Rapid and Sustained Homeostatic Control of Presynaptic Exocytosis at a Central Synapse

Abstract

Animal behavior is remarkably robust despite constant changes in neural activity. Homeostatic plasticity stabilizes central nervous system (CNS) function on time scales of hours to days. If and how CNS function is stabilized on more rapid time 15 scales remains unknown. Here we discovered that mossy fiber synapses in the mouse cerebellum homeostatically control synaptic efficacy within minutes after pharmacological glutamate receptor impairment. This rapid form of homeostatic plasticity is expressed presynaptically. We show that modulations of readilyreleasable vesicle pool size and release probability normalize synaptic strength in a 20 hierarchical fashion upon acute pharmacological and prolonged genetic receptor perturbation. Presynaptic membrane capacitance measurements directly demonstrate regulation of vesicle pool size upon receptor impairment. Moreover, presynaptic voltage-clamp analysis revealed increased calcium-current density under specific experimental conditions. Thus, homeostatic modulation of presynaptic 25 exocytosis through specific mechanisms stabilizes synaptic transmission in a CNS circuit on time scales ranging from minutes to months. Rapid presynaptic homeostatic plasticity may ensure stable neural circuit function in light of rapid activity-dependent plasticity.30

Optical monitoring of glutamate release at multiple synapses in situ detects changes following LTP induction

“…Experimental evidence for the alternative hypothesis, such as an increase in glutamate release probability [5][6][7], has been countered by an elegant hypothesis of silent synapses [8,9] and by documenting no increases in astroglial glutamate uptake post-induction [10,11]. However, the LTP-associated boost of release probability at non-silent synapses has subsequently been reported [12,13] whereas no change in overall glutamate release can reflect hetero-synaptic depression at nonactive connections [14] or, more generally, rapid (pre) synaptic scaling [15,16]. The uncertainty has remained, largely because documenting glutamate release at individual synapses has had to rely on its physiological consequences rather than on release readout per se.…”

A Novel Optical Quantal Analysis of Miniature Events Reveals Enhanced Frequency Following Amyloid β Exposure

“…It is possible that enhanced neurotransmitter release (spontaneous and/or evoked) might result from the induction of homeostatic plasticity in response to postsynaptic weakening caused by Aβo, as can occur rapidly when the postsynaptic terminus is blocked or pharmacologically suppressed (Davis and Muller, 2015 ; Delvendahl et al, 2019 ). However, synaptic activity can itself homeostatically regulate postsynaptic strength on relatively short timescales (Ibata et al, 2008 ), and it remains possible that changes in presynaptic function are a primary event.…”

GluA4 enables associative memory formation by facilitating cerebellar expansion coding

“…GluA4 shows a regional expression pattern in the CNS with strongest detection in the cerebellum (Sjöstedt et al, 2020). Within the cerebellar cortex, this AMPAR subunit has been described in Bergmann glia (Saab et al, 2012) and in GCs (Mosbacher et al, 1994), where GluA4 is the major AMPAR subunit at MF→GC synapses (Delvendahl et al, 2019). To investigate the role of GluA4 for cerebellar function, we performed whole-cell patch-clamp recordings at excitatory synapses in slices of adult WT and GluA4-KO mice ( Figure 1A).…”