Luo JH

References (7)

Title : Frontostriatal circuit dysfunction leads to cognitive inflexibility in neuroligin-3 R451C knockin mice - Lin_2024_Mol.Psychiatry__
Author(s) : Lin S , Fan CY , Wang HR , Li XF , Zeng JL , Lan PX , Li HX , Zhang B , Hu C , Xu J , Luo JH
Ref : Mol Psychiatry , : , 2024
Abstract : Cognitive and behavioral rigidity are observed in various psychiatric diseases, including in autism spectrum disorder (ASD). However, the underlying mechanism remains to be elucidated. In this study, we found that neuroligin-3 (NL3) R451C knockin mouse model of autism (KI mice) exhibited deficits in behavioral flexibility in choice selection tasks. Single-unit recording of medium spiny neuron (MSN) activity in the nucleus accumbens (NAc) revealed altered encoding of decision-related cue and impaired updating of choice anticipation in KI mice. Additionally, fiber photometry demonstrated significant disruption in dynamic mesolimbic dopamine (DA) signaling for reward prediction errors (RPEs), along with reduced activity in medial prefrontal cortex (mPFC) neurons projecting to the NAc in KI mice. Interestingly, NL3 re-expression in the mPFC, but not in the NAc, rescued the deficit of flexible behaviors and simultaneously restored NAc-MSN encoding, DA dynamics, and mPFC-NAc output in KI mice. Taken together, this study reveals the frontostriatal circuit dysfunction underlying cognitive inflexibility and establishes a critical role of the mPFC NL3 deficiency in this deficit in KI mice. Therefore, these findings provide new insights into the mechanisms of cognitive and behavioral inflexibility and potential intervention strategies.
ESTHER : Lin_2024_Mol.Psychiatry__
PubMedSearch : Lin_2024_Mol.Psychiatry__
PubMedID: 38459194

Title : NMDA receptor hypofunction underlies deficits in parvalbumin interneurons and social behavior in neuroligin 3 R451C knockin mice - Cao_2022_Cell.Rep_41_111771
Author(s) : Cao W , Li JH , Lin S , Xia QQ , Du YL , Yang Q , Ye YZ , Zeng LH , Li XY , Xu J , Luo JH
Ref : Cell Rep , 41 :111771 , 2022
Abstract : Neuroligins (NLs), a family of postsynaptic cell-adhesion molecules, have been associated with autism spectrum disorder. We have reported that dysfunction of the medial prefrontal cortex (mPFC) leads to social deficits in an NL3 R451C knockin (KI) mouse model of autism. However, the underlying molecular mechanism remains unclear. Here, we find that N-methyl-D-aspartate receptor (NMDAR) function and parvalbumin-positive (PV+) interneuron number and expression are reduced in the mPFC of the KI mice. Selective knockdown of NMDAR subunit GluN1 in the mPFC PV+ interneuron decreases its intrinsic excitability. Restoring NMDAR function by its partial agonist D-cycloserine rescues the PV+ interneuron dysfunction and social deficits in the KI mice. Interestingly, early D-cycloserine administration at adolescence prevents adult KI mice from social deficits. Together, our results suggest that NMDAR hypofunction and the resultant PV+ interneuron dysfunction in the mPFC may constitute a central node in the pathogenesis of social deficits in the KI mice.
ESTHER : Cao_2022_Cell.Rep_41_111771
PubMedSearch : Cao_2022_Cell.Rep_41_111771
PubMedID: 36476879

Title : Neuroligin 3 Regulates Dendritic Outgrowth by Modulating Akt\/mTOR Signaling - Xu_2019_Front.Cell.Neurosci_13_518
Author(s) : Xu J , Du YL , Xu JW , Hu XG , Gu LF , Li XM , Hu PH , Liao TL , Xia QQ , Sun Q , Shi L , Luo JH , Xia J , Wang Z
Ref : Front Cell Neurosci , 13 :518 , 2019
Abstract : Neuroligins (NLs) are a group of postsynaptic cell adhesion molecules that function in synaptogenesis and synaptic transmission. Genetic defects in neuroligin 3 (NL3), a member of the NL protein family, are associated with autism. Studies in rodents have revealed that mutations of NL3 gene lead to increased growth and complexity in dendrites in the central nervous system. However, the detailed mechanism is still unclear. In our study, we found that deficiency of NL3 led to morphological changes of the pyramidal neurons in layer II/III somatosensory cortex in mice, including enlarged somata, elongated dendritic length, and increased dendritic complexity. Knockdown of NL3 in cultured rat neurons upregulated Akt/mTOR signaling, resulting in both increased protein synthesis and dendritic growth. Treating neurons with either rapamycin to inhibit the mTOR or LY294002 to inhibit the PI3K/Akt activity rescued the morphological abnormalities resulting from either NL3 knockdown or knockout (KO). In addition, we found that the hyperactivated Akt/mTOR signaling associated with NL3 defects was mediated by a reduction in phosphatase and tensin (PTEN) expression, and that MAGI-2, a scaffold protein, interacted with both NL3 and PTEN and could be a linker between NL3 and Akt/mTOR signaling pathway. In conclusion, our results suggest that NL3 regulates neuronal morphology, especially dendritic outgrowth, by modulating the PTEN/Akt/mTOR signaling pathway, probably via MAGI-2. Thereby, this study provides a new link between NL3 and neuronal morphology.
ESTHER : Xu_2019_Front.Cell.Neurosci_13_518
PubMedSearch : Xu_2019_Front.Cell.Neurosci_13_518
PubMedID: 31849609

