SynGAP regulates synaptic plasticity and cognition independently of its catalytic activity.

SynGAP is an abundant synaptic GTPase-activating protein (GAP) critical for synaptic plasticity, learning, memory, and cognition. Mutations in SYNGAP1 in humans result in intellectual disability, autistic-like behaviors, and epilepsy. Heterozygous Syngap1-knockout mice display deficits in synaptic plasticity, learning, and memory and exhibit seizures. It is unclear whether SynGAP imparts structural properties at synapses independently of its GAP activity. Here, we report that inactivating mutations within the GAP domain do not inhibit synaptic plasticity or cause behavioral deficits. Instead, SynGAP modulates synaptic strength by physically competing with the AMPA-receptor-TARP excitatory receptor complex in the formation of molecular condensates with synaptic scaffolding proteins. These results have major implications for developing therapeutic treatments for SYNGAP1-related neurodevelopmental disorders.

SynGAP isoforms differentially regulate synaptic plasticity and dendritic development.

SynGAP is a synaptic Ras GTPase-activating protein (GAP) with four C-terminal splice variants: α1, α2, ß, and γ. Although studies have implicated SYNGAP1 in several cognitive disorders, it is not clear which SynGAP isoforms contribute to disease. Here, we demonstrate that SynGAP isoforms exhibit unique spatiotemporal expression patterns and play distinct roles in neuronal and synaptic development in mouse neurons. SynGAP-α1, which undergoes liquid-liquid phase separation with PSD-95, is highly enriched in synapses and is required for LTP. In contrast, SynGAP-ß, which does not bind PSD-95 PDZ domains, is less synaptically targeted and promotes dendritic arborization. A mutation in SynGAP-α1 that disrupts phase separation and synaptic targeting abolishes its ability to regulate plasticity and instead causes it to drive dendritic development like SynGAP-ß. These results demonstrate that distinct intrinsic biochemical properties of SynGAP isoforms determine their function, and individual isoforms may differentially contribute to the pathogenesis of SYNGAP1-related cognitive disorders.

Twenty Years of SynGAP Research: From Synapses to Cognition.

SynGAP is a potent regulator of biochemical signaling in neurons and plays critical roles in neuronal function. It was first identified in 1998, and has since been extensively characterized as a mediator of synaptic plasticity. Because of its involvement in synaptic plasticity, SynGAP has emerged as a critical protein for normal cognitive function. In recent years, mutations in the SYNGAP1 gene have been shown to cause intellectual disability in humans and have been linked to other neurodevelopmental disorders, such as autism spectrum disorders and schizophrenia. While the structure and biochemical function of SynGAP have been well characterized, a unified understanding of the various roles of SynGAP at the synapse and its contributions to neuronal function remains to be achieved. In this review, we summarize and discuss the current understanding of the multifactorial role of SynGAP in regulating neuronal function gathered over the last two decades.

Synergistic effects of ß-amyloid and ceramide-induced insulin resistance on mitochondrial metabolism in neuronal cells.

A large body of evidence support major roles of mitochondrial dysfunction and insulin action in the Alzheimer's disease (AD) brain. However, interaction between cellular expression of ß-amyloid (Aß) and insulin resistance on mitochondrial metabolism has not been explored in neuronal cells. We investigated the additive and synergistic effects of intracellular Aß42 and ceramide-induced insulin resistance on mitochondrial metabolism in SH-SY5Y and Neuro-2a cells. In our model, mitochondria take-up Aß42 expressed through viral-mediated transfection and exposure of the same cells to ceramide produces resistance to insulin signaling. Ceramide alone increased phosphorylated MAP kinases while decreasing phospho-Akt (Ser473). The combination of Aß42 and ceramide synergistically decreased phospho-Thr308 on Akt. Aß42 and ceramide synergistically also decreased mitochondrial complex III activity and ATP generation whereas Aß alone was largely responsible for complex IV inhibition and increases in mitochondrial reactive oxygen species production (ROS). Proteomic analysis showed that a number of mitochondrial respiratory chain and tricarboxylic acid cycle enzymes were additively or synergistically decreased by ceramide in combination with Aß42 expression. Mitochondrial fusion and fission proteins were notably dysregulated by Aß42 (Mfn1) or Aß42 plus ceramide (OPA1, Drp1). Antioxidant vitamins blocked the Aß42 alone-induced ROS production, but did not reverse Aß42-induced ATP reduction or complex IV inhibition. Aß expression combined with ceramide exposure had additive effects to decrease cell viability. Taken together, our data demonstrate that Aß42 expression and ceramide-induced insulin resistance synergistically interact to exacerbate mitochondrial damage and that therapeutic efforts to reduce insulin resistance could lessen failures of energy production and mitochondrial dynamics.