subtype ◽

Concentration Response Curve

Although the physiological function of the cellular prion protein (PrPC) remains unknown, several evidences support the notion of its role in copper homeostasis. PrPCbinds Cu2+through a domain composed by four to five repeats of eight amino acids. Previously, we have shown that the perfusion of this domain prevents and reverses the inhibition by Cu2+of the adenosine triphosphate (ATP)-evoked currents in the P2X4receptor subtype, highlighting a modulatory role for PrPCin synaptic transmission through regulation of Cu2+levels. Here, we study the effect of full-length PrPCin Cu2+inhibition of P2X4receptor when both are coexpressed. PrPCexpression does not significantly change the ATP concentration-response curve in oocytes expressing P2X4receptors. However, the presence of PrPCreduces the inhibition by Cu2+of the ATP-elicited currents in these oocytes, confirming our previous observations with the Cu2+binding domain. Thus, our observations suggest a role for PrPCin modulating synaptic activity through binding of extracellular Cu2+.

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5-HT Prolongs Ventral Root Bursting Via Presynaptic Inhibition of Synaptic Activity During Fictive Locomotion in Lamprey

Journal of Neurophysiology ◽

10.1152/jn.00669.2004 ◽

2005 ◽

Vol 93 (2) ◽

pp. 980-988 ◽

Cited By ~ 34

Author(s):

Eric J. Schwartz ◽

Tatyana Gerachshenko ◽

Simon Alford

Keyword(s):

Synaptic Transmission ◽

Presynaptic Inhibition ◽

Cellular Level ◽

Ventral Horn ◽

Pattern Generation ◽

Ventral Root ◽

Synaptic Activity ◽

Fictive Locomotion ◽

Cellular Mechanisms ◽

Bath Application

Locomotor pattern generation is maintained by integration of the intrinsic properties of spinal central pattern generator (CPG) neurons in conjunction with synaptic activity of the neural network. In the lamprey, the spinal locomotor CPG is modulated by 5-HT. On a cellular level, 5-HT presynaptically inhibits synaptic transmission and postsynaptically inhibits a Ca2+-activated K+ current responsible for the slow afterhyperpolarization (sAHP) that follows action potentials in ventral horn neurons. To understand the contribution of these cellular mechanisms to the modulation of the spinal CPG, we have tested the effect of selective 5-HT analogues against fictive locomotion initiated by bath application of N-methyl-d-aspartate (NMDA). We found that the 5-HT1D agonist, L694-247, dramatically prolongs the frequency of ventral root bursting. Furthermore, we show that L694-247 presynaptically inhibits synaptic transmission without altering postsynaptic Ca2+ -activated K+ currents. We also confirm that 5-HT inhibits synaptic transmission at concentrations that modulate locomotion. To examine the mechanism by which selective presynaptic inhibition modulates the frequency of fictive locomotion, we performed voltage- and current-clamp recordings of CPG neurons during locomotion. Our results show that 5-HT decreases glutamatergic synaptic drive within the locomotor CPG during fictive locomotion. Thus we conclude that presynaptic inhibition of neurotransmitter release contributes to 5-HT–mediated modulation of locomotor activity.

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Dopamine Modulates Synaptic Transmission in the Nucleus of the Solitary Tract

Journal of Neurophysiology ◽

10.1152/jn.00224.2002 ◽

2002 ◽

Vol 88 (5) ◽

pp. 2736-2744 ◽

Cited By ~ 76

Author(s):

David D. Kline ◽

Kristin N. Takacs ◽

Eckhard Ficker ◽

Diana L. Kunze

Keyword(s):

Synaptic Transmission ◽

Nucleus Tractus Solitarius ◽

Integration Site ◽

Cell Voltage ◽

Input Resistance ◽

D2 Receptors ◽

Synaptic Activity ◽

Solitary Tract ◽

Afferent Fibers ◽

Sensory Fibers

10.1152/jn.00224.2002. Dopamine (DA) modulates the cardiorespiratory reflex by peripheral and central mechanisms. The aim of this study was to examine the role of DA in synaptic transmission of the nucleus tractus solitarius (NTS), the major integration site for cardiopulmonary reflexes. To examine DA's role, we used whole cell, voltage-clamp recordings in a rat horizontal brain stem slice. Solitary tract stimulation evoked excitatory postsynaptic currents (EPSCs) that were reduced to 70 ± 5% of control by DA (100 μM). The reduction in EPSCs by DA was accompanied by a decrease in the paired pulse depression ratio with little or no change in input resistance or EPSC decay, suggesting a presynaptic mechanism. The D1-like agonist SKF 38393 Br (30 μM) did not alter EPSC amplitude, whereas the D2-like agonist, quinpirole HCl (30 μM), depressed EPSCs to 73 ± 4% of control. The D2-like receptor antagonist, sulpiride (20 μM), abolished DA modulation of EPSCs. Most importantly, sulpiride alone increased EPSCs to 131 ± 10% of control, suggesting a tonic D2-like modulation of synaptic transmission in the NTS. Examination of spontaneous EPSCs revealed DA reversibly decreased the frequency of events from 9.4 ± 2.2 to 6.2 ± 1.4 Hz. Sulpiride, however, did not alter spontaneous events. Immunohistochemistry of NTS slices demonstrated that D2 receptors colocalized with synaptophysin and substance P, confirming a presynaptic distribution. D2 receptors also localized to cultured petrosal neurons, the soma of presynaptic afferent fibers. In the petrosal neurons, D2 was found in cells that were TH-immunopositive, suggesting they were chemoreceptor afferent fibers. These results demonstrate that DA tonically modulates synaptic activity between afferent sensory fibers and secondary relay neurons in the NTS via a presynaptic D2-like mechanism.

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