Title : Neuroligins Differentially Mediate Subtype-Specific Synapse Formation in Pyramidal Neurons and Interneurons - Xia_2019_Neurosci.Bull_35_497
Author(s) : Xia QQ , Xu J , Liao TL , Yu J , Shi L , Xia J , Luo JH
Ref : Neurosci Bull , 35 :497 , 2019
Abstract : Neuroligins (NLs) are postsynaptic cell-adhesion proteins that play important roles in synapse formation and the excitatory-inhibitory balance. They have been associated with autism in both human genetic and animal model studies, and affect synaptic connections and synaptic plasticity in several brain regions. Yet current research mainly focuses on pyramidal neurons, while the function of NLs in interneurons remains to be understood. To explore the functional difference among NLs in the subtype-specific synapse formation of both pyramidal neurons and interneurons, we performed viral-mediated shRNA knockdown of NLs in cultured rat cortical neurons and examined the synapses in the two major types of neurons. Our results showed that in both types of neurons, NL1 and NL3 were involved in excitatory synapse formation, and NL2 in GABAergic synapse formation. Interestingly, NL1 affected GABAergic synapse formation more specifically than NL3, and NL2 affected excitatory synapse density preferentially in pyramidal neurons. In summary, our results demonstrated that different NLs play distinct roles in regulating the development and balance of excitatory and inhibitory synapses in pyramidal neurons and interneurons.
ESTHER : Xia_2019_Neurosci.Bull_35_497
PubMedSearch : Xia_2019_Neurosci.Bull_35_497
PubMedID: 30790215

Title : Gamma Oscillation Dysfunction in mPFC Leads to Social Deficits in Neuroligin 3 R451C Knockin Mice - Cao_2018_Neuron_97_1253
Author(s) : Cao W , Lin S , Xia QQ , Du YL , Yang Q , Zhang MY , Lu YQ , Xu J , Duan SM , Xia J , Feng G , Luo JH
Ref : Neuron , 97 :1253 , 2018
Abstract : Neuroligins (NLs) are critical for synapse formation and function. NL3 R451C is an autism-associated mutation. NL3 R451C knockin (KI) mice exhibit autistic behavioral abnormalities, including social novelty deficits. However, neither the brain regions involved in social novelty nor the underlying mechanisms are clearly understood. Here, we found decreased excitability of fast-spiking interneurons and dysfunction of gamma oscillation in the medial prefrontal cortex (mPFC), which contributed to the social novelty deficit in the KI mice. Neuronal firing rates and phase-coding abnormalities were also detected in the KI mice during social interactions. Interestingly, optogenetic stimulation of parvalbumin interneurons in the mPFC at 40 Hz nested at 8 Hz positively modulated the social behaviors of mice and rescued the social novelty deficit in the KI mice. Our findings suggest that gamma oscillation dysfunction in the mPFC leads to social deficits in autism, and manipulating mPFC PV interneurons may reverse the deficits in adulthood.
ESTHER : Cao_2018_Neuron_97_1253
PubMedSearch : Cao_2018_Neuron_97_1253
PubMedID: 29503190
Gene_locus related to this paper: mouse-3neur

Title : The Interplay between Synaptic Activity and Neuroligin Function in the CNS - Hu_2015_Biomed.Res.Int_2015_498957
Author(s) : Hu X , Luo JH , Xu J
Ref : Biomed Res Int , 2015 :498957 , 2015
Abstract : Neuroligins (NLs) are postsynaptic transmembrane cell-adhesion proteins that play a key role in the regulation of excitatory and inhibitory synapses. Previous in vitro and in vivo studies have suggested that NLs contribute to synapse formation and synaptic transmission. Consistent with their localization, NL1 and NL3 selectively affect excitatory synapses, whereas NL2 specifically affects inhibitory synapses. Deletions or mutations in NL genes have been found in patients with autism spectrum disorders or mental retardations, and mice harboring the reported NL deletions or mutations exhibit autism-related behaviors and synapse dysfunction. Conversely, synaptic activity can regulate the phosphorylation, expression, and cleavage of NLs, which, in turn, can influence synaptic activity. Thus, in clinical research, identifying the relationship between NLs and synapse function is critical. In this review, we primarily discuss how NLs and synaptic activity influence each other.
ESTHER : Hu_2015_Biomed.Res.Int_2015_498957
PubMedSearch : Hu_2015_Biomed.Res.Int_2015_498957
PubMedID: 25839034

Title : PICK1 Mediates Synaptic Recruitment of AMPA Receptors at Neurexin-Induced Postsynaptic Sites - Xu_2014_J.Neurosci_34_15415
Author(s) : Xu J , Kam C , Luo JH , Xia J
Ref : Journal of Neuroscience , 34 :15415 , 2014
Abstract : In the CNS, synapse formation and maturation play crucial roles in the construction and consolidation of neuronal circuits. Neurexin and neuroligin localize on the opposite sides of synaptic membrane and interact with each other to promote the assembly and specialization of synapses. However, the excitatory synapses induced by the neurexin-neuroligin complex are initially immature synapses that lack AMPA receptors. Previously, PICK1 (protein interacting with C kinase 1) was shown to cluster and regulate the synaptic localization of AMPA receptors. Here, we report that during synaptogenesis induced by neurexin in cultured neurons from rat hippocampus, PICK1 recruited AMPA receptors to immature postsynaptic sites. This synaptic recruitment of AMPA receptors depended on the interaction between GluA2 and PICK1, and on the lipid-binding ability of PICK1, but not the interaction between PICK1 and neuroligin. Last, our results demonstrated that the recruitment of GluA2 to synapses could be prevented by ICA69 (islet cell autoantigen 69 kDa), a key binding partner of PICK1. Our study showed that PICK1, being negatively regulated by ICA69, could facilitate synapse maturation.
ESTHER : Xu_2014_J.Neurosci_34_15415
PubMedSearch : Xu_2014_J.Neurosci_34_15415
PubMedID: 25392508