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1.
J Cell Biol ; 223(6)2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38568173

ABSTRACT

Disruption of synapse assembly and maturation leads to a broad spectrum of neurodevelopmental disorders. Presynaptic proteins are largely synthesized in the soma, where they are packaged into precursor vesicles and transported into distal axons to ensure precise assembly and maintenance of presynapses. Due to their morphological features, neurons face challenges in the delivery of presynaptic cargos to nascent boutons. Thus, targeted axonal transport is vital to build functional synapses. A growing number of mutations in genes encoding the transport machinery have been linked to neurodevelopmental disorders. Emerging lines of evidence have started to uncover presynaptic mechanisms underlying axonal transport defects, thus broadening the view of neurodevelopmental disorders beyond postsynaptic mechanisms. In this review, we discuss presynaptic perspectives of neurodevelopmental disorders by focusing on impaired axonal transport and disturbed assembly and maintenance of presynapses. We also discuss potential strategies for restoring axonal transport as an early therapeutic intervention.


Subject(s)
Axonal Transport , Neurodevelopmental Disorders , Presynaptic Terminals , Humans , Axons , Cell Body , Mutation , Neurodevelopmental Disorders/genetics
2.
Mol Psychiatry ; 26(5): 1472-1490, 2021 05.
Article in English | MEDLINE | ID: mdl-32332993

ABSTRACT

The formation and maintenance of synapses require long-distance delivery of newly synthesized synaptic proteins from the soma to distal synapses, raising the fundamental question of whether impaired transport is associated with neurodevelopmental disorders such as autism. We previously revealed that syntabulin acts as a motor adapter linking kinesin-1 motor and presynaptic cargos. Here, we report that defects in syntabulin-mediated transport and thus reduced formation and maturation of synapses are one of core synaptic mechanisms underlying autism-like synaptic dysfunction and social behavioral abnormalities. Syntabulin expression in the mouse brain peaks during the first 2 weeks of postnatal development and progressively declines during brain maturation. Neurons from conditional syntabulin-/- mice (stb cKO) display impaired transport of presynaptic cargos, reduced synapse density and active zones, and altered synaptic transmission and long-term plasticity. Intriguingly, stb cKO mice exhibit core autism-like traits, including defective social recognition and communication, increased stereotypic behavior, and impaired spatial learning and memory. These phenotypes establish a new mechanistic link between reduced transport of synaptic cargos and impaired maintenance of synaptic transmission and plasticity, contributing to autism-associated behavioral abnormalities. This notion is further confirmed by the human missense variant STB-R178Q, which is found in an autism patient and loses its adapter capacity for binding kinesin-1 motors. Expressing STB-R178Q fails to rescue reduced synapse formation and impaired synaptic transmission and plasticity in stb cKO neurons. Altogether, our study suggests that defects in syntabulin-mediated transport mechanisms underlie the synaptic dysfunction and behavioral abnormalities that bear similarities to autism.


Subject(s)
Autistic Disorder , Animals , Autistic Disorder/genetics , Cells, Cultured , Humans , Mice , Neurons , Synapses , Synaptic Transmission
3.
Nat Metab ; 2(10): 1077-1095, 2020 10.
Article in English | MEDLINE | ID: mdl-33020662

ABSTRACT

Mitochondria supply ATP essential for synaptic transmission. Neurons face exceptional challenges in maintaining energy homoeostasis at synapses. Regulation of mitochondrial trafficking and anchoring is critical for neurons to meet increased energy consumption during sustained synaptic activity. However, mechanisms recruiting and retaining presynaptic mitochondria in sensing synaptic ATP levels remain elusive. Here we reveal an energy signalling axis that controls presynaptic mitochondrial maintenance. Activity-induced presynaptic energy deficits can be rescued by recruiting mitochondria through the AMP-activated protein kinase (AMPK)-p21-activated kinase (PAK) energy signalling pathway. Synaptic activity induces AMPK activation within axonal compartments and AMPK-PAK signalling triggers phosphorylation of myosin VI, which drives mitochondrial recruitment and syntaphilin-mediated anchoring on presynaptic filamentous actin. This pathway maintains presynaptic energy supply and calcium clearance during intensive synaptic activity. Disrupting this signalling cross-talk triggers local energy deficits and intracellular calcium build-up, leading to impaired synaptic efficacy during trains of stimulation and reduced recovery from synaptic depression after prolonged synaptic activity. Our study reveals a mechanistic cross-talk between energy sensing and mitochondria anchoring to maintain presynaptic metabolism, thus fine-tuning short-term synaptic plasticity and prolonged synaptic efficacy.


