Excitatory And Inhibitory Amino Acid Neurotransmitters In The Context Of Neural Circuitry

The amino acid neurotransmitters are the most abundant and widely used neurotransmitters in the brain. The excitatory neurotransmitter glutamate and the inhibitory neurotransmitter GABA are the predominant transmitters in both the local and long-range circuits that form distributed neural networks. In the brain, L-glutamate is synthesized in axon terminals from glucose (via the Krebs cycle) or from glutamine that is converted into glutamate by the enzyme glutaminase. The synaptic action of glutamate is terminated by the glutamate transporter, which is located on the presynaptic axon terminal. GABA is synthesized in the brain by the decarboxylation of L-glutamic acid, which is catalyzed by the enzyme glutamic acid decarboxylase. As in other neurotransmitter systems, the synaptic action of GABA is terminated by the GABA transporter. In the following section, we focus on the cell types and projections utilizing these two neurotransmitters in the neocortex, basal ganglia, and thalamus, given that these brain regions have been implicated in the pathophysiology of a number of psychiatric disorders.

Cerebral Cortex

Pyramidal cells, the predominant projection neurons of the cerebral cortex, utilize glutamate as their neurotransmitter. Most pyramidal neurons are characteristically shaped and possess a single apical dendrite that extends toward the pial surface. In addition, several basilar dendrites extend from the base of the cell body in a radial fashion. Dendritic spines, short extensions of the dendritic shafts, coat both apical and basilar dendrites. Pyramidal neurons have principal axons that enter the white matter and project to other cortical regions, as well as axon collaterals that travel either horizontally or vertically within the gray matter. In all cortical areas, pyramidal cells are located in layers 2-6, and the laminar location of a pyramidal cell often indicates its projection target. For example, cortically projecting pyramidal neurons are predominantly located in layer 3, whereas striatal- and thalamic-projecting cells reside in layers 5 and 6, respectively (DeFelipe and Farinas 1992).

Nonpyramidal neurons are the other major class of cortical neuron, and the majority (90%) of these neurons utilize GABA as their neurotransmitter. Also known as interneurons, the axons of cortical GABA cells arborize within the gray matter and thus do not project out of the cortical region in which they reside. As many as 12 different subtypes of GABA neurons can be found in the cortex, and these can be distinguished biochemically, electrophysiologically, and morphologically (Figure 4-8) (Fairen et al. 1984; Krimer et al. 2005; Lund and Lewis 1993). For example, subpopulations of GABA cells can be distinguished by the presence of certain neuropeptides or calcium-binding proteins (Conde et al. 1994; Gabbott and Bacon 1996). In addition, the organization of the axonal arbor and synaptic targets of the axon terminals differ greatly across these different subtypes (Lund and Lewis 1993). As depicted in Figure 4-8, the chandelier class of GABA cell expresses the calcium-binding protein parvalbumin (DeFelipe et al. 1989; Lund and Lewis 1993) and has axon terminals that are arrayed as distinct vertical structures, termed cartridges (Fairen and Valverde 1980; Goldman-Rakic and Brown 1982). These axon terminals form inhibitory or symmetric synapses exclusively with the axon initial segments of pyramidal cells (DeFelipe et al. 1985). Parvalbumin-containing basket neurons form symmetric synapses with the cell bodies and dendrites of pyramidal neurons (Melchitzky et al. 1999; Williams et al. 1992). Parvalbumin-containing neurons are predominantly located in layers 3 and 4. Martinotti cells contain somatostatin and form symmetric synapses with the tuft dendrites of pyramidal neurons (Kawaguchi and Kubota 1997; Wang et al. 2004) and, to a lesser extent, with the dendrites of GABA neurons (Melchitzky and Lewis 2008). Double bouquet neurons have radially oriented axonal arbors and contain either somatostatin and the calcium-binding protein calbindin (DeFelipe 1993) or the calcium-binding protein calretinin (Conde et al. 1994). The somatostatin- and calbindin-containing double bouquet cells form symmetric synapses with the distal dendritic shafts and spines of pyramidal neurons. By contrast, the calretinin-containing double bouquet cells form symmetric synapses predominantly with the dendritic shafts of other GABA neurons (Gonchar and Burkhalter 1999; Meskenaite 1997), although they also target distal dendritic shafts and spines of pyramidal neurons to a lesser extent (Melchitzky et al. 2005). Calretinin-containing Cajal-Retzius cells reside solely in layer 1 and target the tuft dendrites of pyramidal neurons. These subpopulations of GABA neurons have differing laminar patterns of distribution (see Figure 4-8). For example, in the prefrontal cortex, layers deep 3 and 4 have the majority of parvalbumin-containing neurons (Conde et al. 1994; Gabbott and Bacon 1996); layers 2, superficial 3, and 5 have the greatest density of somatostatin-containing neurons (Lewis et al. 1986); and layer 2 has the highest density of calretinin-containing cells (Conde et al. 1994; Gabbott and Bacon 1996).

