Hypersocial behavior and biological redundancy in mice with reduced expression of PSD95 or PSD93

Winkler, Daniela; Daher, Fernanda; Wüstefeld, Liane; Hammerschmidt, Kurt; Poggi, Giulia; Seelbach, Anna; Krueger‐Burg, Dilja; Vafadari, Behnam; Ronnenberg, Anja; Liu, Yanling; Kaczmarek, Leszek; Schlüter, Oliver M.; Ehrenreich, Hannelore; Dere, Ekrem

doi:10.1016/j.bbr.2017.02.011

Cited by 47 publications

(61 citation statements)

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“…Both DLG2/ PSD-93 and DLG4/PSD-95 are members of the MAGUK family that play important roles as scaffolding proteins at excitatory synapses. It has been previously reported that DLG4/PSD-95-deficient mice have increased levels of DLG2 expression, implying potential compensatory responses [19]. After first confirming knockout of DLG2 protein upon deletion of exon 14 of the Dlg2 gene ( Fig.…”

Section: A Dlg2 Deficiency Does Not Affect Dlg4/psd-95 Protein Expresmentioning

confidence: 69%

“…Previous studies have reported decreased open-field locomotion of DLG2-and DLG4-deficient mice [19,30]. To investigate whether this abnormal-locomotion phenotype is replicated in Dlg2 -/mice lacking exon 14, we tested locomotor traits in two different settings: home cage and open-field arena (Fig.…”

Section: Dlg2 -/Mice Show Aberrant Locomotor Responses To Noveltymentioning

confidence: 99%

“…Recently, a study using largescale whole-genome sequencing identified the recurrent deletions in the promotor region of DLG2 gene that were significantly associated with ASD, suggesting that such variations in its non-coding regulatory region may play a role in ASD [17]. In addition, studies using mice lacking exon 9 of the Dlg2 gene have shown that DLG2 plays a role in controlling complex learning and cognitive flexibility [18] and direct social interactions [19]. Nevertheless, the mechanisms that link DLG2-associated mutations to autism-relevant behavioral abnormalities have remained elusive.…”

Section: Introductionmentioning

confidence: 99%

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A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum

et al. 2020

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Background: DLG2, also known as postsynaptic density protein-93 (PSD-93) or chapsyn-110, is an excitatory postsynaptic scaffolding protein that interacts with synaptic surface receptors and signaling molecules. A recent study has demonstrated that mutations in the DLG2 promoter region are significantly associated with autism spectrum disorder (ASD). Although DLG2 is well known as a schizophrenia-susceptibility gene, the mechanisms that link DLG2 gene disruption with ASD-like behaviors remain unclear. Methods: Mice lacking exon 14 of the Dlg2 gene (Dlg2-/mice) were used to investigate whether Dlg2 deletion leads to ASD-like behavioral abnormalities. To this end, we performed a battery of behavioral tests assessing locomotion, anxiety, sociability, and repetitive behaviors. In situ hybridization was performed to determine expression levels of Dlg2 mRNA in different mouse brain regions during embryonic and postnatal brain development. We also measured excitatory and inhibitory synaptic currents to determine the impacts of Dlg2 deletion on synaptic transmission in the dorsolateral striatum. Results: Dlg2-/mice showed hypoactivity in a novel environment. They also exhibited decreased social approach, but normal social novelty recognition, compared with wild-type animals. In addition, Dlg2-/mice displayed strong self-grooming, both in home cages and novel environments. Dlg2 mRNA levels in the striatum were heightened until postnatal day 7 in mice, implying potential roles of DLG2 in the development of striatal connectivity. In addition, the frequency of excitatory, but not inhibitory, spontaneous postsynaptic currents in the Dlg2-/dorsolateral striatum was significantly reduced. Conclusion: These results suggest that homozygous Dlg2 deletion in mice leads to ASD-like behavioral phenotypes, including social deficits and increased repetitive behaviors, as well as reductions in excitatory synaptic input onto dorsolateral spiny projection neurons, implying that the dorsal striatum is one of the brain regions vulnerable to the developmental dysregulation of DLG2.

