Df(h22q11)/+ mouse model exhibits reduced binding levels of GABAA receptors and structural and functional dysregulation in the inhibitory and excitatory networks of hippocampus

Abdel-Rahman Al-Absi; Sakeerthi Kethees Thambiappa; Ahmad Raza Khan; Simon Glerup; Connie Sanchez; Anne M Landau; Jens R Nyengaard

doi:10.1016/j.mcn.2022.103769

Df(h22q11)/+ mouse model exhibits reduced binding levels of GABA_A receptors and structural and functional dysregulation in the inhibitory and excitatory networks of hippocampus

Abdel-Rahman Al-Absi^*, Sakeerthi Kethees Thambiappa, Ahmad Raza Khan, Simon Glerup, Connie Sanchez, Anne M Landau, Jens R Nyengaard

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

3 Citations (Scopus)

Abstract

The 22q11.2 hemizygous deletion confers high risk for multiple neurodevelopmental disorders. Inhibitory signaling, largely regulated through GABAA receptors, is suggested to serve a multitude of brain functions that are disrupted in the 22q11.2 deletion syndrome. We investigated the putative deficit of GABAA receptors and the potential substrates contributing to the inhibitory and excitatory dysregulations in hippocampal networks of the Df(h22q11)/+ mouse model of the 22q11.2 hemizygous deletion. The Df(h22q11)/+ mice exhibited impairments in several hippocampus-related functional domains, represented by impaired spatial memory and sensory gating functions. Autoradiography using the [3H]muscimol tracer revealed a significant reduction in GABAA receptor binding in the CA1 and CA3 subregions, together with a loss of GAD67+ interneurons in CA1 of Df(h22q11)/+ mice. Furthermore, electrophysiology recordings exhibited significantly higher neuronal activity in CA3, in response to the GABAA receptor antagonist, bicuculline, as compared with wild type mice. Density and volume of dendritic spines in pyramidal neurons were reduced and Sholl analysis also showed a reduction in the complexity of basal dendritic tree in CA1 and CA3 subregions of Df(h22q11)/+ mice. Overall, our findings demonstrate that hemizygous deletion in the 22q11.2 locus leads to dysregulations in the inhibitory circuits, involving reduced binding levels of GABAA receptors, in addition to functional and structural modulations of the excitatory networks of hippocampus.

Original language	English
Article number	103769
Journal	Molecular and Cellular Neuroscience
Volume	122
Number of pages	11
ISSN	1044-7431
DOIs	https://doi.org/10.1016/j.mcn.2022.103769
Publication status	Published - Sept 2022

Keywords

22q11.2 hemizygous deletion
GABA receptors
Hippocampus
Pyramidal neurons
[ H]muscimol
Pyramidal Cells/metabolism
gamma-Aminobutyric Acid/metabolism
Animals
Hippocampus/metabolism
Receptors, GABA-A/genetics
Mice
Muscimol/metabolism
Disease Models, Animal

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Cite this

Al-Absi, A.-R., Thambiappa, S. K., Khan, A. R., Glerup, S., Sanchez, C., Landau, A. M., & Nyengaard, J. R. (2022). Df(h22q11)/+ mouse model exhibits reduced binding levels of GABA_A receptors and structural and functional dysregulation in the inhibitory and excitatory networks of hippocampus. Molecular and Cellular Neuroscience, 122, Article 103769. https://doi.org/10.1016/j.mcn.2022.103769

@article{df609e60395140378a8fbdaa111813d5,

title = "Df(h22q11)/+ mouse model exhibits reduced binding levels of GABAA receptors and structural and functional dysregulation in the inhibitory and excitatory networks of hippocampus",

abstract = "The 22q11.2 hemizygous deletion confers high risk for multiple neurodevelopmental disorders. Inhibitory signaling, largely regulated through GABAA receptors, is suggested to serve a multitude of brain functions that are disrupted in the 22q11.2 deletion syndrome. We investigated the putative deficit of GABAA receptors and the potential substrates contributing to the inhibitory and excitatory dysregulations in hippocampal networks of the Df(h22q11)/+ mouse model of the 22q11.2 hemizygous deletion. The Df(h22q11)/+ mice exhibited impairments in several hippocampus-related functional domains, represented by impaired spatial memory and sensory gating functions. Autoradiography using the [3H]muscimol tracer revealed a significant reduction in GABAA receptor binding in the CA1 and CA3 subregions, together with a loss of GAD67+ interneurons in CA1 of Df(h22q11)/+ mice. Furthermore, electrophysiology recordings exhibited significantly higher neuronal activity in CA3, in response to the GABAA receptor antagonist, bicuculline, as compared with wild type mice. Density and volume of dendritic spines in pyramidal neurons were reduced and Sholl analysis also showed a reduction in the complexity of basal dendritic tree in CA1 and CA3 subregions of Df(h22q11)/+ mice. Overall, our findings demonstrate that hemizygous deletion in the 22q11.2 locus leads to dysregulations in the inhibitory circuits, involving reduced binding levels of GABAA receptors, in addition to functional and structural modulations of the excitatory networks of hippocampus.",

keywords = "22q11.2 hemizygous deletion, GABA receptors, Hippocampus, Pyramidal neurons, [ H]muscimol, Pyramidal Cells/metabolism, gamma-Aminobutyric Acid/metabolism, Animals, Hippocampus/metabolism, Receptors, GABA-A/genetics, Mice, Muscimol/metabolism, Disease Models, Animal",

