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Experience-dependent serotonergic signaling in glia regulates targeted synapse elimination [1]

['Vanessa Kay Miller', 'Department Of Biological Sciences', 'Vanderbilt University', 'Medical Center', 'Nashville', 'Tennessee', 'United States Of America', 'Kendal Broadie', 'Department Of Cell', 'Developmental Biology']

Date: 2024-10

The optimization of brain circuit connectivity based on initial environmental input occurs during critical periods characterized by sensory experience-dependent, temporally restricted, and transiently reversible synapse elimination. This precise, targeted synaptic pruning mechanism is mediated by glial phagocytosis. Serotonin signaling has prominent, foundational roles in the brain, but functions in glia, or in experience-dependent brain circuit synaptic connectivity remodeling, have been relatively unknown. Here, we discover that serotonergic signaling between glia is essential for olfactory experience-dependent synaptic glomerulus pruning restricted to a well-defined Drosophila critical period. We find that experience-dependent serotonin signaling is restricted to the critical period, with both (1) serotonin production and (2) 5-HT 2A receptors specifically in glia, but not neurons, absolutely required for targeted synaptic glomerulus pruning. We discover that glial 5-HT 2A receptor signaling limits the experience-dependent synaptic connectivity pruning in the critical period and that conditional reexpression of 5-HT 2A receptors within adult glia reestablishes “critical period-like” experience-dependent synaptic glomerulus pruning at maturity. These results reveal an essential requirement for glial serotonergic signaling mediated by 5-HT 2A receptors for experience-dependent synapse elimination.

Serotonin (5-HT) signaling plays requisite foundational roles mediating brain plasticity [ 21 , 22 ]. Serotonergic cells uniquely express tryptophan hydroxylase (Trhn), the rate-limiting enzyme for serotonin biosynthesis [ 23 ]. Serotonin signaling regulates both excitatory and inhibitory synapses, functioning in a gatekeeping mechanism controlling synaptic output and ratio changes [ 24 , 25 ]. Downstream, the G-protein-coupled 5-HT 2A receptor (5-HT 2A R) regulates plasticity signaling [ 26 , 27 ] and is expressed in neurons and glia, including microglia and astrocytes [ 28 – 31 ]. 5-HT 2A R has long been closely linked to learning and memory [ 32 ], polarizing synaptic modifications that drive both long-term depression (LTD) and potentiation [ 33 ]. Importantly, the 5-HT 2A R has emerging roles in regulating brain circuit maturation and remodeling [ 21 , 34 ]. Serotonin signaling defects are linked to numerous neurological disorders, such as autism spectrum disorder (ASD), posttraumatic stress disorder (PTSD), depression, and schizophrenia [ 35 , 36 ], with serotonergic drugs at the forefront of patient symptom management [ 37 , 38 ]. Moreover, other serotonin pathway drugs (e.g., LSD, psilocybin) appear to increase the capacity in the adult brain for circuit remodeling [ 39 , 40 ], with the novel aspirational objective of reopening “critical period-like” remodeling in adults widely touted as a panacea for a myriad of mature brain limitations and impairments [ 41 – 43 ]. However, the putative role of serotonin signaling in experience-dependent brain circuit remodeling still remains largely unknown. There is no connection linking serotonergic signaling to glial function in synapse pruning during the early-life critical period, let alone such a role in later reopening this remodeling capacity in adults. Here, we employ a well-characterized critical period in the Drosophila genetic model system to test the requirements for serotonin signaling in sensory experience-dependent glial synapse pruning in both the juvenile and mature adult brain. We discover experience-dependent serotonergic signaling within glia is essential for targeted synapse pruning during the early-life critical period and that the conditional introduction of serotonin signaling in adult glia reopens this experience-dependent synapse pruning mechanism at maturity.

The brain first receives information from the environment during early critical periods and uses this input to optimize neural circuitry via large-scale changes in synapse connectivity [ 1 , 2 ]. Critical periods are defined as opening with sensory experience onset, a transiently reversible and dramatically heightened synaptic remodeling capacity, and then permanent closure resulting in the consolidation of mature brain circuits [ 3 , 4 ]. The closing of critical period remodeling limits later behavioral adaptability and prevents correction of subsequent impairments from injury, trauma, or disease but is presumed to be necessary to secure the maintained stability of brain circuit connectivity [ 5 , 6 ]. The large-scale changes in brain circuitry during critical periods occur through dynamic fluctuations between 2 opposing remodeling processes: synapse formation and synapse elimination. Both the genesis and pruning of synapses is tightly regulated by glia [ 7 , 8 ], with critical period remodeling overall characterized by the large net loss of synapses directly mediated by experience-targeted glial phagocytosis [ 9 – 12 ]. Precise glial pruning is important to properly streamline information flow by adapting brain circuit synaptic connectivity to the unpredictable demands of a highly variable environment [ 13 , 14 ]. In mammals, microglia and astrocytes function as the phagocytes for synapse elimination, with multiple signaling cues to target and prune away unwanted synapses [ 14 – 16 ]. Microglia are the innate immune cells of the brain, and astrocytes are closely associated with synapses. Both glial classes can function as either primary or secondary phagocytes, with orchestrated roles in the engulfment and removal of neuron cell bodies, proximal dendritic arbors, and distal axonal synapses [ 17 , 18 ]. Microglia are key synaptic phagocytes, but astrocyte glia are reportedly the phagocytes mediating the elimination of excitatory synapses during the experience-dependent pruning of synaptic connections in adult mice [ 15 , 19 , 20 ]. In contrast, the glial mechanisms mediating synaptic pruning during experience-dependent critical period brain circuit remodeling have been much less studied. In particular, we know little about the molecular signaling mechanisms underlying critical period glial function.

Results

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[1] Url: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3002822

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