scholarly journals Colocalization of distinct NMDA receptor subtypes at excitatory synapses in the entorhinal cortex

2019 ◽  
Vol 121 (1) ◽  
pp. 238-254 ◽  
Author(s):  
Stephen Beesley ◽  
Thomas Sullenberger ◽  
Jyotsna Pilli ◽  
Saad Abbasi ◽  
Akash Gunjan ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Entorhinal Cortex ◽  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
Brain Regions ◽  
Subunit Composition ◽  
Negative Slope ◽  
Receptor Subtypes ◽  
Decay Kinetics ◽  
Synaptic Inputs

The subunit composition of N-methyl-d-aspartate receptors (NMDARs) at synaptic inputs onto a neuron can either vary or be uniform depending on the type of neuron and/or brain region. Excitatory pyramidal neurons in the frontal and somatosensory cortices (L5), for example, show pathway-specific differences in NMDAR subunit composition in contrast with the entorhinal cortex (L3), where we now show colocalization of NMDARs with distinct subunit compositions at individual synaptic inputs onto these neurons. Subunit composition was deduced electrophysiologically based on alterations of current-voltage relationship ( I–V) profiles, amplitudes, and decay kinetics of minimally evoked, pharmacologically isolated, NMDAR-mediated excitatory postsynaptic currents by known subunit-preferring antagonists. The I–Vs were outwardly rectifying in a majority of neurons assayed (~80%), indicating expression of GluN1/GluN2/GluN3-containing triheteromeric NMDARs ( t-NMDARs) and of the conventional type, reversing close to 0 mV with prominent regions of negative slope, in the rest of the neurons sampled (~20%), indicating expression of GluN1/GluN2-containing diheteromeric NMDARs ( d-NMDARs). Blocking t-NMDARs in neurons with outwardly rectifying I–Vs pharmacologically unmasked d-NMDARs, with all responses antagonized using D-AP5. Coimmunoprecipitation assays of membrane-bound protein complexes isolated from the medial entorhinal area using subunit-selective antibodies corroborated stoichiometry and together suggested the coexpression of t- and d-NMDARs at these synapses. Colocalization of functionally distinct NMDAR subtypes at individual synaptic inputs likely enhances the repertoire of pyramidal neurons for information processing and plasticity within the entorhinal cortex. NEW & NOTEWORTHY The subunit composition of a N-methyl-d-aspartate (NMDA) receptor, which dictates most aspects of its function, can vary between neurons in different brain regions and/or between synaptic inputs onto single neurons. Here we demonstrate colocalization of tri- and diheteromeric-NMDA receptors at the same/single synaptic input onto excitatory neurons in the entorhinal cortex. Synaptic colocalization of distinct NMDAR subtypes might endow entorhinal cortical neurons with the ability to encode distinct patterns of neuronal activity through single synapses.

Properties of amino acid neurotransmitter receptors of embryonic cortical neurons when activated by exogenous and endogenous agonists

1992 ◽  
Vol 67 (5) ◽  
pp. 1185-1200 ◽  
Author(s):  
M. G. Blanton ◽  
A. R. Kriegstein
Keyword(s):  
Amino Acid ◽  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Cortical Neurons ◽  
Nmda Receptor Antagonist ◽  
Chloride Ions ◽  
Negative Slope ◽  
Equilibrium Potential ◽  
Slow Response ◽  
Postmitotic Neurons

