Glossary

Action potential:  Neurons (nerve cells) communicate with each other via electrical events called ‘action potentials’ and chemicals called neurotransmitters (chemical messengers). When a neuron is activated, an electrical action potential is produced in that neuron, which causes the release of neurotransmitters onto the neighboring neuron. This process sends the message from one neuron to another.   

Agonist: a substance that binds to and activates a receptor (protein that receives signals), producing a biological response. For example, glutamate is an agonist of the NMDA receptor. There are 2 types of agonists: 

Endogenous agonists are naturally produced in the body (such as hormones and neurotransmitters).  

Exogenous agonists are external factors (such as drugs).   

Allele: A gene can exist in different forms and these different forms are called alleles. Alleles can be normal, also called wildtype, or they can be abnormal, or mutant. For each gene, you inherit one allele from your mother and one from your father. 

Allosteric modulator: something that binds to a receptor at a binding site other than the one used by its primary binding molecule (ligand). The result is that it activates or deactivates the function of the receptor (for example, the NMDA receptor). 

Amino acid: the “building blocks” of proteins. There are 20 amino acids.  

Amino acid sequence: the order of the amino acids in a protein.  

AMPA receptor: The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (known as the AMPA receptor or AMPAR), is a glutamate receptor and ion channel protein found in neurons (nerve cells). It is similar to the NMDA receptor but affects ions slightly differently. The AMPA receptor is formed of 4 subunits encoded by different genes. GRIA1 gene encodes GRIA1 subunit (also known as GluA1 or GluR1), GRIA2 gene encodes GRIA2 subunit (GluA2 or GluR2), GRIA3 gene encodes GRIA3 subunit (GluA3 or GluR3) and GRIA4 gene encodes GRIA4 subunit (GluA4 or GluRA-D2). Variants in GRIA2, GRIA3 and GRIA4 genes are associated with developmental delay, intellectual disability and seizures.  

Antagonist: a substance which interferes with or inhibits the physiological action of the receptor. An example of an NMDA receptor antagonist is memantine.  

Autosomal Dominant: the characterization of a condition in which a single copy of the disease-associated mutation will cause the disease. A child who has a parent with the mutated gene has a 50% chance of inheriting the harmful gene copy and inheriting the disease.  

Benign: thought to be tolerated (not harmful) 

Calcium influx: calcium (Ca2+) channels (like NMDA receptors) open and calcium enters the neuron (nerve cell). Calcium influx is induced by glutamate binding to the NMDA receptor. Calcium influx is important because it alters synaptic activity; it causes the release of neurotransmitters (chemical messengers) that pass a message to the next neuron. Magnesium binds to NMDA receptors and blocks calcium influx. The result is that no neurotransmitter can be released. Magnesium is released when glutamate and glycine/ serine bind to the NMDA receptor.  

Cell: the basic building block of all living things. The brain has specific cells, nerve cells, which are called neurons. 
Cell culture: is a method used to cultivate and grow a large number of cells in a dish.  

Cellular models: (or cell-based models) are mathematical models that represent biological cells as separate entities.  

Chromosome: is a structure made of DNA (genetic code). There are 23 pairs of chromosomes (46 chromosomes) in the human body, that each contain hundreds to thousands of genes.   

Circuit (neural circuit): a population of neurons (nerve cells) that are interconnected and carry out a specific function when activated. Single neurons act together through complex neural circuits and networks in order to generate sensory perceptions, actions, memories, and thoughts. 

 CNS: Short for central nervous system. It is the part of the nervous system consisting of the brain and spinal cord. 

CRISPR/ Cas9: a system to edit the DNA (genetic code) in the cells of an organism. A specific sequence of DNA in this system recognizes where to cut the organism’s DNA. Then, the Cas9 protein cuts the DNA. At the cut region, new DNA can be added so that the mutation is corrected. As a result, a “spelling error” in the DNA can be changed to the normal ”letter”.  

Deleterious: harmful 

Delta receptors: receptors including GluD1 (GluRδ1) which is encoded by the GRID1 gene and GluD2 (GluR δ2) which is encoded by the GRID2 gene. Variants in the GRID2 gene are known to be linked to cognitive dysfunction. 

De novo variant: a genetic alteration that is present for the first time in one family member, meaning that the individual’s parents do not have the mutation. Also called de novo variant, new mutation and new variant.  

GRIN FACT: In most of the GRIN cases the dysfunctional gene is not inherited but a “de novo” mutation.  

DNA: a series of “letters” of genetic code that makes you you. There are 3 billion “letters” that carry your genetic information. 

EEG: EEG, which stands for electroencephalography, is a monitoring method to record electrical activity of the brain. For example, EEG can be used to detect and monitor seizures.  

Excitotoxicity: is the process by which neurons (nerve cells) are damaged or killed by excessive stimulation by neurotransmitters (chemical messengers) such as glutamate. For example, cytotoxicity occurs when receptors like the NMDA and AMPA receptors are overactivated by glutamate.  

