Synaptic Ras GTPase-activating protein 1, also known as synaptic Ras-GAP 1 or SYNGAP1, is a protein that in humans is encoded by the SYNGAP1 gene. [5] [6] [7] SYNGAP1 is a ras GTPase-activating protein that is critical for the development of cognition and proper synapse function. Mutations in humans can cause intellectual disability, epilepsy, autism and sensory processing deficits.
SynGAP1 is a complex protein with several functions that may be regulated temporally via complex isoforms. [8] A well-documented function of SynGAP1 involves NMDA receptor-mediated synaptic plasticity and membrane insertion of AMPA receptors through the suppression of upstream signaling pathways. [9] However, SynGAP1 has also been shown to function cooperatively with Unc51.1 in axon formation. [10] One way SynGAP1 affects these processes is through the MAP kinase signaling pathway by attenuation of Ras signalling. [11] However, alternative splicing and multiple translational start sites have been shown to cause opposing effects, illustrating the importance of multiple functional domains that reside within the c- and n-termini. For example, the expression of an α1 or α2 c-terminal variant of SynGAP1 will either increase or decrease synaptic strength, respectively. [8] Overall, SynGAP1 is essential for development and survival, which is evident as knockout mice die perinatally. [12]
SynGAP1 is shown to localize at the postsynaptic density on the dendritic spines of excitatory synapses. [6] Cultured neurons of SynGAP heterozygotic and homozygotic knockout mice display accelerated maturation of dendritic spines, including an increase in overall spine size, which produces more mushroom shaped and less stubby spines. [9] [11] [13] Spine heads are enlarged due to the increased phosphorylation of cofilin, leading to a decrease in F-actin severing and turnover. [14] The increased size of the dendritic spines also corresponded to an increase in membrane bound AMPARs or a decrease in silent synapses. These neurons displayed a higher frequency and larger amplitudes of miniature excitatory postsynaptic potentials (mEPSP). [13] Mice models with domain specific mutations led to neonatal hyperactivity of the hippocampal trisynaptic circuit. Mutations had the greatest impact during the first 3 weeks of development, and reversal of mutations in adults did not improve behavior and cognition. [9]
Several mutations in the SYNGAP1 gene were identified as the cause of intellectual disability. Intellectual disability is sometimes associated with syndromes of other defects caused by the same gene, but SYNGAP1-associated intellectual disability is not; it is therefore called non-syndromic intellectual disability. Since neither of the parents of children with this condition have the mutation, this means it was a sporadic mutation that occurred during division of the parents' gametes (meiosis) or fertilization of the egg. It is a dominant mutation, which means that the individual will be developmentally disabled even if only one allele is mutated. [15]
Mutations in this gene have also been found associated to cases of developmental and epileptic encephalopathies, autism spectrum disorder, and touch-related sensory processing deficits. [16] [17] [18]
Epilepsy in this disorder is distinctive, combining eyelid myoclonia with absences and myoclonic-atonic seizures. Seizures are often triggered by eating. [19] [20]
A causal therapy was the first successful worldwide by the group of Prof. Gerhard Kluger tested at the Schön Klinik in Vogtareuth with statins. In the process, the RAS pathway, which is overactive in SYNGAP1-associated intellectual disability is inhibited by statins. Further clinical studies by the group of Prof. Gerhard Kluger are in preparation. [21]
SYNGAP1 has been shown to interact with DLG3 [6] and ULK1. [10]
A dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body. Most spines have a bulbous head, and a thin neck that connects the head of the spine to the shaft of the dendrite. The dendrites of a single neuron can contain hundreds to thousands of spines. In addition to spines providing an anatomical substrate for memory storage and synaptic transmission, they may also serve to increase the number of possible contacts between neurons. It has also been suggested that changes in the activity of neurons have a positive effect on spine morphology.
In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons. The opposite of LTP is long-term depression, which produces a long-lasting decrease in synaptic strength.
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is an ionotropic transmembrane receptor for glutamate (iGluR) that mediates fast synaptic transmission in the central nervous system (CNS). It has been traditionally classified as a non-NMDA-type receptor, along with the kainate receptor. Its name is derived from its ability to be activated by the artificial glutamate analog AMPA. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring agonist quisqualate and was only later given the label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen. The GRIA2-encoded AMPA receptor ligand binding core was the first glutamate receptor ion channel domain to be crystallized.
In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuits in the brain, synaptic plasticity is one of the important neurochemical foundations of learning and memory.
Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canonical nerve growth factor. Neurotrophic factors are found in the brain and the periphery. BDNF was first isolated from pig brain in 1982 by Yves-Alain Barde and Hans Thoenen.
The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals. Proteins containing PDZ domains play a key role in anchoring receptor proteins in the membrane to cytoskeletal components. Proteins with these domains help hold together and organize signaling complexes at cellular membranes. These domains play a key role in the formation and function of signal transduction complexes. PDZ domains also play a highly significant role in the anchoring of cell surface receptors to the actin cytoskeleton via mediators like NHERF and ezrin.
In cell signalling, Son of Sevenless (SOS) refers to a set of genes encoding guanine nucleotide exchange factors that act on the Ras subfamily of small GTPases.