1. The properties of receptors for amino acid neurotransmitters expressed by developing cortical neurons were studied with the use of whole-cell recording in the intact cerebral cortex of embryonic turtles in vitro. The inhibitory agonist gamma-aminobutyric acid (GABA) and the excitatory agonist glutamate were focally applied to single cells under voltage clamp, and the ionic dependence, voltage dependence, and pharmacological sensitivity of the responses were characterized. The responses mediated by a glutamate receptor subtype, the N-methyl-D-aspartate (NMDA) receptor, produced by glutamate and by evoked release of an endogenous excitatory agonist, were compared further. Fluctuation analysis was used to characterize the properties of the NMDA channels and the mechanism of action of receptor antagonists. 2. When postmitotic neurons first appeared at stage 15, all neurons tested responded to GABA with a current that reversed at the equilibrium potential for chloride ions and that was sensitive to the GABAA receptor antagonist bicuculline methiodide (BMI). As development proceeded, an increasing proportion of neurons also responded with a BMI-insensitive current that reversed near the equilibrium potential for potassium ions. This current was blocked by the GABAB receptor antagonist 3-amino-2-propyl phosponic acid (phaclofen). The GABAB agonist baclofen, however, failed to produce a detectable postsynaptic current. 3. Neurons at stage 15 showed a biphasic response to glutamate that reversed at the equilibrium potential for cations. All neurons tested showed a slow, sustained response associated with an increase in current variance compared with background, and, as development proceeded, an increasing proportion also exhibited a fast, transient response. Both fast and slow responses varied linearly with voltage in the absence of Mg2+ ions, but the addition of Mg2+ ions to the bathing medium attenuated the slow response at hyperpolarized potentials. As a result, the current-voltage relation of the slow response in the presence of Mg2+ ions exhibited a region of negative slope conductance, like that of currents mediated by NMDA receptors. 4. The fast and slow responses to glutamate differed in their pharmacological sensitivity. The fast responses were sensitive to the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), whereas the slow responses were sensitive to the NMDA receptor antagonist D(-)-2-amino-5-phosphonovalerate (D-APV). 5. When cells were held at -70 mV, glutamate evoked a fluctuating current consisting of channel currents with a mean open time, tau, of 4.42 +/- 0.47 (SE) ms in early postmitotic neurons at stage 15 and 4.99 +/- 0.38 ms at stages 17-20.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Ampicillin/Sulbactam Treatment Modulates NMDA Receptor NR2B Subunit and Attenuates Neuroinflammation and Alcohol Intake in Male High Alcohol Drinking Rats

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1030 ◽  
Author(s):  
Fawaz Alasmari ◽  
Hasan Alhaddad ◽  
Woonyen Wong ◽  
Richard L. Bell ◽  
Youssef Sari
Keyword(s):  
Nmda Receptor ◽  
Alcohol Drinking ◽  
Glutamate Transporter ◽  
High Mobility ◽  
Ethanol Consumption ◽  
Brain Regions ◽  
Receptor Subtypes ◽  
High Alcohol ◽  
Necrosis Factor Alpha ◽  
Ethanol Drinking

Exposure to ethanol commonly manifests neuroinflammation. Beta (β)-lactam antibiotics attenuate ethanol drinking through upregulation of astroglial glutamate transporters, especially glutamate transporter-1 (GLT-1), in the mesocorticolimbic brain regions, including the nucleus accumbens (Acb). However, the effect of β-lactam antibiotics on neuroinflammation in animals chronically exposed to ethanol has not been fully investigated. In this study, we evaluated the effects of ampicillin/sulbactam (AMP/SUL, 100 and 200 mg/kg, i.p.) on ethanol consumption in high alcohol drinking (HAD1) rats. Additionally, we investigated the effects of AMP/SUL on GLT-1 and N-methyl-d-aspartate (NMDA) receptor subtypes (NR2A and NR2B) in the Acb core (AcbCo) and Acb shell (AcbSh). We found that AMP/SUL at both doses attenuated ethanol consumption and restored ethanol-decreased GLT-1 and NR2B expression in the AcbSh and AcbCo, respectively. Moreover, AMP/SUL (200 mg/kg, i.p.) reduced ethanol-increased high mobility group box 1 (HMGB1) and receptor for advanced glycation end-products (RAGE) expression in the AcbSh. Moreover, both doses of AMP/SUL attenuated ethanol-elevated tumor necrosis factor-alpha (TNF-α) in the AcbSh. Our results suggest that AMP/SUL attenuates ethanol drinking and modulates NMDA receptor NR2B subunits and HMGB1-associated pathways.

scholarly journals The molecular basis of NMDA receptor subtypes: native receptor diversity is predicted by subunit composition

