@article {2401,
	title = {Pharmacological intervention in young adolescents rescues synaptic physiology and behavioural deficits in Syngap1 mice.},
	journal = {Exp Brain Res},
	year = {2021},
	month = {2021 Nov 05},
	abstract = {<p>Haploinsufficiency in SYNGAP1 is implicated in intellectual disability (ID) and autism spectrum disorder (ASD) and affects the maturation of dendritic spines. The abnormal spine development has been suggested to cause a disbalance of excitatory and inhibitory (E/I) neurotransmission at distinct developmental periods. In addition, E/I imbalances in Syngap1 mice might be due to abnormalities in K-Cl co-transporter function (NKCC1, KCC2), in a maner similar to the murine models of Fragile-X and Rett syndromes. To study whether an altered intracellular chloride ion concentration represents an underlying mechanism of modified function of GABAergic synapses in Dentate Gyrus Granule Cells of Syngap1 recordings were performed at different developmental stages of the mice. We observed depolarised neurons at P14-15 as illustrated by decreased Cl reversal potential in Syngap1 mice. The KCC2 expression was decreased compared to Wild-type (WT) mice at P14-15. The GSK-3β inhibitor, 6-bromoindirubin-3{\textquoteright}-oxime (6BIO) that crosses the blood-brain barrier, was tested to restore the function of GABAergic synapses. We discovered that the intraperitoneal administration of 6BIO during the critical period or young adolescents [P30 to P80 (4-week to 10-week)] normalised an altered E/I balance, the deficits of synaptic plasticity, and behavioural performance like social novelty, anxiety, and memory of the Syngap1 mice. In summary, altered GABAergic function in Syngap1 mice is due to reduced KCC2 expression leading to an increase in the intracellular chloride concentration that can be counteracted by the 6BIO, which restored cognitive, emotional, and social symptoms by pharmacological intervention, particularly in adulthood.</p>
},
	issn = {1432-1106},
	doi = {10.1007/s00221-021-06254-x},
	author = {Verma, Vijaya and Kumar, M J Vijay and Sharma, Kavita and Rajaram, Sridhar and Muddashetty, Ravi and Manjithaya, Ravi and Behnisch, Thomas and Clement, James P}
}
@article {1982,
	title = {Differential Regulation of  Translation by FMRP Modulates eEF2 Mediated Response on NMDAR Activity.},
	journal = {Front Mol Neurosci},
	volume = {12},
	year = {2019},
	month = {2019},
	pages = {97},
	abstract = {<p>SYNGAP1, a Synaptic Ras-GTPase activating protein, regulates synapse maturation during a critical developmental window. Heterozygous mutation in () has been shown to cause Intellectual Disability (ID) in children. Recent studies have provided evidence for altered neuronal protein synthesis in a mouse model of . However, the molecular mechanism behind the same is unclear. Here, we report the reduced expression of a known translation regulator, FMRP, during a specific developmental period in mice. Our results demonstrate that FMRP interacts with and regulates the translation of mRNA. We further show reduced translation leads to decreased FMRP level during development in which results in an increase in translation. These developmental changes are reflected in the altered response of eEF2 phosphorylation downstream of NMDA Receptor (NMDAR)-mediated signaling. In this study, we propose a cross-talk between FMRP and SYNGAP1 mediated signaling which can also explain the compensatory effect of impaired signaling observed in mice.</p>
},
	issn = {1662-5099},
	doi = {10.3389/fnmol.2019.00097},
	author = {Paul, Abhik and Nawalpuri, Bharti and Shah, Devanshi and Sateesh, Shruthi and Muddashetty, Ravi S and Clement, James P}
}
