Heterosynaptic GABAergic plasticity bidirectionally driven by the activity of pre- and postsynaptic NMDA receptors

Abstract

Dynamic changes of the strength of inhibitory synapses play a crucial role in processing neural information and in balancing network activity. Here, we report that the efficacy of GABAergic connections between Golgi cells and granule cells in the cerebellum is persistently altered by the activity of glutamatergic synapses. This form of plasticity is heterosynaptic and is expressed as an increase (long-term potentiation, LTP GABA ) or a decrease (long-term depression, LTD GABA ) of neurotransmitter release. LTP GABA is induced by postsynaptic NMDA receptor activation, leading to calcium increase and retrograde diffusion of nitric oxide, whereas LTD GABA depends on presynaptic NMDA receptor opening. The sign of plasticity is determined by the activation state of target granule and Golgi cells during the induction processes. By controlling the timing of spikes emitted by granule cells, this form of bidirectional plasticity provides a dynamic control of the granular layer encoding capacity.inhibitory plasticity | heterosynaptic plasticity | cerebellum | GABA | NMDA

Inhibitory Plasticity: Balance, Control, and Codependence

“…Recent experimental evidence from studies that monitored more than one synapse simultaneously demonstrates such coordinated effects. In mouse auditory cortex, inhibitory synapses change according to the E/I balance prior to induction (Figure 7a (Figure 7b) (Mapelli et al 2016). The fact that synaptic changes occur only when excitatory inputs are coactive and the E/I balance is perturbed suggests that ISP integrates neighboring excitatory and inhibitory inputs (Figure 7c) to maintain a local E/I balance rather than, for instance, to impose an activity set point (as in Vogels et al 2011).…”

“…Abbreviations: IPSC, inhibitory postsynaptic current; PV+, parvalbumin positive; SOM+, somatostatin positive; VIP, vasoactive intestinal polypeptide expressing. Panel a modified from D'amour & Froemke (2015), panel b from Mapelli et al (2016), panel e from Sjöström & Häusser (2006), panel f from Paille et al (2013), and panel g from Wang & Maffei (2014).…”

Inhibitory Plasticity: From Molecules to Computation and Beyond

“…For instance, the dopamine receptors type 2 (D2R) were shown to suppress GABA release in the prefrontal cortex [74] and in the Ventral Tegmental Area [75] through a coactivation of the D2R and Cannabinoid Receptors by an increase of endogenous dopamine levels. As in the case of inhibitory presynaptic LTP, also the depression of GABA release can be induced by the direct activation of presynaptic NMDA-Rs by glutamate released from excitatory synapses in the next proximity [46,76]. Interestingly, our recent results show that the cerebellar inhibitory synapse As in the case of i-LTP, the identified forms of i-LTD presynaptically expressed depend either on the direct NMDA-Rs activation in the GABAergic terminals [67] (Figure. 2) or through the retrograde diffusion of endocannabinoid (eCB) [49] ( Figure 2D).…”

“…Modifies at the presynaptic side require retrograde signaling that can persistently modulate GABA release [44], whereas purely postsynaptic mechanisms involve alterations of GABA receptors machinery [45]. The modulation of neurotransmitter vesicles release from presynaptic boutons is mainly triggered by heterosynaptic mechanisms, thus requiring non-GABAergic stimuli [44,46] from nearby synapses, and actually, the activation of inhibitory fibers is indeed not required. In order for this to happen, signals must be communicated to the presynaptic terminals following the postsynaptic induction, which can involve a wide series of mechanisms.…”

“…The retrograde messengers, a class of molecules produced in the postsynaptic cell in an activity-dependent manner and traveling backward, are essential to modulate neurotransmitter release, therefore, allowing the expression of LTP. Various pathways involving retrograde messengers and participating in the triggering of inhibitory plasticity have been identified; however, two main molecules modulating heterosynaptic LTP are more recurrently found in different brain regions: i) the diffusible nitric oxide (NO) [44,46] and the brain-derived neurotrophic factor (BDNF) [58,59]. The NO originates in the postsynaptic compartment following calcium entry ( Figure 1B).…”