Glutamate was only relatively recently recognized as the major excitatory neurotransmitter in human brain. Glutamate as a neurotransmitter is ubiquitous in nature and has diverse metabolic roles within the CNS. It is important to note that in addition to its role as a neurotransmitter, glutamate also functions as a metabolic precursor to GABA and as a component of the natural antioxidant glutathione. GABA (gamma-aminobutyric acid) is the major inhibitory neurotransmitter involved in the tight regulation of the excitatory neurotransmission. Neurons in every region of the brain use GABA to fine-tune neurotransmission to ensure optimal excitatory neurotransmission but limit excitotoxicity (or excitotoxic damage – effects due to excess excitatory neurotransmitter release). Excessive activation of glutamatergic system can damage neurons by activating proteases, lipases, endonucleases and nitric oxide synthases and by generating more free radicals. GABA occurs in 30-40% of all synapses and is the second most abundantly distributed neurotransmitter in the brain. Only glutamate is more widely distributed. Metabolic studies have determined that virtually all of the glucose (energy) that enters the CNS is eventually converted to glutamate.
Glutamate was initially studied in neuropsychiatric diseases. It has been found and hypothesized that neuropsychiatric diseases are the consequence of imbalance or dysfunction of the monoaminergic neurotransmission systems (dopamine, seretonin, and norepinephrine). It was discovered that antidepressants and antipsychotics that modulate monoaminergic neurotransmission also modulate glutamatergic neurotransmission. This finding leads to the belief of glutamatergic system’s contribution to the pathophysiology or pathogenesis of neuropsychiatric diseases. Since this time, the implication of the glutamate system in the brain diseases has expanded and recent research has focused on glutamatergic neurotransmission as the therapeutic approach to disorders as diverse as various psychiatric disorders, (age-related) neurodegenerative diseases, cognitive impairments, amyotrophic lateral sclerosis (ALS: a type of motor neuron disease) and others.
Glutamate system – the interaction and participation of glutamate with specific membrane receptors in neuro-plastic changes in the efficacy of synaptic transmission are responsible for many neurological functions, including cognition, memory, behavior, movement, sensation. Our knowledge of the glutamatergic synapses had advanced enormously in the last decade, primarily through applications of molecular biology techniques to the study of glutamate receptors (GluRs: ionotropic and metabotropic) and transporters.
NMDA receptor – one of the ionotropic glutamate receptors – have a capacity for a type of neuroplasticity known as long term potentiation (LTP) which is crucial to long-term memory creation and storage. (see post “memory processes”). NMDA receptors are most densely concentrated in the cerebral cortex, especially hippocampus (important for declarative memory), amygdala (emotional memory), and basal ganglia.
AMPA receptor, – one of the metabotropic glutamate receptors – are widely expressed in the CNS and mediate fast excitatory neurotransmission in response to glutamate binding. A physiological role for AMPA receptor in the neocortical and hippocampus synapses has been implicated in learning and memory. Stress hormones have also been found to affect AMPA receptor. This effect is believed to be one of the reasons for the observed inverted U facilitative and suppressive effect of stress hormone corticosteroid on synaptic plasticity and cognition. (see post “How Stress Affect Memory?”).
One significant progression in aging brain is the broad range of chemical changes, more specifically, changes in the amount of neurotransmitters. Studies has revealed marked alterations in neurotransmitters as well as their receptors in different regions of the brain as part of the normal aging process. These include monoamine neurotransmitter – dopamine and serotonin. An overwhelming number of studies have reported age-related changes in dopamine synthesis, binding sites and number of receptors. Decreasing levels of different serotonin receptors and the serotonin transporter have also been shown to occur with age. Glutamate content in the brain tends to decrease with age. This tendency of decrease associated with aging have been found in cerebral cortex (parietal cortex, basal ganglia, hippocampus, motor cortex), and to a lesser degree, the frontal white matter. The age-related decrease of glutamate in parietal cortex and basal ganglia is significantly larger than other regions. On the other hand, the glutamate release from neurons to the extracellular synapse doe not appear to change with age from both in vitro and in vivo studies. Although there are only few studies investigating the glutamate trafficking (the process of absorb of glutamate by transporters on the neuron cell membrane and recycle it for re-release), loss of transporter system for re-use of glutamate was found associated with aging. Moreover, glutamate receptors system are also affected. A decrease with age in the density of glutamatergic receptors of the NMDA has been reported. Decreases in glutamatergic AMPA receptor density have also been reported in prefrontal (important for working memory) and parietal cortex. More significantly is the finding of the decrease of NMDA and AMPA receptors in hippocampus (the cortex for declarative memory) and this observation was correlated with age-related memory impairments.
Not only the functional aspects of glutamatergic neurotransmission declines with age that could contribute to the neurodenegrative neuropsychological diseases. Aging also increased susceptibility of brain to glutamate excitotoxicity (damage of neurons), perhaps due to the change of GABA inhibitory system in its capacity in balancing the excitatory neurotransmission. Increased vulnerability to glutamate excitotoxity is believed and implicated by studies to contribute to the development of a number of age-related neurodegenerative diseases when more neurons are being damaged.