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Section: A Dlg2 Deficiency Does Not Affect Dlg4/psd-95 Protein Expresmentioning

confidence: 69%

Section: Dlg2 -/Mice Show Aberrant Locomotor Responses To Noveltymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum

et al. 2020

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“…In most disease-related studies, tested mice emit fewer calls as compared to controls [42] although this behavioral pattern cannot be generalized. Indeed, female PSD95 +/− mice exhibit increased vocalization upon exposure to another mouse [48], while BTBR T + tf/J and SAPAP3-deficient (SAP90/PSD95-associated protein 3) mice pups present a higher number of calls when separated from their mother [49,50]. Winkler and colleagues suggested that transgenic mice displaying fewer calls may carry a monogenic mutation with restricted and narrow functions, while mutations targeting proteins responsible for the organization of multiple proteins complexes may lead to more intricate behavioral outcomes [48].…”

Section: Discussionmentioning

confidence: 99%

Alteration in the time and/or mode of delivery differentially modulates early development in mice

2020

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Delivery is a complex biological process involving hormonal and mechanical stimuli that together condition the survival and development of the fetus out of the womb. Accordingly, changes in the time or way of being born are associated with an alteration of fundamental biological functions and hypothesized to promote the emergence of neurodevelopmental disorders. Hence, the steadily rise in preterm birth and cesarean section (CS) delivery rates over the past years has become a worldwide health concern. In our previous work, we reported that even though no long-term autistic-like deficits were observed, mice born preterm by CS presented early transient neuronal and communicative defects. However, understanding if these alterations were due to an early birth combined with CS delivery, or if prematurity solely could lead to a similar outcome remained to be evaluated. Using mice born either at term or preterm by vaginal or CS delivery, we assessed early life ultrasonic vocalizations and the onset of eye opening. We report that alterations in communicative behaviors are finely attuned and specifically affected either by preterm birth or by the association between CS delivery and preterm birth in mice, while delayed onset of eye opening is due to prematurity. Moreover, our work further underlies a gender-dependent vulnerability to changes in the time and/or way of being born with distinct outcomes observed in males and females. Thus, our results shed light on the intricacy of birth alterations and might further explain the disparities reported in epidemiological studies.

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“…A third Dlg4 −/+ mouse model found that mice displayed hypersocial behavior in the dyadic interaction test, mild hypoactivity in the open field but no obvious motor deficit 27. Thus, DLG4-related disorder can be classified within the group of synaptopathies comprising different alterations of proteins such as neurologins, neurexins and SHANK proteins, which are responsible for diverse neurological and neurodevelopemental phenotypes, including epilepsy, ID, ASD and schizophrenia 28.…”

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confidence: 99%

Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features

et al. 2018

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Marfanoid habitus (MH) combined with intellectual disability (ID) is a genetically and clinically heterogeneous group of overlapping disorders. We performed exome sequencing in 33 trios and 31 single probands to identify novel genes specific to MH-ID. After the search for variants in known disease-causing genes and non-disease-causing genes with classical approaches, we searched for variants in non-disease-causing genes whose pLI was above 0.9 (ExAC Consortium data), in which truncating variants were found in at least 3 unrelated patients. Only DLG4 gene met these criteria. Data from the literature and various databases also indicated its implication in ID. DLG4 encodes post-synaptic density protein 95 (PSD-95), a protein expressed in various tissues, including the brain. In neurons, PSD-95 is located at the post-synaptic density, and is associated with glutamatergic receptor signaling (NMDA and AMPA). PSD-95 probably participates in dendritogenesis. Two patients were heterozygous for de novo frameshift variants and one patient carried a a consensus splice site variant. Gene expression studies supported their pathogenicity through haploinsufficiency and loss-of-function. Patients exhibited mild-to-moderate ID, similar marfanoid features, including a long face, high-arched palate, long and thin fingers, pectus excavatum, scoliosis and ophthalmological manifestations (nystagmus or strabismus). Our study emphasizes the role of DLG4 as a novel post-synaptic-associated gene involved in syndromic ID associated with MH.

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Hypersocial behavior and biological redundancy in mice with reduced expression of PSD95 or PSD93

Cited by 47 publications

References 47 publications

A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum

A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum

Alteration in the time and/or mode of delivery differentially modulates early development in mice

Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features

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