Reduced Cognition in Syngap1 Mutants Is Caused by Isolated Damage within Developing Forebrain Excitatory Neurons

• Published in: Neuron (Cambridge, Mass.) Mass.), 2014-06, Vol.82 (6), p.1317-1333
• Main Authors: Ozkan, Emin D., Creson, Thomas K., Kramár, Enikö A., Rojas, Camilo, Seese, Ron R., Babyan, Alex H., Shi, Yulin, Lucero, Rocco, Xu, Xiangmin, Noebels, Jeffrey L., Miller, Courtney A., Lynch, Gary, Rumbaugh, Gavin
• Format: Article
• Language: English
• Subjects: Animals; Cognition Disorders - genetics; Excitatory Postsynaptic Potentials - genetics; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mutation - genetics; Neurons - pathology; Neurons - physiology; Prosencephalon - growth & development; Prosencephalon - pathology; Random Allocation; ras GTPase-Activating Proteins - genetics
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2014.05.015

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. •Adult Syngap1 mutants have altered cortical rhythms and network hyperexcitability•Early glutamatergic neuron dysfunction is necessary and sufficient to cause phenotype•Early glutamatergic neuron dysfunction causes synaptic dyshomeostasis in adulthood•Excitatory synaptic dyshomeostasis predicts cognitive dysfunction Syngap1 haploinsufficiency is a common cause of intellectual disability. It remains unclear how these genetic mutations cause cognitive impairments. Ozkan et al. found that reduced cognition in Syngap1 mutants is caused by isolated damage to developing, but not mature, forebrain glutamatergic neurons.