Inhibitory interneurons mediate autism-associated behaviors via 4E-BP2

Wiebe, Sabrina; Nagpal, Anmol; Truong, Vinh Tai; Park, Jeehyun; Skalecka, Agnieszka; He, Alexander J.; Gamache, Karine; Khoutorsky, Arkady; Gantois, Ilse; Sonenberg, Nahum

doi:10.1073/pnas.1908126116

Cited by 44 publications

(34 citation statements)

References 62 publications

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“…Our prior studies demonstrated that abnormal mitochondrial dynamics, caused by conditional genetic ablation of Mfn2, cause mitochondrial dysfunction and neurodegeneration in AD-affected brain areas, which supports a causal role of abnormal mitochondrial dynamics in mitochondrial dysfunction and neurodegeneration in vivo [24]. However, since Mfn2 is knocked out at as early as 2 or 3 weeks of age [25][26][27], a potential contribution of abnormal developmental changes to our observations may not be completely ruled out. To better understand the contribution of abnormal mitochondrial dynamics in age-related neurodegeneration disorders such as AD, investigation of a Mfn2 knockout mouse model in adult neurons will be more convincing.…”

Section: Introductionsupporting

confidence: 51%

Mfn2 Ablation in the Adult Mouse Hippocampus and Cortex Causes Neuronal Death

Han

Nandy

Austria

et al. 2020

Cells

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It is believed that mitochondrial fragmentation cause mitochondrial dysfunction and neuronal deficits in Alzheimer’s disease. We recently reported that constitutive knockout of the mitochondria fusion protein mitofusin2 (Mfn2) in the mouse brain causes mitochondrial fragmentation and neurodegeneration in the hippocampus and cortex. Here, we utilize an inducible mouse model to knock out Mfn2 (Mfn2 iKO) in adult mouse hippocampal and cortical neurons to avoid complications due to developmental changes. Electron microscopy shows the mitochondria become swollen with disorganized and degenerated cristae, accompanied by increased oxidative damage 8 weeks after induction, yet the neurons appear normal at the light level. At later timepoints, increased astrocyte and microglia activation appear and nuclei become shrunken and pyknotic. Apoptosis (Terminal deoxynucleotidyl transferase dUTP nick end labeling, TUNEL) begins to occur at 9 weeks, and by 12 weeks, most hippocampal neurons are degenerated, confirmed by loss of NeuN. Prior to the loss of NeuN, aberrant cell-cycle events as marked by proliferating cell nuclear antigen (PCNA) and pHistone3 were evident in some Mfn2 iKO neurons but do not colocalize with TUNEL signals. Thus, this study demonstrated that Mfn2 ablation and mitochondrial fragmentation in adult neurons cause neurodegeneration through oxidative stress and neuroinflammation in vivo via both apoptosis and aberrant cell-cycle-event-dependent cell death pathways.

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Section: Introductionsupporting

confidence: 51%

Mfn2 Ablation in the Adult Mouse Hippocampus and Cortex Causes Neuronal Death

Han

Nandy

Austria

et al. 2020

Cells

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“…These behaviors are commonly found in preterm infants, as described above, and in other NDDs, thus supporting the face validity of these models. This is further supported by an extensive body of work showing reduction in GABAergic interneurons or expression of parvalbumin (as distinct from a reduction in cell number) in clinical ASD cases (144)(145)(146) and genetic models of NDDs (147)(148)(149).…”

Section: Moderate/mild Injurymentioning

confidence: 80%

Cortical Gray Matter Injury in Encephalopathy of Prematurity: Link to Neurodevelopmental Disorders

2020

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Preterm-born infants frequently suffer from an array of neurological damage, collectively termed encephalopathy of prematurity (EoP). They also have an increased risk of presenting with a neurodevelopmental disorder (e.g., autism spectrum disorder; attention deficit hyperactivity disorder) later in life. It is hypothesized that it is the gray matter injury to the cortex, in addition to white matter injury, in EoP that is responsible for the altered behavior and cognition in these individuals. However, although it is established that gray matter injury occurs in infants following preterm birth, the exact nature of these changes is not fully elucidated. Here we will review the current state of knowledge in this field, amalgamating data from both clinical and preclinical studies. This will be placed in the context of normal processes of developmental biology and the known pathophysiology of neurodevelopmental disorders. Novel diagnostic and therapeutic tactics required integration of this information so that in the future we can combine mechanism-based approaches with patient stratification to ensure the most efficacious and cost-effective clinical practice.