FIGURE 4-8. (A) Schematic illustration of synaptic contacts between different subpopulations of GABA neurons and a layer 3 pyramidal neuron in monkey prefrontal cortex. (B) Film autoradiograms showing signals for parvalbumin (PV), somatostatin (SST), and calretinin (CR) mRNAs in human prefrontal cortex.

Copyright © American Psychiatric Publishing, Inc., or American Psychiatric Association, unless otherwise indicated in figure legend. All rights reserved.

Copyright © American Psychiatric Publishing, Inc., or American Psychiatric Association, unless otherwise indicated in figure legend. All rights reserved.

(A) The indicated synaptic connections of each subpopulation of GABA neuron are based on previous studies (see text for details).

(B) Note the different laminar distribution of these three subclasses of GABA neurons. GABA = 7-aminobutyric acid; WM = white matter.

Source. Adapted from Gonzalez-Burgos G, Hashimoto T, Lewis DA: "Inhibition and Timing in Cortical Neural Circuits" (Images in Neuroscience). American Journal of Psychiatry 164:12, 2007. Copyright 2007, American Psychiatric Association. Used with permission.

Multiple lines of evidence show that GABA neurons in monkey prefrontal cortex are involved in working memory tasks. For example, fast-spiking neurons are active during the delay period of working memory tasks (Wilson et al. 1994), and injection of GABA antagonists into the prefrontal cortex disrupts working memory (Sawaguchi et al. 1989). Patients with schizophrenia perform poorly on working memory tasks (Weinberger et al. 1986), and postmortem studies have demonstrated alterations in markers of GABA neurotransmission in the prefrontal cortex of schizophrenic subjects. For example, reduced mRNA for the 67 kiloDalton isoform of glutamic acid decarboxylase, the principal determinant of GABA synthesis, is one of the most consistent findings in postmortem studies of individuals with schizophrenia (Akbarian and Huang 2006). In addition, mRNA levels of parvalbumin and somatostatin, but not of calretinin, are reduced in the prefrontal cortex of subjects with schizophrenia (Hashimoto et al. 2003, 2008).

Thalamus

The dorsal thalamus is a heterogeneous structure composed of numerous nuclei that are distinguished on the basis of their location, cytoarchitecture, and connections with other brain regions. The projection or relay neurons within these nuclei use glutamate as their neurotransmitter and thus provide excitatory input to their target regions. For example, the axon terminals that project from the thalamus to primary sensory cortices contain glutamate immunoreactivity and form Gray's type I synapses (Kharazia and Weinberg 1994).

There are two groups of GABA-containing neurons in the primate thalamus: the interneurons, whose axons and actions are confined within the various dorsal thalamic nuclei, and the neurons of the reticular nucleus. All of the neurons in the reticular nucleus are GABAergic, and they provide extensive projections to the nuclei of the dorsal thalamus, the principal and possibly sole target of the reticular nucleus (Steriade et al. 1997). Thus, as in the cortex, the activity of the long-range excitatory projections from the thalamus is regulated by inhibitory inputs from nearby GABA neurons.

