PSD-95 deficiency alters GABAergic inhibition in the prefrontal cortex

McEachern, Erin; Coley, Austin A.; Yang, Sha-Sha; Gao, Wenjun

doi:10.1016/j.neuropharm.2020.108277

Cited by 17 publications

(5 citation statements)

References 47 publications

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“…However, it is also possible that the presynaptic role is a secondary effect of postsynaptic maturation. Indeed, we recently reported that PSD-95 deficiency results in a significant increase in synaptic inhibition and thus a dramatic shift in the excitatory-to-inhibitory balance in the prefrontal neurons via upregulation and trafficking of neuroligin-2 and reduced GSK3β activity through tyr-216 phosphorylation (McEachern et al, 2020 ).…”

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confidence: 99%

From Hyposociability to Hypersociability—The Effects of PSD-95 Deficiency on the Dysfunctional Development of Social Behavior

Gao

Mack

2021

Front. Behav. Neurosci.

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Abnormal social behavior, including both hypo- and hypersociability, is often observed in neurodevelopmental disorders such as autism spectrum disorders. However, the mechanisms associated with these two distinct social behavior abnormalities remain unknown. Postsynaptic density protein-95 (PSD-95) is a highly abundant scaffolding protein in the excitatory synapses and an essential regulator of synaptic maturation by binding to NMDA and AMPA receptors. The DLG4 gene encodes PSD-95, and it is a risk gene for hypersocial behavior. Interestingly, PSD-95 knockout mice exhibit hyposociability during adolescence but hypersociability in adulthood. The adolescent hyposociability is accompanied with an NMDAR hyperfunction in the medial prefrontal cortex (mPFC), an essential part of the social brain for control of sociability. The maturation of mPFC development is delayed until young adults. However, how PSD-95 deficiency affects the functional maturation of mPFC and its connection with other social brain regions remains uncharacterized. It is especially unknown how PSD-95 knockout drives the switch of social behavior from hypo- to hyper-sociability during adolescent-to-adult development. We propose an NMDAR-dependent developmental switch of hypo- to hyper-sociability. PSD-95 deficiency disrupts NMDAR-mediated synaptic connectivity of mPFC and social brain during development in an age- and pathway-specific manner. By utilizing the PSD-95 deficiency mouse, the mechanisms contributing to both hypo- and hyper-sociability can be studied in the same model. This will allow us to assess both local and long-range connectivity of mPFC and examine how they are involved in the distinct impairments in social behavior and how changes in these connections may mature over time.

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confidence: 99%

From Hyposociability to Hypersociability—The Effects of PSD-95 Deficiency on the Dysfunctional Development of Social Behavior

Gao

Mack

2021

Front. Behav. Neurosci.

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“…3 a) does not affect N2a neuronal cell morphology (cell eccentricity; Fig. 3 b, p = 0.117; ANOVA) or the mRNA expression of PSD-95, a key regulatory protein that controls the maturation, size, and strength of synapses 50 , 51 ( Fig. 3 c, p = 0.853; ANOVA + Dunnett's).…”

Section: Resultsmentioning

confidence: 94%

Restoring myocardial infarction-induced long-term memory impairment by targeting the cystic fibrosis transmembrane regulator

Vanherle¹,

Lidington²,

Uhl³

et al. 2022

eBioMedicine

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“…Indeed, α7 nAChR binds to the PDZ domain of PICK1 with an affinity of ∼3 μM, , which significantly surpasses the affinities observed for PDZ1 (∼100 μM) and PDZ1–2 (12 μM), and is comparable to the affinity of PDZ-95 (1.2 μM) for binding iGluRs . PDZ-95, a key scaffolding protein, plays a crucial role in anchoring iGluRs and other receptors to the cell surface membranes. − Interestingly, despite similar binding affinities, PICK1 fails to stabilize α7 nAChR clusters in the same manner that PSD-95 does for iGluRs. − The underlying reasons for this discrepancy remain an open question for future research. − …”

Section: Discussionmentioning

confidence: 93%

Unconventional PDZ Recognition Revealed in α7 nAChR-PICK1 Complexes

Bondarenko,

Chen,

Tillman

et al. 2024

ACS Chem. Neurosci.

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PDZ domains are modular domains that conventionally bind to C terminal or internal motifs of target proteins to control cellular functions through the regulation of protein complex assemblies. Almost all reported structures of PDZ-target protein complexes rely on fragments or peptides as target proteins. No intact target protein complexed with PDZ was structurally characterized. In this study, we used NMR spectroscopy and other biochemistry and biophysics tools to uncover insights into structural coupling between the PDZ domain of protein interacting with C-kinase 1 (PICK1) and α7 nicotinic acetylcholine receptors (α7 nAChR). Notably, the intracellular domains of both α7 nAChR and PICK1 PDZ exhibit a high degree of plasticity in their coupling. Specifically, the MA helix of α7 nAChR interacts with residues lining the canonical binding site of the PICK1 PDZ, while flexible loops also engage in protein−protein interactions. Both hydrophobic and electrostatic interactions mediate the coupling. Overall, the resulting structure of the α7 nAChR-PICK1 complex reveals an unconventional PDZ binding mode, significantly expanding the repertoire of functionally important PDZ interactions.

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PSD-95 deficiency alters GABAergic inhibition in the prefrontal cortex

Cited by 17 publications

References 47 publications

From Hyposociability to Hypersociability—The Effects of PSD-95 Deficiency on the Dysfunctional Development of Social Behavior

From Hyposociability to Hypersociability—The Effects of PSD-95 Deficiency on the Dysfunctional Development of Social Behavior

Restoring myocardial infarction-induced long-term memory impairment by targeting the cystic fibrosis transmembrane regulator

Unconventional PDZ Recognition Revealed in α7 nAChR-PICK1 Complexes

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