Autophagy Defciency in Neurodevelopmental Disorders Part 3

FIP200 (also known as Rb1cc1) is an essential gene for autophagy induction. Guan's group previously reported that depletion of FIP200 causes a progressive loss of NSCs and impairs neuronal differentiation in the postnatal brain of mice, which can be rescued by treatment with the antioxidant N-acetylcysteine [58]. 

With the continuous deepening of genetic research in recent years, people have a deeper understanding of the relationship between genes and memory. Each of us has a certain degree of genetic influence on our memory.

Some people are born with excellent memories, while others may forget more easily or have difficulty remembering. The key factor lies in the various genes in our bodies and how they are expressed. Some of these genes are considered "essential genes" and play a vital role in our memory and cognitive abilities.

Specifically, researchers found that essential genes are important factors that can influence the development and function of our brains. These genes can affect our cell function in different ways, affecting our cognition and behavior.

In addition, essential genes are thought to alter our synapses and increase the brain's metabolic rate, increase the number of neurons, and improve memory and learning. Therefore, genetic research can help us better understand memory and cognitive development processes and how to deal with learning and memory disorders.

It is worth mentioning that essential genes occupy specific positions in the human genome. These locations are thought to be areas associated with cognitive and neurological development, illustrating the importance of these genes for human intelligence and memory.

Therefore, we can say that essential genes are an integral part of human memory and they play a crucial role in our cognitive and intellectual development. By better understanding these genes, we can gain greater insight into the nature of memory abilities, helping us study how to enhance memory and cognitive abilities. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola can also promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of neural networks. These effects can help improve memory, learning ability, and thinking speed, and may also prevent the development of cognitive dysfunction and neurodegenerative diseases.

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Recently, the same group found evidence that microglial dysregulation contributes to the impairment of neurogenesis in FIP200-null NSCs from FIP200;p53hGFAP 2cKO mice [59]. 

Mechanistically, the study reveals that ablation of FIP200 leads to increased infiltration of microglia into the subventricular zone and subsequent microglia activation in FIP200; p53hGFAP 2cKO mice [59]. 

Inhibition of microglia infiltration and activation can rescue the defective neurogenesis in these 2cKO mice [59]. These findings demonstrate that FIP200-mediated autophagy plays a critical role in regulating neurogenesis in postnatal NSCs through the control of microglia migration and activation. In addition to embryonic neurogenesis, adult neurogenesis can also be regulated by autophagy [60]. 

The Notch signaling pathway has an important role in adult neurogenesis [61]. Previous studies have shown that activation of Notch signaling inhibits the proliferation and differentiation of NSCs in the adult brain [62, 63]. 

Rubinsztein's group has recently reported that Notch1, a plasma membrane-resident receptor in Notch signaling, is degraded by autophagy through ATG16L1, a crucial autophagy protein [64]Theyey demonstrated that ATG16L1 protein level was reduced, whereas the levels of Notch signaling proteins Notch1, NICD and Hes1 are significantly increased in the brain of ATG16L1- hypomorph mice [64]. They further showed decreadifferentiationtion of NSCs and smaller cortiplateslate in ATG16L1-hypomorph compared with the control mice [64]. Using BrdU labeling, they showed that the number of BrdU-positive cells significantly reduced in ATG16L1-hypomorph mice compared with the controls at 9–11 months old [64]. The results indicate that ATG16L1-mediated autophagy controls both embryonic and adult neurogenesis by regulating the degradation of proteins in the Notch signaling pathway. 

The Forkhead Box O (FOXO) proteins are a class of conserved transcription factors that control gene expression programs involved in multiple cell signaling pathways [65]. Previous studies have reported the roles of FOXO proteins in the regulation of adult NSCs homeostasis and autophagy induction [66–68]. 

A recent study has demonstrated that FOXO3 directly regulates autophagy pathway to maintain the proteostasis in adults NSCs [69]. Wurst et al. recently reported that conditional knockout of FOXO1/3/4 in adult NSCs by using GLAST::CreERT2 impairs autophagy flux both in vitro and in vivo [70]. FOXO1/3deficiencyncy leads to altered dendrite and spine development of adult-generated neurons and impaired long-term survival eventually [70]. 

