Adeno-associated viral overexpression of neuroligin 2 in the mouse hippocampus enhances GABAergic synapses and impairs hippocampal-dependent behaviors

Zandt, Meghan A. Van; Weiss, E.; Almyasheva, A.; Lipior, S.; Maisel, Samantha; Naegele, Janice R.

doi:10.1016/j.bbr.2018.12.052

Cited by 12 publications

(7 citation statements)

References 113 publications

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“…The present study confirmed that exogenous NL2 was expressed on neurons and colocalized with gephyrin, a GABAergic postsynaptic protein. This finding is consistent with a previous study reporting that AAV vector‐mediated local gene delivery of NL2 into hippocampal neurons increased the neuronal expression of NL2, gephyrin and GABAARγ2, suggesting trans‐synaptic enhancement of GABAergic synapses 47 …”

Section: Discussionsupporting

confidence: 93%

Global brain delivery of neuroligin 2 gene ameliorates seizures in a mouse model of epilepsy

Oguro

Shimazaki

Yokota

et al. 2022

The Journal of Gene Medicine

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Background Despite the increasing availability of effective drugs, around one‐third of patients with epilepsy are still resistant to pharmacotherapy. Gene therapy has been suggested as a plausible approach to achieve seizure control, in particular for patients with focal epilepsy. Because seizures develop across wide spans of the brain in many forms of epilepsy, global delivery of the vectors is necessary to tackle such generalized seizures. Neuroligin 2 (NL2) is a postsynaptic cell adhesion molecule that induces or strengthens inhibitory synaptic function by specifically combining with neurexin 1. Methods In the present study, we applied an adeno‐associated virus (AAV) type 9 vector expressing NL2 to modulate neuronal excitability in broad areas of the brain in epileptic (EL) mice, a model of polygene epilepsy. We administered the AAV vector expressing Flag‐tagged NL2 under the synapsin I promoter (AAV‐NL2) via cardiac injection 6 weeks after birth. Results Significant reductions in the duration, strength and frequency of seizure were observed during a 14‐week observation period in NL2‐treated EL mice compared to untreated or AAV‐green fluorescent protein‐treated EL mice. No behavioral abnormality was observed in NL2‐treated EL mice in an open‐field test. Immunohistochemical examination at 14 weeks after AAV‐NL2 injection revealed the expression of exogenous NL2 in broad areas of the brain, including the hippocampus and, in these areas, NL2 co‐localized with postsynaptic inhibitory molecule gephyrin. Conclusions Global brain delivery of NL2 by systemic administration of AAV vector may provide a non‐invasive therapeutic approach for generalized epilepsy.

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Section: Discussionsupporting

confidence: 93%

Global brain delivery of neuroligin 2 gene ameliorates seizures in a mouse model of epilepsy

Oguro

Shimazaki

Yokota

et al. 2022

The Journal of Gene Medicine

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“…Reduced NLGN2 expression in the prefrontal cortex (PFC) is involved in attention deficits induced by peripubertal stress which can be reversed by virus-mediated NLGN2 rescue (Tzanoulinou et al, 2016). Animal models using the genetic engineering method showed that Nlgn 2 R215H knock-in (KI) mouse exhibited schizophrenia-like behaviors and higher anxiety behaviors with significant reduction of mIPSCs in the dentate gyrus (DG), reduced subunit GABA-A γ2 expression levels, and reduced presynaptic PV and VGAT levels, while there were no changes of miniature excitatory postsynaptic currents (mEPSCs), vesicular glutamate transporter (VGLUT), and postsynaptic density protein 95 (PSD95) expression levels (Jiang et al, 2018;Van Zandt et al, 2019). NLGN2 of ACC is involved in KCC2-mediated abnormal GABAergic transmission induced aggressive behaviors (Jager et al, 2020).…”

Section: Nlgn2 3 Andmentioning

confidence: 99%

GABAergic System Dysfunction in Autism Spectrum Disorders

Zhao

Mao

Zhu

et al. 2022

Front. Cell Dev. Biol.