Functional analysis: a test to determine if a specific variant is Loss of Function (decrease in the amount of current flowing into a cell) or Gain of Function (increase in the amount of current flowing into a cell). It is useful to know if a specific GRIN variant is LoF or GoF because the mechanics of the GRIN variant is crucial to determine potential treatments. 

GABA: is the primary inhibitory neurotransmitter (chemical messenger) in the brain and spinal cord. Its principal role is reducing the activation of neurons (nerve cells). In humans, GABA is also directly responsible for the regulation of muscle tone. 

Gain of Function (GoF):  is a mutation resulting in the gene product (protein) having either a stronger effect than normal or a different function. Also called activating mutations. 

GRIN FACT: In relation to GRIN disorder, GoF would result in NMDA receptor hyperfunction. 

Gene: a segment of our genetic code (DNA) that makes a protein, which is a molecule that has a function in the body.  

Gene expression: Most genes contain the information needed to make functional molecules called proteins. The journey from a gene to a protein is called gene expression. It consists of two steps (transcription and translation).  

Gene knock-in: is a genetic engineering method in which one segment of DNA (genetic code) is replaced with another or a new DNA segment is inserted. 

Gene knockdown: is a genetic technique in which the expression, or effect, of a specific gene is reduced. 

Gene knockout: is a genetic technique in which a gene is made non-functional. 

Gene therapy: is the addition of a functional gene or group of genes to a cell by gene insertion. The goal of gene therapy is to genetically correct a disease. 

Genome sequencing: The process of determining an individual’s DNA sequence (genetic code). For example, genome sequencing is used to identify a mutation in one’s GRIN gene. 

GLUN1: Also known as the NR1 subunit (portion) of the NMDA receptor that is encoded by GRIN1 gene. 

GLUN2A: Also known as the NR2A subunit (portion) of the NMDA receptor that is encoded by GRIN2A gene. 

GLUN2B: Also known as the NR2B subunit (portion) of the NMDA receptor that is encoded by GRIN2B gene. 

GLUN2C: Also known as the NR2C subunit (portion) of the NMDA receptor that is encoded by GRIN2C gene. 

GLUN2D: Also known as the NR2D subunit (portion) of the NMDA receptor that is encoded by GRIN2D gene. 

GLUN3A: Also known as the NR3A subunit (portion) of the NMDA receptor that is encoded by GRIN3A gene. 

GLUN3B: Also known as the NR3B subunit (portion) of the NMDA receptor that is encoded by GRIN3B gene. 

GRIN FACT: Disease-causing variants in four of these genes (GRIN1, GRIN2A, GRIN2B and GRIN2D) are known to cause GRIN disorder. 

Glutamate: is the primary excitatory neurotransmitter (chemical messenger) in the central nervous system (brain and spinal cord). It binds to and co-activates NMDA receptors (along with glycine). 

Glycine: is a neurotransmitter (chemical messenger) in the central nervous system (brain and spinal cord). It binds to and co-activates NMDA receptors (along with glutamate).  

Homozygous vs. Heterozygous: Genes come in pairs of alleles, which are different versions of the same gene. When these two alleles are identical, they are homozygous. When the two alleles are different, they are heterozygous.  

GRIN FACT: It is very unlikely that your genetic report says Homozygous, as most GRIN mutations are Heterozygous.   

Hyperfunction: excessive activity or function. 

Hypofunction: decreased or insufficient function. 

Immunotherapy: is the method of using substances that cause an immune response to treat a disorder. Further research is needed to evaluate this type of treatment for GRIN-related disorders.  

In vitro: are studies “in the glass,” also called dish studies. Results obtained from in vitro experiments may not fully or accurately predict the effects on a whole organism. 

In vivo: are studies on living organisms, usually animals but also humans, and plants.  

Ionotropic glutamate receptor: Ion channels that are activated by the neurotransmitter (chemical messenger) glutamate. Ions are small, charged molecules that play an important role in the brain and the body. Ion channels allow ions to pass into or out of a cell.  

Kainate receptor: A type of ionotropic glutamate receptor found in neurons (nerve cells). The kainate receptor is formed of 4 subunits encoded by different genes: GRIK1 gene encodes GRIK1 subunit (also known as GluK1 or GluR5), GRIK2 gene encodes GRIK2 subunit (GluK2 or GluR6), GRIK3 gene encodes GRIK3 subunit (GluK3 or GluR7), GRIK4 gene encodes GRIK4 subunit (GluK4 or KA1) and GRIK5 gene encodes GRIK5 subunit (GluK5 or KA2). Variants in the GRIK2 gene is known to be linked to disease. 

Ligand: a signaling molecule which binds to a specific target. Binding of a ligand to a receptor changes its shape or activity, allowing it to transmit a signal or directly produce a change inside of the cell. 

Ligand binding site: the place on a receptor to which ligands (specific molecules and/or ions) may bind. For example, a ligand binding site on the NMDA receptor is the spot where glutamate binds, which activates of the receptor.  

Loss of function (LoF): a mutation resulting in the change the gene product (protein) that has either less function than normal or no function. Also called inactivating mutations. 