Basal Ganglia

The basal ganglia consist of the striatum (comprising the caudate nucleus, putamen, and nucleus accumbens), the globus pallidus (internal and external segments), and the substantia nigra pars reticulata. The internal segment of the globus pallidus and the substantia nigra pars reticulata are often grouped together and are referred to as the output nuclei of the basal ganglia. In contrast to the cortex and thalamus, the projection neurons of the basal ganglia utilize GABA as a neurotransmitter. For example, the GABA-containing medium spiny neurons of the striatum, which are the principal target of the excitatory projections from cortical pyramidal cells (Alexander and Crutcher 1990), project to the output nuclei of the basal ganglia (Figure 4-9). These medium spiny striatal neurons express substance P and dynorphin as well as GABA (Gerfen and Young 1988). The GABA projection neurons of the output nuclei of the basal ganglia project to the thalamus, where they form inhibitory contacts with thalamic projection neurons. This pathway from the striatum through the output nuclei of the basal ganglia to the thalamus is known as the "direct" pathway through the basal ganglia, and it results in disinhibition of the thalamus, which in turn sends a glutamatergic projection back to the cerebral cortex (Alexander and Crutcher 1990). In the "indirect" pathway (see Figure 4-9), GABA- and enkephalin-containing neurons in the striatum project to the external segment of the globus pallidus (Gerfen and Young 1988), where they target GABA projection neurons. The axons of these pallidal projection neurons target glutamate-containing cells in the subthalamic nucleus, which then project to GABA neurons of the output nuclei of the basal ganglia. Similar to the direct pathway, the output nuclei of the basal ganglia send GABAergic projections to the thalamus. In both the direct and indirect pathways, the cerebral cortex sends glutamatergic projections to the striatum and receives glutamatergic input from the thalamus, thus forming a corticostriatal circuit (see Figure 4-9). DA released from neurons in the substantia nigra pars compacta appears to facilitate transmission through the direct pathway, via Di receptors on the substance P/dynorphin cells, and to inhibit transmission through the indirect pathway, via D2 receptors on the enkephalin cells (Albin et al. i989; Gerfen et al. i990).

FIGURE 4-9. Schematic diagram of basal ganglia circuitry, illustrating the direct and indirect pathways.

FIGURE 4-9. Schematic diagram of basal ganglia circuitry, illustrating the direct and indirect pathways.

See text for details. DA = dopamine; DYN = dynorphin; ENK = enkephalin; GABA = 7-aminobutyric acid; GPe = external globus pallidus; GPi = internal globus pallidus; SNc = substantia nigra pars compacta; SNr = substantia nigra pars reticulata; SP = substance P; STN = subthalamic nucleus.

Source. Adapted from Parent A, Sato F, Wu Y, et al: "Organization of the Basal Ganglia: The Importance of Axonal Collateralization." Trends in Neurosciences 23:S20-S27, 2000. Copyright 2000, Elsevier. Used with permission.

The nigrostriatal projection constitutes one of the major inputs to the basal ganglia. The striatum reciprocates and sends projections back to the midbrain DA neurons (Figure 4-i0), forming a striatonigrostriatal circuit. The midbrain DA neurons can be divided into two tiers: the dorsal tier (which includes neurons of the dorsal substantia nigra pars compacta, the ventral tegmental area, and the retrorubral group) and the ventral tier (composed of the densocellular and cell column neurons of the substantia nigra pars compacta) (Haber and Fudge i997). As illustrated in Figure 4-i0, there is an inverse dorsal-ventral topographical organization to the projection from the dorsal and ventral DA neurons to the striatum (Haber 2003). For example, dorsally and medially located DA neurons project to the ventral and medial parts of the striatum (red and yellow pathways in Figure 4-i0), whereas ventrally and laterally located DA neurons project to the dorsal and lateral parts of the striatum (green and blue pathways in Figure 4-i0). Another prominent input to the striatum derives from the cerebral cortex, and this projection has a topographic organization related to that of the striatonigrostriatal pathway (see Figure 4-i0). The orbital and medial prefrontal cortices project to the ventral striatum, the dorsolateral prefrontal cortex projects to the central striatum, and the premotor and motor cortices project to the dorsolateral striatum. These topographies create limbic, associative, and motor pathways (red/orange, yellow, and green/blue, respectively, in Figure 4-i0) within the corticostriatalcortical and striatonigrostriatal projections.

FIGURE 4-10. Organization of striatonigralstriatal projections.

Copyright © American Psychiatric Publishing, Inc., or American Psychiatric Association, unless otherwise indicated in figure legend. All rights reserved.

The organization of functional corticostriatal inputs (red = limbic, green = associative, blue = motor) is illustrated (see text for details). DL-PFC = dorsolateral prefrontal cortex; IC = internal capsule; OMPFC = orbital and medial prefrontal cortex; SNc = substantia nigra pars compacta; SNr = substantia nigra pars reticulata. VTA = ventral tegmental area.

Source. Adapted from Haber SN, Fudge JH, McFarland NR. "Striatonigrostriatal Pathways in Primates Form an Ascending Spiral From the Shell to the Dorsolateral Striatum." Journal of Neuroscience 20:2369-2382, 2000. Copyright 2000, Society for Neuroscience. Used with permission.

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