Synaptic up-scaling preserves motor circuit output after chronic, natural inactivity

Abstract

Neural systems use homeostatic plasticity to maintain normal brain functions and to prevent abnormal activity. Surprisingly, homeostatic mechanisms that regulate circuit output have mainly been demonstrated during artificial and/or pathological perturbations. Natural, physiological scenarios that activate these stabilizing mechanisms in neural networks of mature animals remain elusive. To establish the extent to which a naturally inactive circuit engages mechanisms of homeostatic plasticity, we utilized the respiratory motor circuit in bullfrogs that normally remains inactive for several months during the winter. We found that inactive respiratory motoneurons exhibit a classic form of homeostatic plasticity, up-scaling of AMPA-glutamate receptors. Up-scaling increased the synaptic strength of respiratory motoneurons and acted to boost motor amplitude from the respiratory network following months of inactivity. Our results show that synaptic scaling sustains strength of the respiratory motor output following months of inactivity, thereby supporting a major neuroscience hypothesis in a normal context for an adult animal.

Motor inactivity in hibernating frogs: Linking plasticity that stabilizes neuronal function to behavior in the natural environment

“…As rhythm generating networks are highly sensitive to inhibition of AMPAR in this preparation (Chen & Hedrick, ; Kottick, Baghdadwala, Ferguson, & Wilson, ), we bath applied a blocker of AMPAR, DNQX, at a low concentration that did not abolish the respiratory rhythm to address its influence on the motor amplitude in control frogs and those after hibernation. We found that acute application of DNQX did not affect the amplitude of the motor output in controls; however, amplitude decreased by about half after blocking AMPAR in preparations from hibernating frogs (Figure 3b; Santin et al, ). Because blocking AMPAR reduced motor output after hibernation, but not before, these results suggest that increases in excitatory synaptic strength contribute to producing an adequate level of motor drive following winter.…”

“…, long‐term potentiation) are unlikely to explain the mEPSC amplitude increases in these neurons (Gainey, Hurvitz‐Wolff, Lambo, & Turrigiano, ). Notwithstanding limitations with interpreting these outcomes as truly global and multiplicative (Kim, Tsien, & Alger, ), these results provide strong evidence that a mechanism identified by the field as homeostatic for neurons can be triggered by the hibernation environment (Santin et al, ).…”

“…This confirms that the synaptic events measured in the hibernation group increased by the same relative amount across the distribution of mEPSCs, a hallmark of synaptic scaling (Turrigiano et al, ). Fourth, the rank order of mEPSCs was poorly fit by an exponential relationship (Santin, Vallejo, & Hartzler, ), suggesting that forms of plasticity that act in a synapse specific manner on shorter time scales (e.g. , long‐term potentiation) are unlikely to explain the mEPSC amplitude increases in these neurons (Gainey, Hurvitz‐Wolff, Lambo, & Turrigiano, ).…”

“…Traces highlight that mEPSC amplitude increases after hibernation. These data traces were part of Santin et al () but were not included as figures in the study. (b) Rank order relationship of individual mEPSCs from control frogs and those after hibernation.…”

“…Does synaptic scaling play a functional role in the network to maintain the capacity for breathing output during months of inactivity? In the same study that identified synaptic scaling in respiratory motoneurons (Santin et al, ), rhythmic activity of the network was recorded extracellularly from in vitro brainstem preparations that produce “fictive breaths.” The frequency of fictive breaths is related to activity of the rhythm generating networks, and amplitude corresponds with motoneuron outflow to breathing muscles (Figure 3a; Sakakibara, , ; Wilson, Vasilakos, Harris, Straus, & Remmers, ). We rationalized that if an upregulation of AMPAR through synaptic scaling influences motoneuron output in a functional context, the motor amplitude would have a greater sensitivity to block of AMPARs after synaptic scaling.…”