GRIN FACT: In relation to GRIN a LoF would result in NMDA receptor hypofunction.  

LTD (Long Term Depression): is a decrease in postsynaptic strength, meaning the strength of the connection between two neurons (nerve cells) becomes weaker. As an example, long-term depression (LTD) is mainly responsible for the removal of old memory traces, which facilitates the formation of new memory traces.  

LTP (Long Term Potentiation): is the long-lasting strengthening connection between two nerve cells. Simply put, it is a persistent strengthening of synapses (connection between 2 neurons) based on recent patterns of activity. LTP plays a major role in the associative type of learning and plays together with LTD to generate a balanced and stable memory mechanism.  

Magnesium block: refers to blocking of the NMDA receptors by a magnesium molecule. The binding of magnesium to the NMDA receptor prohibits calcium influx, so the neuron (nerve cell) is unable to send a message. The magnesium block is lifted after depolarization (change in electrical activity) of the neuron occurs, which in turn opens the NMDA receptor channel and calcium enters the neuron. 

Model organism: a non-human species that is studied to understand biological processes and give insight into these processes in other species. The mouse and zebrafish are two examples of model organisms that are currently being used in GRIN research.  

Modulation (neuromodulation): is the alteration of properties of a) the neuron (nerve cell), b) the synapse (connection between 2 neurons) or c) substances released by neurons. Neuromodulation changes how neurons act. 

mRNA: (messenger RNA) is an RNA molecule that carries the genetic information from DNA in a new format so that proteins can be made. 

Mutation: process by which genes undergo a structural change. 

NAM (negative allosteric modulator): A molecule that blocks the binding of the agonist (activator) to a receptor. A NAM binds to a site on the receptor that is different than the spot where the agonist binds. 

Neuron:  A neuron, also called a nerve cell, is an electrically excitable cell that receives, processes, and transmits information through electrical and chemical signals. These signals between neurons occur via connections called synapses. Neurons can connect to each other to form neural pathways and neural circuits. 

Neurotransmitter:  Neurotransmitters are often referred to as the body’s chemical messengers. They are the molecules used by the nervous system to transmit messages between neurons (nerve cells), or from neurons to muscles. The neurotransmitter can either help (excite) or hinder (inhibit) neurons from passing on a message.    

NIH: National Institutes of Health 

NMDA receptor:  The N-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel protein found in nerve cells. 

Oxidative stress: is an imbalance of free radicals and antioxidants in the body. Free radicals are molecules that are highly reactive with other molecules and antioxidants are molecules that fight free radicals. An imbalance can result in damage to cells and tissues. 

PAMs (positive allosteric modulators): act to enhance the function of a receptor. PAMs work in the presence of agonist (a substance, like glutamate, that activates a receptor) but are not able to directly activate the receptor in the absence of the agonist. 

GRIN FACT: Some of the classes of PAMs investigated in relation to GRIN disorder are: Spermine, Pregnenolone Sulphate, 24 (S)-HC (this one is now in clinical trials at Sage Therapeutics – called SAGE 718). The hurdle has been to find PAM’s that target specific subtypes (NR1, NR2A, NR2B, NR2D).  

Pathogenic: disease-causing 

Phenotype: is an organism’s physical appearance and behavior; in other words, common symptoms and traits. Phenotype is determined by genetic and environmental factors. 

Phosphorylation: is the addition of a phosphate group (chemical compound) to a molecule. Phosphorylation is a type of modification that occurs after a protein is built; it alters the structure of the protein. 

Polarized: when a neuron (nerve cell) is inactive, just waiting for a nerve impulse to come along. 

Postsynaptic neuron: a neuron (nerve cell) that receives a neurotransmitter (chemical messenger) after it has crossed the synapse (connection between 2 neurons). The postsynaptic neuron may experience an action potential (electrical impulse) if the neurotransmitter signal is strong enough.  

Precision medicine: refers to treatment approaches that account for differences between individual patients, including genetic, environment, and lifestyle factors. 

Presynaptic neuron: a neuron (nerve cell) that releases neurotransmitters (chemical messengers) as a result of an electrical impulse.   

Protein: a molecule that has a specific function in the body. For example, the NMDA receptor is a protein. Proteins are made of a specific sequence of amino acids. 

Receptor:  a protein molecule that receives chemical signals from outside a cell. 

Subunit: part of a receptor, like the NMDA receptor. Every NMDA receptor contains four distinctive subunits. Two (Glun1 or NR1) are encoded by the GRIN1 gene. The other two are encoded by other GRIN genes.  

Synapse:  a structure that permits a neuron (nerve cell) to pass an electrical or chemical signal to another neuron.  

Synaptic cleft: (also called synaptic gap) is the space between neurons (nerve cells) across which a nerve impulse is transmitted.  

Synaptic plasticity:  is the ability of synapses (connection between 2 neurons) to strengthen or weaken over time, in response to increases or decreases in their activity. In other words, plasticity is the brain’s ability to change and adapt to new information. For example, it permits learning and memory.  

VUS: variant of unknown or uncertain significance, meaning it is unknown if the variant is disease-causing.