Further evidence indicates that autophagy inducer rapamycin not only rescues the impaired autophagy flux in NSCs but also reverses the impaired phenotypes of dendrite and spine of adult-generated neurons with FOXO1/3/4 deficiency [70]. The findings indicate that FOXO proteins regulate neuronal morphogenesis via the maintenance of autophagy flux during adult neurogenesis.

Autophagy regulates presynaptic and postsynaptic development and synaptic activity
Neurons are postmitotic cells that are maintained for the lifetime of the organism. However, the synapses of neurons are highly dynamic, especially during early lifetime as the growing rate of synapses experiences an initial increase and subsequent decrease before an eventual stabilization of synapse development. 

During synapse development, the properties of synapses can be changed and reshaped, while new neural circuits are developed under circumstances such as learning and stress. 

Available evidence showed that autophagy plays a role in synapse formation and pruning, a process facilitating the removal of exuberant neuronal connections [71]. In addition, autophagy may also regulate synaptic activity, the function of which depends on synapse transmission and plasticity.

Autophagy regulates presynaptic and postsynaptic development

During early development, autophagy is required for pathfinding and synaptic vesicle clustering formation during early synaptogenesis [72–74]. Previous studies showed that loss of autophagic scaffolding protein ALFY leads to a failure in axon guidance and outgrowth in the development of the mouse brain [75]. 

Neural-specific depletion of ATG9 results in abnormal development of axon tracts in mouse brain regions including the corpus callosum and anterior commissure [73]. In C. elegans interneuron, autophagy controls presynaptic assembly and axon outgrowth dynamics, which is spatially regulated through the coordination of ATG9 and synaptic vesicle kinesin, KIF1A/UNC-104 [76]. 

Consistent with this notion, a previous study conducted in Drosophila indicated that Atg1 (an ortholog of ULK1 in S. cerevisiae) mutant causes reduced total neuromuscular junction (NMJ) area and decreased number of synapses [77]. 

However, overexpression of wildtype Atg1 increases NMJ synaptic bouton number in an autophagy-dependent manner [77]. In the postsynaptic site, autophagy was shown to be involved in synaptic pruniDeficienciescies in autophagy result in an overabundance of dendritic spines, ultimately manifesting as autism-like phenotypes [33]. For example, the primary hippocampal neuron cultures with reduced Atg7 expression showed increased PSD95 density, a marker for postsynaptic abundance [33]TheTe similar results were shown in mouse models with Atg7 knockdown [33]. 

Another study showed that NMJs from autophagy-deficient neurons exhibited postsynaptic folds without presynaptic axon terminals as opposed to them, suggesting an abnormal postsynaptic pruning [78]. These results indicate that basal autophagy may play an important role in specific postsynaptic receptor degradation and postnatal spine pruning.

Autophagy regulates synaptic activity

Multiple lines of evidence show that autophagy modulates neurotransmitter release and neural plasticity. Marijn Kuijpers et al. recently found that the neurotransmission and calcium sensitivity significantly increased in primary hippocampus excitatory neurons in Atg5 knock-miceouse due to the deregulation of ER turnover [79]. 

Moreover, a previous study found that depletion of autophagy by using a dopaminergic neuron-specifc Atg7 knock-out mouse mosignificantlyntly affects dopamine release and reuptake [80] The study further showed that striatal slices from Atg7 DAT::Cre mice had increased evoked dopamine release in cyclic voltammetry experiments and enhanced presynaptic recovery following paired-pulse stimulation. 

Moreover, rapamycin treatment reduced stimulus-evoked dopamine release in slices from Atg7 DAT::Cre mice [80] These studies provide evidence for the role of presynaptic autophagy in the regulation of neurotransmission. 

