The human brain and central nervous system (CNS) are notoriously complex, operating through a huge network of neurons that communicate with each other using chemical messengers, or neurotransmitters. Although several neurotransmitters enable the brain to function properly, GABA (gamma-aminobutyric acid) and glutamate are two of the most indispensable [1,2].
They play a fundamental role in regulating excitatory and inhibitory signaling and shape the delicate balance needed for normal brain activity. It’s therefore important to understand the differences in function between these two neurotransmitters and how they relate to brain homeostasis, as well as how imbalances may contribute to neurological disorders.
In today’s article, we explore GABA and glutamate, touch on the molecular mechanisms underpinning their actions, and their contributions to various physiological and pathological processes.
GABA, Glutamate, and the Basics of Neurotransmission
The foremost distinction between GABA and glutamate is their opposing functions in the CNS. GABA is the brain’s main “inhibitory transmitter” whereas glutamate (between glutamate and glutamine, glutamine is the precursor) is the primary “excitatory neurotransmitter” [3-5]. The balance between these two processes underpins brain function and is essential for proper neuronal communication.
GABA reduces neuronal excitability in the adult brain by binding to GABA receptors on postsynaptic neurons [6]. When GABA is released from a presynaptic neuron and binds to its corresponding receptor, it causes an influx of chloride ions into the neuron or an efflux of potassium ions. These shifts effectively hyperpolarize the neuron, making it less likely to fire an action potential and thus “putting the brakes” on the brain, protecting it against seizures, anxiety, and excitotoxicity. GABA therefore helps to regulate mood, motor control, and cognition.
On the other hand, glutamate is the brain’s foremost excitatory neurotransmitter in that it promotes the firing of neurons [7]. When glutamate binds to its corresponding receptors (mainly NMDA, AMPA, and kainate receptors), sodium and calcium ions enter the postsynaptic neuron causing depolarization and therefore increasing the likelihood of an action potential, thus “pressing the accelerator” on the brain [8,9].
Glutamate’s excitatory role is essential to learning, memory formation, and synaptic plasticity. Through its involvement in long-term potentiation (LTP), glutamate contributes to the strengthening of synaptic connections, which underpins vital cognitive functions such as learning and memory recall [10].
The Interplay Between GABA and Glutamate
The balance between GABA and glutamate signaling ensures that the brain can function optimally, by adjusting neuronal activity as needed for many different tasks.
As the chief inhibitory neurotransmitter, GABA is involved in a wide range of functions. For example, GABAergic signaling is at the core of anxiety regulation [11]. Medications like benzodiazepines work by augmenting the effects of GABA at GABA-A receptors, bringing about reduced anxiety and a more sedated state [12,13]. GABAergic inhibition in the basal ganglia is key to regulating movement. Impairments in GABA signaling are associated with movement disorders such as Huntington's disease, dystonia, and Parkinson’s disease. GABA also plays a significant role in the regulation of sleep, which is necessary for restoration of the body.
Glutamate is indispensable for processes related to cognition and neural plasticity. These include learning and memory and support the mechanisms underpinning neuroplasticity (the ability of the brain to reorganize itself by forming new neural connections) [8,10]. Glutamate also excites neurons in pathways related to motor control and sensory perception, facilitating the communication needed for movement and sensation.
Given their opposing roles, dysregulation of GABA and glutamate levels can lead to a broad range of neurological disorders. A deficiency in GABAergic signaling or reduced GABA levels can result in excessive excitatory activity, which is a feature of conditions such as epilepsy [14], anxiety disorders, and insomnia [15]. Conversely, excessive glutamatergic activity or increased glutamate levels can be equally detrimental, contributing to excitotoxicity, a condition whereby overactivation of glutamate receptors leads to neuronal injury or death.
Dysregulated glutamate system signaling is involved in the progression of neurodegenerative conditions such as Alzheimer’s disease [16] and amyotrophic lateral sclerosis (ALS) [17]. During a stroke, excessive glutamate release can occur, which leads to excitotoxicity and the death of neurons.
Therapies Targeting GABA and Glutamate
As discussed above, the critical roles of GABA and glutamate in many facets of brain function have led to their targeting of therapeutic interventions in a variety of neurological and psychiatric conditions.
Drugs that target and enhance GABAergic activity include benzodiazepines for the treatment of anxiety, insomnia, and epilepsy; barbiturates for seizure management [18] (although less so these days due to the risk of dependence), and gabapentin for neuropathic pain, anxiety, and epilepsy.
Conversely, drugs that modulate glutamatergic activity and reduce excitatory signaling include NMDA receptor antagonists such as memantine (which has been used in Alzheimer’s disease) which can block excitotoxicity and have a neuroprotective effect [19,20]. Drugs of this kind (i.e., N-acetylcysteine, acamprosate, modafinil) can also be leveraged for the treatment of drug and behavioral addictions [21].
Summary
In this article, we have discussed how GABA and glutamate are central to the regulation of the activity of neurons and brain networks, and how the interplay between them maintains the brain’s balance (excitation vs. inhibition). While GABA is the primary inhibitory transmitter (the brake), calming neural circuits, glutamate is the accelerator that drives excitatory signals underlying cognition, learning, and memory. When the delicate balance between the two neurotransmitters is compromised, neurological conditions can arise such as anxiety, epilepsy, and neurodegenerative diseases. Understanding the interplay between these pathways might help researchers and clinicians develop more effective treatments for such conditions and improve brain health and function in the long run.
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