1994 ◽  
Vol 14 (9) ◽  
pp. 5471-5484 ◽  
Author(s):  
AL Buller ◽  
HC Larson ◽  
BE Schneider ◽  
JA Beaton ◽  
RA Morrisett ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Molecular Basis ◽  
Subunit Composition ◽  
Receptor Subtypes

scholarly journals Coupling of synaptic inputs to local cortical activity differs among neurons and adapts after stimulus onset

2017 ◽  
Vol 118 (6) ◽  
pp. 3345-3359 ◽  
Author(s):  
Nathaniel C. Wright ◽  
Mahmood S. Hoseini ◽  
Tansel Baran Yasar ◽  
Ralf Wessel
Keyword(s):  
Local Field ◽  
Visual Processing ◽  
Local Field Potential ◽  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
Field Potential ◽  
Cortical Activity ◽  
Stimulus Onset ◽  
Synaptic Inputs ◽  
Network Properties

Cortical activity contributes significantly to the high variability of sensory responses of interconnected pyramidal neurons, which has crucial implications for sensory coding. Yet, largely because of technical limitations of in vivo intracellular recordings, the coupling of a pyramidal neuron’s synaptic inputs to the local cortical activity has evaded full understanding. Here we obtained excitatory synaptic conductance ( g) measurements from putative pyramidal neurons and local field potential (LFP) recordings from adjacent cortical circuits during visual processing in the turtle whole brain ex vivo preparation. We found a range of g-LFP coupling across neurons. Importantly, for a given neuron, g-LFP coupling increased at stimulus onset and then relaxed toward intermediate values during continued visual stimulation. A model network with clustered connectivity and synaptic depression reproduced both the diversity and the dynamics of g-LFP coupling. In conclusion, these results establish a rich dependence of single-neuron responses on anatomical, synaptic, and emergent network properties. NEW & NOTEWORTHY Cortical neurons are strongly influenced by the networks in which they are embedded. To understand sensory processing, we must identify the nature of this influence and its underlying mechanisms. Here we investigate synaptic inputs to cortical neurons, and the nearby local field potential, during visual processing. We find a range of neuron-to-network coupling across cortical neurons. This coupling is dynamically modulated during visual processing via biophysical and emergent network properties.

β-Amyloid Peptides Impair PKC-Dependent Functions of Metabotropic Glutamate Receptors in Prefrontal Cortical Neurons

2005 ◽  
Vol 93 (6) ◽  
pp. 3102-3111 ◽  
Author(s):  
Joanna P. Tyszkiewicz ◽  
Zhen Yan
Keyword(s):  
Nmda Receptor ◽  
Glutamate Receptors ◽  
Cortical Neurons ◽  
Metabotropic Glutamate Receptors ◽  
Pyramidal Neurons ◽  
Amyloid Peptide ◽  
Metabotropic Glutamate ◽  
Prefrontal Cortical ◽  
Group I ◽  
Β Amyloid

The metabotropic glutamate receptors (mGluRs) have been implicated in cognition, memory, and some neurodegenerative disorders, including the Alzheimer's disease (AD). To understand how the dysfunction of mGluRs contributes to the pathophysiology of AD, we examined the β-amyloid peptide (Aβ)-induced alterations in the physiological functions of mGluRs in prefrontal cortical pyramidal neurons. Two potential targets of mGluR signaling involved in cognition, the GABAergic system and the N-methyl-d-aspartate (NMDA) receptor, were examined. Activation of group I mGluRs with (S)-3,5-dihydroxyphenylglycine (DHPG) significantly increased the spontaneous inhibitory postsynaptic current (sIPSC) amplitude, and this effect was protein kinase C (PKC) sensitive. Treatment with Aβ abolished the DHPG-induced enhancement of sIPSC amplitude. On the other hand, activation of group II mGluRs with (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC) significantly increased the NMDA receptor (NMDAR)-mediated currents via a PKC-dependent mechanism, and Aβ treatment also diminished the APDC-induced potentiation of NMDAR currents. In Aβ-treated slices, both DHPG and APDC failed to activate PKC. These results indicate that the mGluR regulation of GABA transmission and NMDAR currents is impaired by Aβ treatment probably due to the Aβ-mediated interference of mGluR activation of PKC. This study provides a framework within which the role of mGluRs in normal cognitive functions and AD can be better understood.

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