**6. Balance is achieved through mutual interactions of the excitatory and inhibitory effects of amino acids**

Because glutamate is the major mediator of excitatory signals as well as of nervous system plasticity, including cell elimination, it follows that glutamate needs to be present at the right concentrations in the right places at the right time [17].

## *Amino Acids as Neurotransmitters. The Balance between Excitation and Inhibition… DOI: http://dx.doi.org/10.5772/intechopen.103760*

These conditions are regulated by GS, GM, and EAATs and convectional diffusion in ISF. There is evidence that extracellular glutamate is not compartmentalized by EAATs under some conditions [62]. The most obvious shift in glutamate levels is observed under high GDH and AT activity. The general activation of bioenergetics decreases the excessive glutamate concentration by stimulating the TCA cycle. Moreover, glycine can participate in this shift in a variety of ways. GlyT-1 controls glycine release and reuptake, determines glycine availability at glycine binding sites on NMDA receptors [36] and coordinates neuronal-glial interactions at glutamatergic synapses [19]. Thus, glycine assists glutamate in the activation of astrocytes and further stimulates the mitochondria according to the ANLS hypothesis. Glycine can conjugate with glutamate in the GSH synthesis pathway (**Figure 1**). This mechanism is essential to maintain the redox status of neurons and to prevent oxidative stress and high levels of reactive oxygen species (ROS) synthesis. Neuronal mitochondria are the target of glutamate, which attenuates succinate dehydrogenase (a key enzyme of the TCA cycle) inhibition by oxaloacetate [63], with further induction of ROS production [64]. However, glycine can prevent excessive hydrogen peroxide production induced by glutamate in brain mitochondria [65], thereby reducing the prooxidant effects of the excessive glutamate concentrations.

#### **Figure 4.**

*The transport and activation of receptors in glycinergic and glutamatergic synapses. The transport system is tightly linked with glucose consumption. This transport system occurs in both astrocytes and neurons, but according to the ANLS model, the majority of glucose is consumed in astrocytes, with further diffusion of lactate to neurons. Lactate transport is facilitated by monocarboxylate transporters (MCTs), which have two different isoenzymes. MCT1 is expressed in astrocytes, and MCT2 is found in neurons [69]. Glutamateglutamine cycling occurs between central astrocytes and neurons, mediated by sodium-coupled neutral amino acid transporters (SNATs). Transport is mediated by two isoforms, SNAT3 and SNAT1 [70]. ISF: interstitial fluid.*

Interestingly, the effects of amino acids can vary depending on the species. For example, in a chick model, injections of L-glutamate, NMDA, and AMPA attenuated total distress vocalizations and induced sedation [66]. The association between glutamate and inhibition/sedation is even stronger because the brain contains a considerable level of glutamate decarboxylase, which directly catalyzes the decarboxylation of glutamate to GABA [27]. Additionally, glycine is not always associated with direct inhibition in the CNS. Indeed, in mature neurons, where there is a low intracellular Cl− concentration maintained by K+ - Cl− cotransporter 2 (KCC2), activation of GlyRs elicits an influx of Cl− , leading to rapid hyperpolarization and postsynaptic inhibition [67]. In contrast, in immature neurons, activation of GlyRs results in efflux of Cl− , leading to neuronal depolarization; this opens voltagedependent Ca2+ channels, elicits action potentials, and establishes early network activity and excitation in the developing nervous system [68].

Thus, the balance between excitation and inhibition is the result of continuous interactions among different processes involving both glutamate and glycine. It is essential that the main reactions and regulatory sites are nonhomogenously distributed in neuronal space and are time-regulated. Convective flow does not restore the homogeneity of mediator and metabolite concentrations because of the tortuosity of the system [63]. A scheme of the balanced interactions between glycinergic and glutamatergic synapses is shown in **Figure 4**.