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Autism spectrum disorder (ASD) refers to a series of neurodevelopmental diseases characterized by two hallmark symptoms, social communication deficits and repetitive behaviors. Gamma-aminobutyric acid (GABA) is one of the most important inhibitory neurotransmitters in the central nervous system (CNS). GABAergic inhibitory neurotransmission is critical for the regulation of brain rhythm and spontaneous neuronal activities during neurodevelopment. Genetic evidence has identified some variations of genes associated with the GABA system, indicating an abnormal excitatory/inhibitory (E/I) neurotransmission ratio implicated in the pathogenesis of ASD. However, the specific molecular mechanism by which GABA and GABAergic synaptic transmission affect ASD remains unclear. Transgenic technology enables translating genetic variations into rodent models to further investigate the structural and functional synaptic dysregulation related to ASD. In this review, we summarized evidence from human neuroimaging, postmortem, and genetic and pharmacological studies, and put emphasis on the GABAergic synaptic dysregulation and consequent E/I imbalance. We attempt to illuminate the pathophysiological role of structural and functional synaptic dysregulation in ASD and provide insights for future investigation.

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“…Two studies have investigated AAV-mediated overexpression of NL2 in the hippocampus. In one study, overexpression of NL2 results in increased gephyrin clusters and VGAT+ puncta by confocal microscopy immunofluorescence and an increase in the gephyrin, VGAT and GABA A R-γ2 subunit protein expression by western blot, suggesting a strengthening inhibitory synapses in the transduced neurons (Van Zandt et al, 2019). In the other study, increased NL2 expression leads to increased mRNA levels for GAD65, but no increase in neurexin-1, gephyrin, or GAD67 mRNAs (Kohl et al, 2013).…”

Section: Discussionmentioning

confidence: 96%

Selective Overexpression of Collybistin in Mouse Hippocampal Pyramidal Cells Enhances GABAergic Neurotransmission and Protects against PTZ-Induced Seizures

George

James

Blas

2021

eNeuro

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Collybistin (CB) is a rho guanine exchange factor found at GABAergic and glycinergic postsynapses that interacts with the inhibitory scaffold protein, gephyrin, and induces accumulation of gephyrin and GABA A receptors (GABA A Rs) to the postsynapse. We have previously reported that the isoform without the src homology 3 (SH3) domain, CBSH3-, is particularly active in enhancing the GABAergic postsynapse in both cultured hippocampal neurons as well as in cortical pyramidal neurons after chronic in vivo expression in in utero electroporated (IUE) rats. Deficiency of CB in knockout mice results in absence of gephyrin and gephyrin-dependent GABA A Rs at postsynaptic sites in several brain regions, including hippocampus. In the present study, we have generated an adeno-associated virus (AAV) that expresses CBSH3-in a cre-dependent manner. Using male and female VGLUT1-IRES-cre or VGAT-IRES-cre mice, we explore the effect of overexpression of CBSH3-in hippocampal pyramidal cells or hippocampal interneurons. The results show that: 1) the accumulation of gephyrin and GABA A Rs at inhibitory postsynapses in hippocampal pyramidal neurons or interneurons can be enhanced by CBSH3-overexpression, 2) overexpression of CBSH3-in hippocampal pyramidal cells can enhance the strength of inhibitory neurotransmission, and 3) these enhanced inhibitory synapses provide protection against PTZ-induced seizures. The results indicate that this AAV vector carrying CBSH3-can be used for in vivo enhancement of GABAergic synaptic transmission in selected target neurons in the brain.Significance statement: Excessive or imbalanced excitation in the hippocampus can result in acute or chronic pathological conditions, such as seizures, epilepsy, and learning impairments. It is therefore important to uncover target genes that can be manipulated to restore or prevent this imbalance. This study uses a novel adeno-associated virus to express collybistin SH3-in select cells of the hippocampus. We have found that overexpression of this protein enhances GABAergic inhibitory synaptic transmission. The results also bring attention to collybistin as a possible target for therapeutic intervention aimed to restore the balance between excitation and inhibition.

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Adeno-associated viral overexpression of neuroligin 2 in the mouse hippocampus enhances GABAergic synapses and impairs hippocampal-dependent behaviors

Cited by 12 publications

References 113 publications

Global brain delivery of neuroligin 2 gene ameliorates seizures in a mouse model of epilepsy

Global brain delivery of neuroligin 2 gene ameliorates seizures in a mouse model of epilepsy

GABAergic System Dysfunction in Autism Spectrum Disorders

Selective Overexpression of Collybistin in Mouse Hippocampal Pyramidal Cells Enhances GABAergic Neurotransmission and Protects against PTZ-Induced Seizures

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