Subject(s)
Energy Metabolism/physiology , Mitochondria/metabolism , Receptor Cross-Talk/physiology , Synapses/metabolism , Synapses/physiology , AMP-Activated Protein Kinases/metabolism , Actins/metabolism , Adenosine Triphosphate/metabolism , Animals , Calcium/metabolism , Excitatory Postsynaptic Potentials , Female , Male , Membrane Potential, Mitochondrial , Membrane Proteins/genetics , Mice , Mice, Knockout , Myosin Heavy Chains/metabolism , Nerve Tissue Proteins/genetics , Phosphorylation , Primary Cell Culture , Receptors, Presynaptic/metabolism , p21-Activated Kinases/metabolism
4.
Nat Commun ; 8(1): 2190, 2017 12 19.
Article in English | MEDLINE | ID: mdl-29259187

ABSTRACT

Encoding specificity theory predicts most effective recall by the original conditions at encoding, while generalization endows recall flexibly under circumstances which deviate from the originals. The CA1 regions have been implicated in memory and generalization but whether and which locally separated mechanisms are involved is not clear. We report here that fear memory is quickly formed, but generalization develops gradually over 24 h. Generalization but not fear memory is impaired by inhibiting ipsilateral (ips) or contralateral (con) CA1, and by optogenetic silencing of the ipsCA1 projections onto conCA1. By contrast, in vivo fEPSP recordings reveal that ipsCA1-conCA1 synaptic efficacy is increased with delay over 24 h when generalization is formed but it is unchanged if generalization is disrupted. Direct excitation of ipsCA1-conCA1 synapses using chemogenetic hM3Dq facilitates generalization formation. Thus, rapid generalization is an active process dependent on bilateral CA1 regions, and encoded by gradual synaptic learning in ipsCA1-conCA1 circuit.


Subject(s)
CA1 Region, Hippocampal/physiology , Conditioning, Psychological/physiology , Fear/psychology , Generalization, Psychological/physiology , Memory/physiology , Animals , Long-Term Potentiation/physiology , Male , Mental Recall/physiology , Mice , Mice, Inbred C57BL , Models, Animal , Neural Pathways/physiology , Optogenetics , Rats , Rats, Sprague-Dawley , Synapses/physiology
5.
Neuropharmacology ; 92: 1-7, 2015 May.
Article in English | MEDLINE | ID: mdl-25576374

ABSTRACT

Early life stress increases risks of fear and anxiety related disorders in adulthood, which may be alleviated by fluoxetine treatment. However, the intergenerational impacts of maternal separation (MS) on fear and anxiety behaviors from father to their offspring are little known. And the potential effects of fluoxetine treatment on the intergenerational transmission have not been well tested. Here, we investigated whether fluoxetine can reverse the intergenerational effects of MS on fear and anxiety behaviors. The first generation (F1) male rats were exposed to MS 3 h daily from postnatal day 2-14 and then treated with fluoxetine for four weeks during adulthood before fear conditioning. We found that maternal separation significantly impaired contextual fear extinction in F1 adult male rats but not in their second generation (F2). Although no obvious effects of MS on anxiety were observed in F1 male rats, the F2 offspring displayed a phenotype of low anxiety-like behaviors despite they were reared in normal condition. Fluoxetine treatment in F1 males not only reversed the impairment of fear extinction in F1 males but also the low anxiety-like behaviors in their F2 offspring. These findings highlight the intergenerational impacts of early life stress on fear and anxiety behaviors, and provide a new sight of the intergenerational effect of fluoxetine therapy for early life stress related mental problems.