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“…Given these results, we opted to target 4EHP in EMX1-expressing cells to study its role in synaptic plasticity and ASD-like behaviors. We chose the EMX1-Cre model over the CaMKIIa-Cre model to delete 4EHP in excitatory neurons because EMX1-driven Cre recombinase activity was reported to occur by e10.5 [ 26 ], whereas CaMKIIa-driven Cre recombinase activity occurs postnatally [ 12 , 30 , 31 ].…”

Section: Resultsmentioning

confidence: 99%

“…Overactivity of eIF4E in humans has been implicated in ASD [ 5 , 6 ] and ASD-like phenotypes in mice [ 7 , 8 ]. Indeed, disruption of the proteins regulating eIF4E activity, such as fragile X mental retardation protein (FMRP) [ 9 ], cytoplasmic FMR1 interacting protein 1 (CYFIP1) [ 10 ], and eIF4E-binding protein 2 (4E-BP2) [ 8 , 11 , 12 ], is implicated in ASD. It is therefore necessary to investigate the function of ASD-linked genes that encode for regulators of translation.…”

Section: Introductionmentioning

confidence: 99%

The eIF4E homolog 4EHP (eIF4E2) regulates hippocampal long-term depression and impacts social behavior

et al. 2020

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Background The regulation of protein synthesis is a critical step in gene expression, and its dysfunction is implicated in autism spectrum disorder (ASD). The eIF4E homologous protein (4EHP, also termed eIF4E2) binds to the mRNA 5′ cap to repress translation. The stability of 4EHP is maintained through physical interaction with GRB10 interacting GYF protein 2 (GIGYF2). Gene-disruptive mutations in GIGYF2 are linked to ASD, but causality is lacking. We hypothesized that GIGYF2 mutations cause ASD by disrupting 4EHP function. Methods Since homozygous deletion of either gene is lethal, we generated a cell-type-specific knockout model where Eif4e2 (the gene encoding 4EHP) is deleted in excitatory neurons of the forebrain (4EHP-eKO). In this model, we investigated ASD-associated synaptic plasticity dysfunction, ASD-like behaviors, and global translational control. We also utilized mice lacking one copy of Gigyf2, Eif4e2 or co-deletion of one copy of each gene to further investigate ASD-like behaviors. Results 4EHP is expressed in excitatory neurons and synaptosomes, and its amount increases during development. 4EHP-eKO mice display exaggerated mGluR-LTD, a phenotype frequently observed in mouse models of ASD. Consistent with synaptic plasticity dysfunction, the mice displayed social behavior impairments without being confounded by deficits in olfaction, anxiety, locomotion, or motor ability. Repetitive behaviors and vocal communication were not affected by loss of 4EHP in excitatory neurons. Heterozygous deletion of either Gigyf2, Eif4e2, or both genes in mice did not result in ASD-like behaviors (i.e. decreases in social behavior or increases in marble burying). Interestingly, exaggerated mGluR-LTD and impaired social behaviors were not attributed to changes in hippocampal global protein synthesis, which suggests that 4EHP and GIGYF2 regulate the translation of specific mRNAs to mediate these effects. Limitations This study did not identify which genes are translationally regulated by 4EHP and GIGYF2. Identification of mistranslated genes in 4EHP-eKO mice might provide a mechanistic explanation for the observed impairment in social behavior and exaggerated LTD. Future experiments employing affinity purification of translating ribosomes and mRNA sequencing in 4EHP-eKO mice will address this relevant issue. Conclusions Together these results demonstrate an important role of 4EHP in regulating hippocampal plasticity and ASD-associated social behaviors, consistent with the link between mutations in GIGYF2 and ASD.

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Inhibitory interneurons mediate autism-associated behaviors via 4E-BP2

Cited by 44 publications

References 62 publications

Mfn2 Ablation in the Adult Mouse Hippocampus and Cortex Causes Neuronal Death

Mfn2 Ablation in the Adult Mouse Hippocampus and Cortex Causes Neuronal Death

Cortical Gray Matter Injury in Encephalopathy of Prematurity: Link to Neurodevelopmental Disorders

The eIF4E homolog 4EHP (eIF4E2) regulates hippocampal long-term depression and impacts social behavior

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