Frequency‐dependent facilitation of synaptic throughput via postsynaptic NMDA receptors in the nucleus of the solitary tract

Abstract

Key pointsr Hindbrain NMDA receptors play important roles in reflexive and behavioural responses to vagal activation.r NMDA receptors have also been shown to contribute to the synaptic responses of neurons in the nucleus of the solitary tract (NTS), but their exact role remains unclear.r In this study we used whole cell patch-clamping techniques in rat horizontal brain slice to investigate the role of NMDA receptors in the fidelity of transmission across solitary tract afferent-NTS neuron synapses.r Results show that NMDA receptors contribute up to 70% of the charge transferred across the synapse at high (>5 Hz) firing rates, but have little contribution at lower firing frequencies. Results also show that NMDA receptors critically contribute to the fidelity of transmission across these synapses during high frequency (>5 Hz) afferent discharge rates.r This novel role of NMDA receptors may explain in part how primary visceral afferents, including vagal afferents, can maintain fidelity of transmission across a broad range of firing frequencies.Abstract Neurons within the nucleus of the solitary tract (NTS) receive vagal afferent innervations that initiate gastrointestinal and cardiovascular reflexes. Glutamate is the fast excitatory neurotransmitter released in the NTS by vagal afferents, which arrive there via the solitary tract (ST). ST stimulation elicits excitatory postsynaptic currents (EPSCs) in NTS neurons mediated by both AMPA-and NMDA-type glutamate receptors (-Rs). Vagal afferents exhibit a high probability of vesicle release and exhibit robust frequency-dependent depression due to presynaptic vesicle depletion. Nonetheless, synaptic throughput is maintained even at high frequencies of afferent activation. Here we test the hypothesis that postsynaptic NMDA-Rs are essential in maintaining throughput across ST-NTS synapses. Using patch clamp electrophysiology in horizontal brainstem slices, we found that NMDA-Rs, including NR2B subtypes, carry up to 70% of the charge transferred across the synapse during high frequency stimulations (>5 Hz). In contrast, their relative contribution to the ST-EPSC is much less during low (<2 Hz) frequency stimulations. Afferent-driven activation of NMDA-Rs produces a sustained depolarization during high, but not low, frequencies of stimulation as a result of relatively slow decay kinetics. Hence, NMDA-Rs are critical for maintaining action potential generation at high firing rates. These results demonstrate a novel role for NMDA-Rs enabling a high probability of release synapse to maintain the fidelity of synaptic transmission during high frequency firing when glutamate release and AMPA-R responses are reduced. They also suggest why NMDA-Rs are critical for responses that may depend on high rates of afferent discharge.

Excitatory amino acid transporters tonically restrain nTS synaptic and neuronal activity to modulate cardiorespiratory function

“…The latter events contribute predominantly to increased neuronal nTS discharge indicating an increase in excitatory drive within the nTS. Depolarization also likely relieves neurons, specifically via postsynaptic NMDA receptors (Zhao et al 2015), of voltage-dependent block. We suggest that the net effect of EAAT blockade is to increase nTS network excitability, which then induces the depressor response, sympathoinhibition and apnea we observed in vivo.…”

“…Reducing EAAT glutamate uptake potentiates the slow excitation observed following repeated afferent stimulation of nTS neurons (Huda et al 2013;Zhao et al 2015). Nevertheless, little is known about the role of EAATs within the nTS in relation to basal synaptic and neuronal function or EAAT influence on autonomic and cardiorespiratory regulation.…”

NMDA-type glutamate receptors participate in reduction of food intake following hindbrain melanocortin receptor activation

“…In addition, NMDAR subunit immunoreactivity and mRNA also occur in nodose ganglion neurons (18,47), and NMDAR subunit immunoreactivity has been localized ultrastructurally to vagal afferent endings in the NTS (1). Electrophysiological results also indicate that activation of presynaptic NMDAR increases glutamate release from vagal afferent endings in the DVC (3), while a recent report reveals that postsynaptic NMDAR on NTS neurons are critical for fidelity of transmission from vagal afferents to NTS neurons (63). Therefore, it is conceivable that NMDARs, expressed both by vagal afferents and NTS neurons, participate in the reduction of food intake by MTII.…”

“…Our use of D-CPP-ene was based on our prior experience with the antagonist and its effectiveness in blocking CCK-induced reduction of food intake when injected into the fourth ventricle or NTS (13,61). In addition, functional electrophysiological experiments indicate that D-CPPene effectively blocks NMDAR participation in vagus-to-NTS synaptic transmission (63). Although NTS and vagal afferent neurons have been found to express all known NR2 subunits (4,18,28), NR2B immunoreactivity is present in nearly all vagal afferent neurons that innervate the gut (19).…”

“…The selection of D-CPP-ene was based on our prior experience with the antagonist and its effectiveness in being able to block CCK-induced reduction of food intake when injected into the fourth ventricle or NTS (14,61). In addition, functional electrophysiological experiments indicate that D-CPP-ene effectively blocks NMDAR-dependent contributions in vagus-to-NTS neurotransmission (63). Injection volumes of 3 l were injected over a 2-min period using a Hamilton syringe (Reno, NV).…”