title: Reduced cognition in Syngap1 mutants is caused by isolated damage within developing forebrain excitatory neurons.
abstract: Syngap1 haploinsufficiency is a common cause of sporadic intellectual disability. Syngap1 mutations disrupt developing pyramidal neurons, although it remains unclear if this process contributes to cognitive abnormalities. Here, we found that haploinsufficiency restricted to forebrain glutamatergic neurons was sufficient to disrupt cognition and removing mutations from this population prevented cognitive abnormalities. In contrast, manipulating Syngap1 function in GABAergic neurons had no effect on cognition, excitability, or neurotransmission, highlighting the specificity of Syngap1 mutations within forebrain excitatory neurons. Interestingly, cognitive abnormalities were reliably predicted by the emergence of enhanced excitatory synaptic function in mature superficial cortical pyramidal cells, which was a neurophysiological disruption caused by Syngap1 dysfunction in developing, but not adult, forebrain neurons. We conclude that reduced cognition in Syngap1 mutants is caused by isolated damage to developing forebrain glutamatergic neurons. This damage triggers secondary disruptions to synaptic homeostasis in mature cortical pyramidal cells, which perpetuates brain dysfunction into adulthood.
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Emin D
authors.initials: ED
authors.lastname: Ozkan
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Creson
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92797, USA.
authors.forename: Enikö A
authors.initials: EA
authors.lastname: Kramár
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Camilo
authors.initials: C
authors.lastname: Rojas
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92797, USA.
authors.forename: Ron R
authors.initials: RR
authors.lastname: Seese
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92797, USA.
authors.forename: Alex H
authors.initials: AH
authors.lastname: Babyan
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92797, USA.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Developmental Neurogenetics Laboratory, Departments of Neurology, Neuroscience, and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Rocco
authors.initials: R
authors.lastname: Lucero
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92797, USA.
authors.forename: Xiangmin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Developmental Neurogenetics Laboratory, Departments of Neurology, Neuroscience, and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Noebels
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA; Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Miller
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92797, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Lynch
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA. Electronic address: grumbaug@scripps.edu.
authors.forename: Gavin
authors.initials: G
authors.lastname: Rumbaugh
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000235:genetics*; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D016548:Prosencephalon / Q000254:growth & development* / Q000473:pathology; D011897:Random Allocation; D020703:ras GTPase-Activating Proteins / Q000235:genetics*
chemical_list: C484512:Syngap1 protein, mouse; D020703:ras GTPase-Activating Proteins