Amin, J. | bioRxiv Science

bioRxiv2020

NMDA receptors require multiple pre-opening gating steps for efficient synaptic activity

NMDA receptors (NMDAR) are glutamate-gated ion channels that mediate the majority of fast excitatory synaptic transmission in the nervous system. A central feature of NMDAR physiology is the opening of the ion channel driven by presynaptically-released glutamate. Using glutamate applications to outside-out patches containing a single NMDAR in the continuous presence of the co-agonist glycine, we find that agonist-bound receptors transition to the open state via two conformations, an unconstrained pre-active state that can rapidly transition to the open state and contributes to synaptic events, and a constrained pre-active state that requires more energy and hence time to open and does not contribute to fast signaling. To define how agonist binding might drive these conformations, we decoupled the ligand-binding domains from specific transmembrane segments for the GluN1 and GluN2A subunits. Displacements of the central pore-forming M3 segments define the energy of fast channel opening. However, to enter the unconstrained conformation and contribute to fast signaling, a peripheral helix, the GluN2 pre-M1, must be displaced before the M3 segments move. This pre-M1 displacement is facilitated by the flexibility of another nearby peripheral element, the GluN1 and GluN2A S2-M4. We conclude that peripheral structural elements - pre-M1 and S2-M4 - work in concert to remove constraints and prime the channel for rapid opening, thus facilitating fast synaptic transmission.

neuroscience↗

bioRxiv2019

A role for the locus coeruleus in the modulation of feeding

Recent data suggest that LC-NE neurons play a role in fear-induced suppression of feeding, but their endogenous activity in naturally behaving animals has not been explored. We found that endogenous activity of LC-NE neurons was enhanced during food approach and suppressed during food consumption, and that these food-evoked LC-NE responses were attenuated in sated mice. Interestingly, visual-evoked LC-NE activity was also attenuated in sated mice, demonstrating that internal satiety state modulates LC-NE encoding of multiple behavioral states. We also found that food intake could be attenuated by brief or longer durations of LC-NE activation. Lastly, we demonstrated that activation of LC neurons suppresses feeding and enhances avoidance and anxiety-like responding through a projection to the lateral hypothalamus. Collectively, our data suggest that LC-NE neurons modulate feeding by integrating both external cues (e.g., anxiogenic environmental cues) and internal drives (e.g., nutritional state).

neuroscience↗