GAD1, NMDA Receptors, and Hyperactivity: A Neurobiological Overview

The Role of GAD1 and GABA

The GAD1 gene encodes the enzyme glutamate decarboxylase 67 (GAD67), which is responsible for converting glutamate (a major excitatory neurotransmitter) into GABA (gamma-aminobutyric acid)—the brain’s primary inhibitory neurotransmitter. Adequate GAD1 expression is crucial for maintaining the balance between neuronal excitation and inhibition.

When GAD1 function is impaired (due to genetic or epigenetic changes), there is a reduction in GABA synthesis. This leads to insufficient inhibitory control over excitatory pathways, resulting in an imbalance that favors hyperexcitability of neural circuits.

NMDA Receptors and Glutamatergic Signaling

NMDA receptors are a subtype of ionotropic glutamate receptors involved in synaptic plasticity, learning, and memory. They are highly permeable to calcium and require both glutamate and glycine for activation. Overactivation of NMDA receptors can lead to calcium overload, neuronal hyperactivity, and even excitotoxicity.

In the context of reduced GABA (from GAD1 dysfunction), glutamate signaling becomes unchecked, leading to overstimulation of NMDA receptors. This contributes to neurodevelopmental and psychiatric symptoms, including hyperactivity, anxiety, and cognitive impairments.

Hyperactivity as a Result of Excitatory-Inhibitory Imbalance

Hyperactivity, particularly in disorders such as ADHD, autism spectrum disorder (ASD), and schizophrenia, is often rooted in an imbalance between excitatory and inhibitory neurotransmission. The combination of low GABAergic tone (due to decreased GAD1 activity) and excessive glutamatergic signaling (especially via NMDA receptors) leads to overexcitation of neural networks, manifesting behaviorally as hyperactivity, impulsivity, and cognitive dysregulation.

Clinical and Research Implications

• In schizophrenia, GAD1 expression is often downregulated in the prefrontal cortex, contributing to cognitive deficits and disorganized behavior.

• In ADHD and ASD, altered GABA/glutamate balance and NMDA receptor dysfunction have been implicated in attention, memory, and behavior regulation problems.

• Pharmacological targets such as GABA agonists, NMDA receptor modulators, and glutamate inhibitors are being explored as treatment options.

GABA Agonists

These enhance the activity of gamma-aminobutyric acid (GABA), the brain's primary inhibitory neurotransmitter, promoting relaxation and reducing neural excitability.

Pharmaceutical Examples:

• Benzodiazepines (e.g., diazepam, lorazepam, alprazolam) – Bind to GABA-A receptors.

• Barbiturates (e.g., phenobarbital) – Potentiate GABA activity.

• Gabapentin – Though not a direct GABA agonist, it increases GABA synthesis.

• Baclofen – A GABA-B receptor agonist used for spasticity.

Natural/Substance-Based Examples:

• Valerian root

• Passionflower

• L-theanine (found in green tea; increases GABA levels)

• Magnesium – Supports GABA receptor function

NMDA Receptor Modulators

These influence N-methyl-D-aspartate (NMDA) receptors, which are involved in excitatory glutamate signaling and neuroplasticity.

Pharmaceutical Examples:

• Ketamine – An NMDA receptor antagonist used for depression and pain.

• Memantine – Used in Alzheimer's; acts as a low-affinity NMDA antagonist.

• Dextromethorphan – Found in cough suppressants; NMDA antagonist at higher doses.

• Amantadine – Mild NMDA antagonist used in Parkinson’s disease.

Natural/Substance-Based Examples:

• Zinc – Modulates NMDA receptor activity.

• Magnesium – Blocks NMDA channels at resting potential.

• Agmatine – A neuromodulator derived from arginine, shown to block NMDA receptors.

Glutamate Inhibitors / Antagonists

These reduce the action of glutamate, the brain's main excitatory neurotransmitter, which can be neurotoxic in excess.

Pharmaceutical Examples:

• Riluzole – Inhibits glutamate release; used in ALS.

• Topiramate – Used for epilepsy and migraines; inhibits glutamate receptors.

• Lamotrigine – Stabilizes neuronal membranes and reduces glutamate release.

• Felbamate – Inhibits NMDA receptors and reduces glutamate activity.

Natural/Substance-Based Examples:

• Curcumin (from turmeric) – May modulate glutamate levels.

• N-acetylcysteine (NAC) – Supports glutamate regulation via the cystine-glutamate antiporter.

• Omega-3 fatty acids – Have neuroprotective effects and may modulate glutamatergic activity.

At Well Mind Body, we embrace an integrative approach to healing that honors the deep connection between the mind, body, and brain. We work collaboratively with our clients to understand not only their personal experiences, values, and goals but also the underlying neurobiological patterns that may be influencing their behavior and emotional well-being. Our care is rooted in both compassion and cutting-edge science, blending relational insight with evidence-based, neuroscience-informed practices.

As part of our commitment to personalized, whole-person wellness, we also offer the NeuroWell+ assessment. This powerful tool allows us to explore genetic factors like the GAD1 gene, which may play a role in how the brain processes GABA, impacting anxiety, mood regulation, and stress response. By integrating this kind of data with our clinical approach, we support healing at the root—helping clients restore balance, build resilience, and thrive from the inside out.

If you are interested in booking a session, please click here. We cant wait to meet you!

Dr. E

References

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