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

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Rapid and Sustained Homeostatic Control of Presynaptic Exocytosis at a Central Synapse Rapid and sustained homeostatic control of presynaptic exocytosis at a central synapse Igor Delvendahla,b, Katarzyna Kitaa,b, and Martin Müllera,b,1 aInstitute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland; and bNeuroscience Center Zurich, University of Zurich, ETH Zurich, 8057 Zurich, Switzerland Edited by Reinhard Jahn, Max Planck Institute for Biophysical Chemistry, Goettingen, Germany, and approved October 10, 2019 (received for review June 6, 2019) Animal behavior is remarkably robust despite constant changes in The maintenance of robust CNS function is strongly chal- neural activity. Homeostatic plasticity stabilizes central nervous lenged by Hebbian plasticity, which is induced on rapid time system (CNS) function on time scales of hours to days. If and how scales (2) and eventually destabilizes neuronal activity (28–30). CNS function is stabilized on more rapid time scales remains In contrast, the expression of presynaptic and postsynaptic ho- unknown. Here, we discovered that mossy fiber synapses in the meostatic plasticity requires perturbation of CNS function for hours mouse cerebellum homeostatically control synaptic efficacy within to days (7), raising the question if and how CNS function is stabi- minutes after pharmacological glutamate receptor impairment. lized on rapid time scales. Given the discrepancy in temporal dy- This rapid form of homeostatic plasticity is expressed presynapti- namics, homeostatic plasticity is thought to slowly integrate and cally. We show that modulations of readily releasable vesicle pool normalize fast neural activity changes (6, 10). However, theoretical size and release probability normalize synaptic strength in a work implies that the slow time course of homeostatic plasticity is hierarchical fashion upon acute pharmacological and prolonged insufficient to prevent instabilities induced by Hebbian plasticity (31). genetic receptor perturbation. Presynaptic membrane capacitance Here, we define the time course of a fast, presynaptic form of measurements directly demonstrate regulation of vesicle pool size homeostatic plasticity at a cerebellar synapse. Employing pre- upon receptor impairment. Moreover, presynaptic voltage-clamp + synaptic and postsynaptic whole-cell recordings in acute brain analysis revealed increased Ca2 -current density under specific ex- slices, we discover that synergistic modulation of readily releas- perimental conditions. Thus, homeostatic modulation of presynap- able vesicle pool size and vesicular release probability through NEUROSCIENCE tic exocytosis through specific mechanisms stabilizes synaptic + elevated Ca2 -current density underlies the homeostatic control transmission in a CNS circuit on time scales ranging from minutes to months. Rapid presynaptic homeostatic plasticity may ensure of exocytosis from these CNS terminals. Rapid PHP may stabi- stable neural circuit function in light of rapid activity-dependent lize synaptic information transfer to balance changes imposed by plasticity. perturbations or Hebbian plasticity. Results homeostatic plasticity | synaptic transmission | exocytosis | mossy fiber | cerebellum Rapid, Reversible Homeostatic Release Modulation. We probed if fast presynaptic homeostatic mechanisms stabilize synaptic transmission in an acute mouse brain slice preparation. To this end, we daptive animal behavior presupposes plastic, and yet stable, recorded miniature excitatory postsynaptic currents (mEPSCs) Aneural function. While neural activity is constantly changing because of activity-dependent plasticity (1, 2), robust animal be- havior can be maintained for a lifetime. However, stable nervous Significance system function and behavior are not a given, as apparent from pathological states such as epilepsy or migraine (3). A number of Homeostatic mechanisms stabilize neural activity, and there studies revealed that homeostatic plasticity actively stabilizes neural are genetic links between homeostatic plasticity and neural excitability and synaptic transmission (4–7). The most widely studied disease. While homeostatic plasticity in the central nervous form of homeostatic synaptic plasticity is synaptic scaling—the bi- system (CNS) operates on relatively slow time scales of hours directional, compensatory regulation of neurotransmitter receptor to days, activity-dependent forms of synaptic plasticity alter abundance (5). This postsynaptic type of homeostatic plasticity is neural activity on much faster time scales. It is unclear if ho- typically observed after chronic pharmacological blockade of action meostatic plasticity stabilizes CNS synapses on rapid time potentials (APs) or neurotransmitter receptors in