PT  - JOURNAL ARTICLE
AU  - Thomas K. Creson
AU  - Camilo Rojas
AU  - Ernie Hwaun
AU  - Thomas Vaissiere
AU  - Murat Kilinc
AU  - J. Lloyd Holder, Jr.
AU  - Jianrong Tang
AU  - Laura Lee Colgin
AU  - Courtney A. Miller
AU  - Gavin Rumbaugh
TI  - Re-expression of SynGAP Protein in Adulthood Improves Translatable Measures of Brain Function and Behavior in a Model of Neurodevelopmental Disorders
AID  - 10.1101/474965
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 474965
4099  - http://biorxiv.org/content/early/2018/11/20/474965.short
4100  - http://biorxiv.org/content/early/2018/11/20/474965.full
AB  - Background Neurodevelopmental disorder (NDD) risk genes have pleiotropic biological functions, such as control over both developmental and non-developmental processes that influence disease-related phenotypes. Currently, it remains unclear how developmental versus non-developmental processes influence the duration and/or effectiveness of permissive treatment windows for NDDs. SYNGAP1 haploinsufficiency causes an NDD defined by autistic traits, cognitive impairment, and epilepsy. Syngap1 heterozygosity in mice disrupts a developmental critical period, and, consistent with this, certain behavioral abnormalities are resistant to gene therapy initiated in adulthood. However, the Syngap1 endophenotype is extensive and this protein has diverse cell biological functions. Therefore, SynGAP pleiotropy may influence the permissive treatment window for previously untested disease-relevant phenotypes.Methods A whole-body gene restoration technique was used to determine how restoration of SynGAP protein in adult heterozygous mice impacted previously untested phenotypes, such as memory, seizure susceptibility, systems-level cortical hyperexcitability, and hippocampal oscillations linked to mnemonic processes.Results Adult restoration of SynGAP protein in haploinsufficient mice reversed long-term contextual memory deficits and behavioral measures of seizure susceptibility. Moreover, SynGAP re-expression in adult mice eliminated brain state-dependent, patient-linked paroxysmal interictal spiking and increased the amplitude of hippocampal theta oscillations.Conclusions SynGAP protein in the mature brain dynamically regulates neural circuit function and influences disease-relevant phenotypes. The impact of these findings is that treatments targeting certain debilitating aspects of SYNGAP1-related disorders may be effective throughout life. Moreover, the efficacy of experimental treatments for SYNGAP1 patients may be quantifiable through changes in species-conserved, state-dependent pathological electroencephalogram signals.Author ContributionsTKC, CR, JT and MK performed experiments. TKC, CR, JT, LLC, CAM, and GR designed experiments. TKC, CR, MK, TV, JLH, EH, CAM, and GR analyzed data. GR wrote the manuscript and conceived the study. TKC, CR JLH, LLC, EH and CAM edited the manuscript.This work was supported in part by NIH grants from the National Institute of Mental Health [MH096847 and MH108408 (GR), MH105400 (CAM), MH102450 (LLC)], the National Institute for Neurological Disorders and Stroke [NS064079 (GR)], and the National Institute for Drug Abuse [DA034116 and DA036376 (CAM), T32DA01892 (EH)]. JLH is supported by a National Institute for Neurological Disorders and Stroke Mentored Clinical Scientist Research Career Development Award [NS091381] and the Robbins Foundation.The video-EEG experiments were performed by the IDDRC Neuroconnectivity Core at Baylor College of Medicine.