author = "Abdel-Rahman Al-Absi and Thambiappa, {Sakeerthi Kethees} and Khan, {Ahmad Raza} and Simon Glerup and Connie Sanchez and Landau, {Anne M} and Nyengaard, {Jens R}",

year = "2022",

month = sep,

doi = "10.1016/j.mcn.2022.103769",

language = "English",

volume = "122",

journal = "Molecular and Cellular Neuroscience",

issn = "1044-7431",

publisher = "Academic Press Inc.",

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Al-Absi, A-R, Thambiappa, SK, Khan, AR, Glerup, S , Sanchez, C , Landau, AM & Nyengaard, JR 2022, 'Df(h22q11)/+ mouse model exhibits reduced binding levels of GABA_A receptors and structural and functional dysregulation in the inhibitory and excitatory networks of hippocampus', Molecular and Cellular Neuroscience, vol. 122, 103769. https://doi.org/10.1016/j.mcn.2022.103769

Df(h22q11)/+ mouse model exhibits reduced binding levels of GABA_A receptors and structural and functional dysregulation in the inhibitory and excitatory networks of hippocampus. / Al-Absi, Abdel-Rahman; Thambiappa, Sakeerthi Kethees; Khan, Ahmad Raza et al.
In: Molecular and Cellular Neuroscience, Vol. 122, 103769, 09.2022.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Df(h22q11)/+ mouse model exhibits reduced binding levels of GABAA receptors and structural and functional dysregulation in the inhibitory and excitatory networks of hippocampus

AU - Al-Absi, Abdel-Rahman

AU - Thambiappa, Sakeerthi Kethees

AU - Khan, Ahmad Raza

AU - Glerup, Simon

AU - Sanchez, Connie

AU - Landau, Anne M

AU - Nyengaard, Jens R

PY - 2022/9

Y1 - 2022/9

N2 - The 22q11.2 hemizygous deletion confers high risk for multiple neurodevelopmental disorders. Inhibitory signaling, largely regulated through GABAA receptors, is suggested to serve a multitude of brain functions that are disrupted in the 22q11.2 deletion syndrome. We investigated the putative deficit of GABAA receptors and the potential substrates contributing to the inhibitory and excitatory dysregulations in hippocampal networks of the Df(h22q11)/+ mouse model of the 22q11.2 hemizygous deletion. The Df(h22q11)/+ mice exhibited impairments in several hippocampus-related functional domains, represented by impaired spatial memory and sensory gating functions. Autoradiography using the [3H]muscimol tracer revealed a significant reduction in GABAA receptor binding in the CA1 and CA3 subregions, together with a loss of GAD67+ interneurons in CA1 of Df(h22q11)/+ mice. Furthermore, electrophysiology recordings exhibited significantly higher neuronal activity in CA3, in response to the GABAA receptor antagonist, bicuculline, as compared with wild type mice. Density and volume of dendritic spines in pyramidal neurons were reduced and Sholl analysis also showed a reduction in the complexity of basal dendritic tree in CA1 and CA3 subregions of Df(h22q11)/+ mice. Overall, our findings demonstrate that hemizygous deletion in the 22q11.2 locus leads to dysregulations in the inhibitory circuits, involving reduced binding levels of GABAA receptors, in addition to functional and structural modulations of the excitatory networks of hippocampus.

AB - The 22q11.2 hemizygous deletion confers high risk for multiple neurodevelopmental disorders. Inhibitory signaling, largely regulated through GABAA receptors, is suggested to serve a multitude of brain functions that are disrupted in the 22q11.2 deletion syndrome. We investigated the putative deficit of GABAA receptors and the potential substrates contributing to the inhibitory and excitatory dysregulations in hippocampal networks of the Df(h22q11)/+ mouse model of the 22q11.2 hemizygous deletion. The Df(h22q11)/+ mice exhibited impairments in several hippocampus-related functional domains, represented by impaired spatial memory and sensory gating functions. Autoradiography using the [3H]muscimol tracer revealed a significant reduction in GABAA receptor binding in the CA1 and CA3 subregions, together with a loss of GAD67+ interneurons in CA1 of Df(h22q11)/+ mice. Furthermore, electrophysiology recordings exhibited significantly higher neuronal activity in CA3, in response to the GABAA receptor antagonist, bicuculline, as compared with wild type mice. Density and volume of dendritic spines in pyramidal neurons were reduced and Sholl analysis also showed a reduction in the complexity of basal dendritic tree in CA1 and CA3 subregions of Df(h22q11)/+ mice. Overall, our findings demonstrate that hemizygous deletion in the 22q11.2 locus leads to dysregulations in the inhibitory circuits, involving reduced binding levels of GABAA receptors, in addition to functional and structural modulations of the excitatory networks of hippocampus.

KW - 22q11.2 hemizygous deletion

KW - GABA receptors

KW - Hippocampus

KW - Pyramidal neurons

KW - [ H]muscimol

KW - Pyramidal Cells/metabolism

KW - gamma-Aminobutyric Acid/metabolism

KW - Animals

KW - Hippocampus/metabolism

KW - Receptors, GABA-A/genetics

KW - Mice

KW - Muscimol/metabolism

KW - Disease Models, Animal

U2 - 10.1016/j.mcn.2022.103769

DO - 10.1016/j.mcn.2022.103769

M3 - Journal article

C2 - 35988854

SN - 1044-7431

VL - 122

JO - Molecular and Cellular Neuroscience

JF - Molecular and Cellular Neuroscience

M1 - 103769

ER -