neuronal cell- scales. Here, we uncovered that cerebellar synapses stabilize transmission within minutes upon activity perturbation. This is culture systems (8–10), but also stabilizes AP firing rates after achieved through homeostatic control of presynaptic exo- sensory deprivation in vivo (11, 12). cytosis. We show that synergistic modulation of distinct pre- There is also evidence for presynaptic forms of homeostatic synaptic mechanisms not only maintains synaptic efficacy on synaptic plasticity. Presynaptic homeostatic plasticity (PHP) rapid, but also on prolonged time scales. Homeostatic control stabilizes synaptic efficacy at neuromuscular synapses after acute of presynaptic exocytosis may be a general mechanism for or sustained neurotransmitter receptor perturbation in several stabilizing CNS function. species (13–16). In the mammalian central nervous system (CNS), PHP is mostly studied in cell culture after prolonged Author contributions: I.D. and M.M. designed research; I.D. and K.K. performed research; perturbation of neural activity (7). The expression of PHP depends I.D. and K.K. analyzed data; and I.D. and M.M. wrote the paper. on cell-culture age, with cultures older than 2 wk compensating for The authors declare no competing interest. prolonged activity deprivation through concomitant regulation of This article is a PNAS Direct Submission. presynaptic release, postsynaptic receptor abundance, and synapse This open access article is distributed under Creative Commons Attribution License 4.0 number (17–20). Despite evidence for compensatory changes in (CC BY). presynaptic structure and function (21–25), it is currently not well 1To whom correspondence may be addressed. Email: [email protected]. understood how these relate to the postsynaptic modifications This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. during synaptic scaling. Moreover, it has remained largely elusive if 1073/pnas.1909675116/-/DCSupplemental. PHP stabilizes the activity of native neural circuits (7, 26, 27). First published November 4, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1909675116 PNAS | November 19, 2019 | vol. 116 | no. 47 | 23783–23789 Downloaded by guest on September 27, 2021 and AP-evoked excitatory postsynaptic currents (EPSCs) at adult (Fig. 1 C and D), indicative of enhanced neurotransmitter re- cerebellar mossy fiber (MF)-granule cell (GC) synapses (Fig. 1A) lease. The increase in quantal content scaled with the degree of (32, 33) after various incubation times with the noncompetitive mEPSC reduction, such that EPSC amplitudes were precisely AMPA receptor (AMPAR) blocker GYKI 53655. GYKI appli- maintained at control levels (SI Appendix, Fig. S1H), consistent cation at subsaturating concentration (2 μM, ref. 34) for 5 to 20 with the phenomenology of PHP at the neuromuscular junction min reduced mEPSC and evoked EPSC amplitudes by ∼30% (NMJ) (15, 35). These data demonstrate a rapid form of PHP at without affecting their kinetics (Fig. 1 B and C and SI Appendix, mammalian CNS synapses upon acute, subsaturating AMPAR Fig. S1 A–G). By contrast, recordings obtained after 20 min of blockade on the minute time scale. GYKI incubation revealed EPSC amplitudes that were compa- To investigate the reversibility of PHP, we recorded from MF- rable to control levels (Fig. 1 B–D). Longer incubation times of GC synapses following GYKI washout. Slices were incubated up to 100 min gave similar results (Fig. 1 B–D). Because GYKI with GYKI for 30 min and then exposed to control artificial equally reduced mEPSC amplitudes at all incubation times, cerebrospinal fluid (ACSF) for varying times before obtaining there was a significant increase in quantal content after 20 min whole-cell recordings (Fig. 1E). While mEPSC amplitudes re- covered to control levels, EPSC amplitudes, and quantal content remained significantly larger than under control conditions up to ∼20 min after GYKI washout (Fig. 1F). This implies that PHP A Granule B CONTROL GYKI 15 min GYKI 100 min expression persists when AMPAR perturbation is removed on a cell (GC) E P S C m E P S C short time scale. Additional recordings demonstrated that PHP was fully reversible within ∼20–40 min after GYKI washout (Fig. 1F), similar to previous reports at the mouse NMJ (16). Thus, 10 pA 2 s PHP completely reverses within tens of minutes after reattained Mossy fiber (MF) receptor function. 20 pA Acute Homeostatic Readily Releasable Pool Size Modulation. To as- 2 ms C D sess the presynaptic mechanisms underlying neurotransmitter release ( p A ) 15 D potentiation upon AMPAR perturbation, we tested if changes in the m E P S C 10 number of readily releasable vesicles (readily releasable pool, RRP) **** n.s. *** 5 ( p A ) 15 100 10 contribute to PHP following GYKI application. To estimate RRP ) ( p A c o n t e n t 0 size, we
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