A recent study showed that autophagy regulates development-related synaptic plasticity and memory [81]. NMDA receptor-dependent long-term depression (NMDAR-LTD) is a long-lasting form of synaptic plasticity [82]. The induction of NMDAR-LTD is mediated by the removal of AMPA receptors from postsynaptic membranes to late endosomes for degradation [83]. It is induced in early stage of neuronal development while greatly reduced in adulthood during CNS development. 

Down-regulation of NMDAR-LTD in adults is physiologically signifcant for memory formation. Shen et al. revealed that autophagic flux in CA1 neurons was transiently decreased during the induction phase of NMDAR-LTD. Autophagy inhibition caused a reduction of endocytic recycling and is required for AMPA receptor internalization and synaptic depression in mouse CA1 neurons. 

In adulthood, autophagy is up-regulated to decrease the inducibility of LTD, thereby preventing the adverse effect of excessive LTD on memory consolidation [81]. Additionally, Compans et al. found that autophagy is required for the degradation of the T19-phosphorylated form of PSD95 in NMDAR-LTD induction, which triggers a depletion of PSD95 from synapses and eventually increases short-term plasticity to improve neuronal responsiveness of depressed synapses [84]. 

A most recent study has shown that constitutive induction of mTOR-dependent autophagy rescues the prevention of NMDAR-LTD induced by disrupting synergistic action of CREB and CRTC1, two essential transcriptional factors for late-phase long-term synaptic potentiation [85]. These findings reveal the previously unrecognized functions of autophagy in the regulation of synaptic plasticity and memory (Fig. 1).

Conclusive remarks

Growing evidence has highlighted the important role of autophagy in regulating neurodevelopment and synaptic plasticity. 

Alteration of autophagy may lead the abnormal neurodevelopment and malfunction of synapses in the brain. Recent human genetic and clinical studies have identified the link of congenital mutations in key autophagy-related genes to neurodevelopmental disorders (Table  1). 

However, the causality of the autophagy deficiency in the disease awaits further clarification due to non-autophagy functions associated with many autophagy-related genes. It is also extremely challenging to address the specific role of autophagy because of the difficulty of monitoring autophagy function directly in the human brain. While rodent models are valuable tools to dissect the roof for autophagy in neurodevelopment and diferentiation (e.g., engineering autophagy gene deletion in CNS), the possibdifferentialial functions of autophagy homologous genes betwrodentsdent humansuman were noticed, and may complicate the interpretation of the results [86]. 

A most recent study has identified recessive and loss-of-function mutations in both ATG7 alleles in patients with neurodevelopmental disorders in five unrelated families [15]. Despite the complete absence of ATG7 protein, the patients carrying the missense variants of ATG7 had approached population life expectancy [15, 87]. In contrast, mice lacking the Atg7 gene die early postnatal. 

The data suggests that humans are much more tolerant of the loss of ATG7 or ATG7-mediated autophagy. Alternative explanation is that cellular functions that can compensate for the loss of ATG7 function in survival are more robust in humans than in rodents. To dissect directly ATG7-mediated autophagy in neurodevelopment in humans, future experiments should use human neurons carrying corresponding mutants. The human neurons derived from induced pluripotent stem cells (iPSCs) would provide an important model to investigate the mechanism whereby autophagy deficiency leads to neurodevelopmental disease, and to test therapeutic strategy by restoring autophagy function.

Acknowledgments

We thank members of Yue lab and Lu lab for their suggestions.

Authors' contributions

ZY, JL, and ZD conceived the project. ZD and XZ searched the literature and drafted the manuscript. ZY, JL, ZD, and XZ edited and revised the manuscript. All authors read and approved the financial manuscript.

Funding

This study was supported by ChinaMinisterr of Science and Technology grant MoST-2017YFE0120100, the Science and Technology Development Fund, Macau SAR (No. 0110/2018/A3, 0128/2019/A3, China), the University of Macau grants (No. MYRG2019-00129-ICMS, China) awarded to Jia-Hong Lu, and NIH/ R01NS060123 and R01 R01AG072520 awarded to Zhenyu Yue.

Availability of data and materials

Not applicable.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

AuthoDetailsls

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China. 2 Department of Neurology, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. 3 Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.

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