Subject(s)
Antidepressive Agents, Second-Generation/therapeutic use , Anxiety , Fear/drug effects , Fluoxetine/therapeutic use , Maternal Deprivation , Analysis of Variance , Animals , Anxiety/drug therapy , Anxiety/etiology , Anxiety/genetics , Conditioning, Classical/drug effects , Disease Models, Animal , Exploratory Behavior/drug effects , Extinction, Psychological/drug effects , Fear/psychology , Female , Male , Maze Learning/drug effects , Pregnancy , Rats , Rats, Sprague-Dawley
6.
Behav Brain Res ; 269: 75-80, 2014 Aug 01.
Article in English | MEDLINE | ID: mdl-24746487

ABSTRACT

Early life stress increases the risk of posttraumatic stress disorders (PTSD). Patients with PTSD show impaired extinction of traumatic memory, and in women, this occurs more often when PTSD is preceded by child trauma. However, it is still unclear how early life stress accounts for extinction impairment. Here, we studied the effects of maternal separation (MS, postnatal day 2 to 14) on contextual fear extinction in adult female rats. Additionally, to examine changes in synaptic function affected by MS, we measured long-term potentiation (LTP) in prefrontal cortex and hippocampus in vitro, both of which have been implicated in fear extinction. We found that adult female rats had been subjected to MS exhibited significant spontaneous recovery of fear to the extinguished context. Furthermore, MS exposure resulted in LTP impairment in both infralimbic prefrontal cortex layer 2/3-layer 5 and hippocampal SC-CA1 pathways. Interestingly, no obvious effects of MS on contextual fear conditioning, fear recall as well as extinction training and recall were observed. Innate fear in the elevated plus maze or open field test remained nearly unaffected. These findings provided the first evidence that MS may exaggerate spontaneous recovery after contextual fear extinction, for which LTP impairment in the medial prefrontal cortex and hippocampus may be responsible, thereby possibly leading to impaired extinction associated with PTSD.


Subject(s)
Conditioning, Psychological/physiology , Extinction, Psychological/physiology , Fear/physiology , Hippocampus/physiopathology , Maternal Deprivation , Prefrontal Cortex/physiopathology , Animals , Exploratory Behavior/physiology , Female , Long-Term Potentiation/physiology , Maze Learning/physiology , Mental Recall/physiology , Neuropsychological Tests , Rats, Sprague-Dawley , Stress Disorders, Post-Traumatic/physiopathology , Tissue Culture Techniques
7.
Toxicol Lett ; 214(1): 63-8, 2012 Oct 02.
Article in English | MEDLINE | ID: mdl-22922007

ABSTRACT

Foods contaminated with melamine potentially cause risk to human health. However, the neurotoxicity of melamine has not been adequately assessed. Here, we aimed to examine the effects of acute low-dose exposure to melamine on hippocampal synaptic plasticity and behaviors in rats. We found that bath application of 50-500µg/ml melamine decreased basal synaptic transmission in the Schaffer collateral-CA1 pathway of hippocampal slices from postnatal days (P) 10-14 rats in a concentration-dependent manner; furthermore, this decrease in transmission was related to the reduction of presynaptic function as indicated by the increased paired-pulse facilitation ratio. Rats at 2-3months old were less vulnerable to the effects of 500µg/ml melamine on basal synaptic transmission when compared with P10-14 and P21-28 rats. Melamine (50µg/ml) significantly impaired long-term potentiation (LTP), without affecting long-term depression (LTD), in both P10-14 and 2-3month-old rats. Oral treatment with melamine (5 and 25mg/kg) 1h before behavioral tests significantly decreased the immobility time of the forced swim test in 2-3month-old rats and had no effect on locomotor activity in the open field test in both P21-28 and 2-3month-old rats. Our findings reveal some of the aspects of neurotoxicity induced by acute low-dose of melamine in hippocampal synaptic plasticity and behavior.


Subject(s)
Behavior, Animal/drug effects , Hippocampus/cytology , Hippocampus/drug effects , Motor Activity/drug effects , Neuronal Plasticity/drug effects , Triazines/toxicity , Animals , Male , Rats , Rats, Sprague-Dawley
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