Distinct Target-Specific Mechanisms Homeostatically Stabilize Transmission at Pre- and Post-synaptic Compartments

Abstract

Neurons must establish and stabilize connections made with diverse targets, each with distinct demands and functional characteristics. At Drosophila neuromuscular junctions (NMJs), synaptic strength remains stable in a manipulation that simultaneously induces hypo-innervation on one target and hyper-innervation on the other. However, the expression mechanisms that achieve this exquisite target-specific homeostatic control remain enigmatic. Here, we identify the distinct target-specific homeostatic expression mechanisms. On the hypo-innervated target, an increase in postsynaptic glutamate receptor (GluR) abundance is sufficient to compensate for reduced innervation, without any apparent presynaptic adaptations. In contrast, a target-specific reduction in presynaptic neurotransmitter release probability is reflected by a decrease in active zone components restricted to terminals of hyper-innervated targets. Finally, loss of postsynaptic GluRs on one target induces a compartmentalized, homeostatic enhancement of presynaptic neurotransmitter release called presynaptic homeostatic potentiation (PHP) that can be precisely balanced with the adaptations required for both hypo- and hyper-innervation to maintain stable synaptic strength. Thus, distinct anterograde and retrograde signaling systems operate at pre- and post-synaptic compartments to enable target-specific, homeostatic control of neurotransmission.

Botulinum neurotoxin accurately separates tonic vs phasic transmission and reveals heterosynaptic plasticity rules in Drosophila

“…For example, total bouton number remained highly reduced following phasic MN-Is ablation (wild type: 52±1.5; Is>rpr.hid: 32±0.8 bouton numbers), with a corresponding reduction in synaptic strength (wild type: 32.6±2.2 mV; Is>rpr.hid: 14.2±0.7 mV EPSP values). However, while loss of transmission or innervation to a particular target muscle does not induce homeostatic plasticity, a converse manipulation, in which innervation is biased between adjacent muscle targets, does elicit two distinct forms of target-specific homeostatic plasticity that stabilizes synaptic strength (Davis and Goodman, 1998; Goel et al, 2020). Hyper-innervation of both tonic and phasic inputs on muscle 6 homeostatically reduces release probability from both inputs without any obvious postsynaptic changes (Davis and Goodman, 1998; Goel et al, 2020).…”

Disruption of Cholinergic Circuits as an Area for Targeted Drug Treatment of Alzheimer’s Disease: In Vivo Assessment of Short-Term Plasticity in Rat Brain

“…Abnormally increased Aβ blocks neuronal glutamate uptake at synapses, which enhances glutamate levels in the synaptic cleft [ 34 ]. Moreover, Aβ-induced synaptic collapse may be a result of a primary increase in synaptic activation by glutamate followed by synaptic NMDAR desensitization, NMDAR, and AMPAR internalization [ 34 , 35 , 36 ]…”

“…Hence it could be speculated that the opposite effects of Aβ 25–35 in the hippocampus and amygdala are determined by the differential response of the corresponding nAChR receptors. The striking interplay in target-specific homeostasis modulates the efficacy of neurotransmission required for both hypo- and hyper-innervation to maintain stable synaptic strength [ 35 ]. Presynaptic plasticity optimally tunes presynaptic filtering, acting as a gain controller to amplify or depress transmission maximizing the efficiency of information transfer [ 46 ].…”

“…In general, our findings are consistent with the notion that both the expansive, diffuse innervations by the cholinergic system and the varied array of cholinergic activity apparently can edge the balance in favor of or against the induction of STP [ 45 ]. This type of synaptic activity enables the flexibility to locally adjust synaptic strength through input- and target-specificity to stabilize total network activity [ 35 ]. Therapeutic interventions aiming to stabilize synaptic integrity and cholinergic neurotransmission efficacy could have the potential to modify AD progression.…”

“…Abnormally increased Aβ blocks neuronal glutamate uptake at synapses, which enhances glutamate levels in the synaptic cleft [34]. Moreover, Aβ-induced synaptic collapse may be a result of a primary increase in synaptic activation by glutamate followed by synaptic NMDAR desensitization, NMDAR, and AMPAR internalization [34][35][36] Alteration in the variables of presynaptic neurotransmitter vesicle stores and the Ca 2+ microenvironment involves the strength and fidelity of PTP, and therefore interferes with long-term plasticity gating within individual synapses and across networks [37]. PTP, which is a form of presynaptic short-term plasticity (STP), results from a presynaptic increase of synaptic vesicle deliverance lasting for tens of seconds after discontinuance of tetanic stimulation [38].…”