Glutamate decarboxylase (GAD) is an enzyme in the central nervous system that synthesizes gamma-aminobutyric acid (GABA). GABA is the main inhibitory neurotransmitter, or chemical messenger, in the mature brain, meaning it reduces neuronal activity. By producing GABA, GAD helps regulate brain function, modulate anxiety and stress, and maintain a balance between neuronal excitation and inhibition.
The GAD Enzymatic Process
Glutamate decarboxylase catalyzes the conversion of glutamate into GABA. Glutamate is the nervous system’s most abundant excitatory neurotransmitter, stimulating neurons to fire. GAD performs an irreversible decarboxylation reaction, removing a carboxyl group from glutamate to form GABA and carbon dioxide. This process transforms a primary “on” signal for neurons into the primary “off” signal.
This conversion requires a cofactor, a non-protein compound necessary for the enzyme’s activity. For GAD, the cofactor is pyridoxal phosphate (PLP), the active form of vitamin B6. PLP binds to GAD’s active site, enabling the reaction with glutamate. Insufficient vitamin B6 compromises GAD efficiency and can reduce GABA synthesis.
This process occurs in the cytoplasm of GABAergic neurons, which are specialized to produce and release GABA. Once synthesized, GABA is packaged into synaptic vesicles at the neuron’s terminal. From there, it is released into the synapse—the gap between neurons—to transmit its inhibitory signal to a neighboring nerve cell.
GABA’s Role in the Nervous System
As the principal inhibitory neurotransmitter, GABA reduces neuronal excitability, acting as a brake on brain activity. When released into a synapse, GABA binds to receptors on the next neuron. This binding opens ion channels, allowing negatively charged chloride ions to flow into the receiving cell.
The influx of negative ions makes the neuron hyperpolarized, meaning its internal electrical charge becomes more negative and further away from the threshold required to fire an action potential. This makes it harder for the neuron to fire, thereby dampening nerve signals. This inhibitory action maintains the equilibrium between excitation and inhibition, and a disruption in this balance is linked to various neurological conditions.
GABA’s inhibitory effects contribute to broader physiological functions, including managing anxiety, stress, and fear. Its calming influence helps regulate mood and promotes relaxation. Many sedative and anti-anxiety medications work by enhancing GABA’s effects, highlighting its role in neurological stability.
Key Isoforms of Glutamate Decarboxylase
Glutamate decarboxylase exists in two primary isoforms, GAD65 and GAD67, named for their molecular weights. They are encoded by different genes (GAD2 and GAD1, respectively). Although both convert glutamate to GABA, their distinct properties, locations, and regulation mean they fulfill different roles in GABA synthesis.
GAD67 provides the brain’s basal, or tonic, GABA levels. It is distributed throughout the neuron’s cytoplasm and is constitutively active, constantly producing GABA for general cellular functions like metabolism. GAD67 synthesizes about 90% of the brain’s GABA and is important during early development for processes like neural stem cell growth.
In contrast, GAD65 is located in nerve terminals and synthesizes GABA for phasic release—the rapid, on-demand release during signaling. Unlike the constantly active GAD67, GAD65 can be inactive until a sudden demand for GABA activates it. This functional difference allows the nervous system to maintain a steady background level of GABA via GAD67, while using GAD65 to respond dynamically to changing patterns of neuronal activity.
Clinical Relevance of GAD
The GAD65 isoform is a target in several autoimmune diseases where the immune system produces autoantibodies against it. The presence of these glutamic acid decarboxylase autoantibodies (GADA) is a diagnostic marker for disorders ranging from type 1 diabetes to rare neurological syndromes. These autoantibodies can reduce GABA production, disrupting the balance of signaling in the nervous system.
In type 1 diabetes, the immune system attacks GAD65 in the insulin-producing beta cells of the pancreas. GADA is found in about 75% of individuals with this condition and can be detected in the blood years before diagnosis, making it a predictive marker. The concentration of these autoantibodies in type 1 diabetes is much lower than in associated neurological disorders.
Stiff Person Syndrome (SPS) is a rare neurological disorder associated with very high concentrations of GAD autoantibodies. In SPS, the autoimmune attack on GAD impairs GABAergic neurons, reducing inhibitory signaling in the spinal cord and brainstem. This deficit causes the characteristic symptoms of progressive muscle stiffness, rigidity, and painful spasms.
Autoantibodies against GAD are implicated in other neurological conditions, creating a spectrum of GAD-antibody-associated disorders. One is cerebellar ataxia, a movement disorder where the autoimmune response targets GABAergic neurons in the cerebellum. GAD autoantibodies have also been linked to some forms of autoimmune epilepsy and limbic encephalitis.