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    • We found that decreased Ng levels

    2024-03-22

    We found that decreased Ng levels lead to a lower threshold for LTD induction at L4–L2/3 synapses. Previous studies in hippocampal slice culture have shown that LTD at individual synapses induces spine elimination at both the targeted synapse and selective neighboring synapses when spines are monitored a few days following stimulation (Wiegert and Oertner, 2013). It is therefore conceivable that visual input triggers spine elimination in L2/3 pyramidal neurons in V1 using the cellular mechanism of LTD, and that a decrease in Ng enhances this vulnerability by lowering the threshold for LTD. Given the high proportion of AMPAR-silent synapses after reduction of Ng, it is likely that the conversion of AMPAR-silent synapses to AMPAR-positive synapses is also impaired. Our results support the hypothesis that Ng levels in L2/3 pyramidal neurons control the Ca2+/CaM-dependent signaling sensitivity and orchestrate experience-dependent AMPAR-silent synapse conversion and synapse elimination. It is noteworthy that dysfunction of Ca2+ homeostasis is involved in many neurological and neuropsychiatric diseases (Bojarski et al., 2010; Chan et al., 2009; Green and LaFerla, 2008). Genome-wide association studies have identified Ng as a candidate gene close to a risk-carrying allele (Stefansson et al., 2009), and Ng levels are significantly reduced in the prefrontal Senegenin of schizophrenia patients (Broadbelt et al., 2006). Interestingly, recent genetic evidence highlighted the complement component 4 (C4) genes, suggesting a potential role of heightened synapse elimination during postnatal development in schizophrenia (Sekar et al., 2016). Dendritic spine loss is also observed in neurodegenerative diseases including Alzheimer’s disease and Huntington’s disease (Fiala et al., 2002; Spires et al., 2004). It has been shown that overexpression of Ng restores synaptic transmission and LTP, both of which are impaired by amyloid V application (Kaleka and Gerges, 2016). Our results thus provide a potential clue to the pathophysiology underlying aberrant neural circuit refinement in neuropsychiatric and neurodegenerative disorders associated with aberrant Ca2+-dependent signaling. In conclusion, our studies offer insight into how Ng regulates experience-dependent cortical excitatory circuit optimization. Our analyses reconcile the functional and anatomical observations in experience-dependent developmental modification of glutamatergic cortical synapses and provide a general mechanism concerning experience-dependent dynamic reorganization of glutamatergic synaptic transmission: progressive elimination of glutamatergic synapses upon experience and conversion of AMPAR-silent synapses to AMPAR-positive synapses together maintain AMPAR-positive synapses at equilibrium during the critical period to achieve cortical excitatory circuit maturation. Decreased Ng expression breaks the balance of these processes and leads to a loss of AMPAR-positive synapses and delayed AMPAR-silent synapse maturation. We propose that sensory experience coordinates these two experience-dependent cellular processes through Ng-dependent regulation of Ca2+/CaM-dependent signaling pathways to functionally optimize neural circuits.
    Experimental Procedures
    Author Contributions
    Acknowledgments This work was supported by the JPB Foundation, Whitehall Foundation, and Broad Institute Stanley Center. We thank Drs. Mark F. Bear, Elly Nedivi, Oliver M. Schluter, Steven Flavell, Martha Constantine-Paton, Jianhua Cang, and members of the W.X. laboratory for their helpful comments, Drs. Wen-Jie Bian and Xiang Yu for their help with spine imaging, and Cynthia Hou, Emily Liao, Xiaobai Ren, and Taekeun Kim for their excellent technical support.
    Introduction The ability of networks to maintain stable function over time, and to efficiently store information, is thought to rely on homeostatic plasticity mechanisms that stabilize neuronal and network activity (Davis, 2013; Turrigiano and Nelson, 2004). Synaptic scaling is a form of homeostatic plasticity that scales postsynaptic strength up or down in response to perturbations in neuronal firing (Gainey et al., 2009, 2015; Goold and Nicoll, 2010; Ibata et al., 2008), a process thought to contribute to the stabilization of firing rates both in vitro (Turrigiano et al., 1998) and in vivo (Hengen et al., 2013, 2016). Synaptic scaling is accomplished through changes in the abundance of postsynaptic AMPA receptors (AMPARs), but despite great effort, the full set Senegenin of molecular trafficking events that homeostatically adjust synaptic AMPAR abundance is poorly understood (Pozo and Goda, 2010; Turrigiano, 2012). In particular, although synaptic scaling is known to be transcription dependent (Gainey et al., 2015; Goold and Nicoll, 2010; Ibata et al., 2008; Meadows et al., 2015), the factor or factors that are transcriptionally regulated to drive synaptic scaling are largely unknown. We thus set out to devise an unbiased screen for factors that are persistently upregulated during synaptic scaling in the hopes of gaining deeper insight into the transcription-dependent AMPAR trafficking pathways involved in this critical form of synaptic plasticity.