RAS p21 protein activator 1 or RasGAP, also known as RASA1, is a 120-kDa cytosolic human protein that provides two principal activities:
Disks large homolog 3 (DLG3) also known as neuroendocrine-DLG or synapse-associated protein 102 (SAP-102) is a protein that in humans is encoded by the DLG3 gene. DLG3 is a member of the membrane-associated guanylate kinase (MAGUK) superfamily of proteins.
Kalirin, also known as Huntingtin-associated protein-interacting protein (HAPIP), protein duo (DUO), or serine/threonine-protein kinase with Dbl- and pleckstrin homology domain, is a protein that in humans is encoded by the KALRN gene. Kalirin was first identified in 1997 as a protein interacting with huntingtin-associated protein 1. Is also known to play an important role in nerve growth and axonal development.
Glutamate receptor 1 is a protein that in humans is encoded by the GRIA1 gene.
Homer protein homolog 1 or Homer1 is a neuronal protein that in humans is encoded by the HOMER1 gene. Other names are Vesl and PSD-Zip45.
Disks large-associated protein 4 (DAP-4) also known as SAP90/PSD-95-associated protein 4 (SAPAP-4) is a protein that in humans is encoded by the DLGAP4 gene.
Activity-dependent plasticity is a form of functional and structural neuroplasticity that arises from the use of cognitive functions and personal experience; hence, it is the biological basis for learning and the formation of new memories. Activity-dependent plasticity is a form of neuroplasticity that arises from intrinsic or endogenous activity, as opposed to forms of neuroplasticity that arise from extrinsic or exogenous factors, such as electrical brain stimulation- or drug-induced neuroplasticity. The brain's ability to remodel itself forms the basis of the brain's capacity to retain memories, improve motor function, and enhance comprehension and speech amongst other things. It is this trait to retain and form memories that is associated with neural plasticity and therefore many of the functions individuals perform on a daily basis. This plasticity occurs as a result of changes in gene expression which are triggered by signaling cascades that are activated by various signaling molecules during increased neuronal activity.
Activity-regulated cytoskeleton-associated protein is a plasticity protein that in humans is encoded by the ARC gene. It was first characterized in 1995. ARC is a member of the immediate-early gene (IEG) family, a rapidly activated class of genes functionally defined by their ability to be transcribed in the presence of protein synthesis inhibitors. ARC mRNA is localized to activated synaptic sites in an NMDA receptor-dependent manner, where the newly translated protein is believed to play a critical role in learning and memory-related molecular processes. Arc protein is widely considered to be important in neurobiology because of its activity regulation, localization, and utility as a marker for plastic changes in the brain. Dysfunction in the production of Arc protein has been implicated as an important factor in understanding various neurological conditions, including amnesia, Alzheimer's disease, Autism spectrum disorders, and Fragile X syndrome. Along with other IEGs such as ZNF268 and HOMER1, ARC is also a significant tool for systems neuroscience as illustrated by the development of the cellular compartment analysis of temporal activity by fluorescence in situ hybridization, or catFISH technique.
Long-term potentiation (LTP), thought to be the cellular basis for learning and memory, involves a specific signal transmission process that underlies synaptic plasticity. Among the many mechanisms responsible for the maintenance of synaptic plasticity is the cadherin–catenin complex. By forming complexes with intracellular catenin proteins, neural cadherins (N-cadherins) serve as a link between synaptic activity and synaptic plasticity, and play important roles in the processes of learning and memory.
Glutamate receptor-interacting protein (GRIP) refers to either a family of proteins that bind to the glutamate receptor or specifically to the GRIP1 protein within this family. Proteins in the glutamate receptor-interacting protein (GRIP) family have been shown to interact with GluR2, a common subunit in the AMPA receptor. This subunit also interacts with other proteins such as protein interacting with C-kinase1 (PICK1) and N-ethylmaleimide-sensitive fusion protein (NSF). Studies have begun to elucidate its function; however, much is still to be learned about these proteins.
Mary Bernadette Kennedy is an American biochemist and neuroscientist. She is a member of the American Academy of Arts and Sciences, and is the Allen and Lenabelle Davis Professor of Biology at the California Institute of Technology, where she has been a member of the faculty since 1981. Her research focuses on the molecular mechanisms of synaptic plasticity, the process underlying formation of memory in the central nervous system. Her lab uses biochemical and molecular biological methods to study the protein machinery within a structure called the postsynaptic density. Kennedy has published over 100 papers with over 17,000 total citations.
Synaptic stabilization is crucial in the developing and adult nervous systems and is considered a result of the late phase of long-term potentiation (LTP). The mechanism involves strengthening and maintaining active synapses through increased expression of cytoskeletal and extracellular matrix elements and postsynaptic scaffold proteins, while pruning less active ones. For example, cell adhesion molecules (CAMs) play a large role in synaptic maintenance and stabilization. Gerald Edelman discovered CAMs and studied their function during development, which showed CAMs are required for cell migration and the formation of the entire nervous system. In the adult nervous system, CAMs play an integral role in synaptic plasticity relating to learning and memory.
SYNGAP1-related intellectual disability is a monogenetic developmental and epileptic encephalopathy that affects the central nervous system. Symptoms include intellectual disability, epilepsy, autism, sensory processing deficits, hypotonia and unstable gait.
