Brain glutamatergic neurons

Glutamatergic neurons are widely distributed throughout the entire brain. Most glutamatergic neurons are so-called projection neurons their axon projects into distant brain regions. Prominent glutamatergic pathways are the connections between different regions of the cerebral cortex (cortico-cortical projections), the connections between thalamus and cortex, and the projections from cortex to striatum (extrapyramidal pathway) and from cortex to brain stem/spinal chord (pyramidal pathway). 

The hippocampus is characterized by a series of glutamatergic neurons, which can create rhythms of electrical activity necessary for the generation of memory traces in the brain. The cerebellum, a region dedicated to the temporal processing of motor and cognitive in-... 

The widespread distribution of glutamatergic neurons explains why glutamate is involved in many brain functions. Modulation of glutamatergic activity is therefore most likely to have widespread effects. Excess stimulation of glutamatergic receptors, as seen in seizures or stroke, can lead to unregulated Ca + influx and neuronal damage (Dingledine et ah, 1990 Coyle and PuTtfarcken, 1993 Loscher, 1998). 

Several brain functions have been linked to specific glutamate receptor subtypes in selected brain regions. For example, glutamatergic neurons and NMDA receptors in the hippocampus are important for longterm potentiation (FTP), a crucial component in the formation of memory (Wilson and Tonegawa, 1997). Animal models with selective lesioning or strengthen-... 

Figure 30-13 Section through a rat brain. This brain, which has been very widely used in neurochemical studies, appears superficially to be quite different from the human brain (Fig. 30-1), which is characterized by its large cerebral cortex. However, basic pathways are the same. Some major pathways for glutamate-secreting (glutamatergic) neurons are marked by arrows. Most of these originate in the neocortex (outer layers of the cerebral cortex) and the hippocampus. From Nicholls.149 Courtesy of David G. Nicholls.

The stargazer mutant mouse is ataxic and epileptic. It lacks functional AMPA receptors (Fig. 30-1), which apparently are not delivered successfully to the synapses in the cerebellum in which they function.380 386 Mutation of a transmembrane protein stargazin, which may interact with the AMP receptor, causes the symptoms.457 458 NMDA receptors (Fig. 30-20) are involved in synapse formation in the brain. Filopodial extensions on dendrites, triggered by electrical activity, are essential for synapse formation,459 which occurs rapidly.4593 Activation of NMDA receptors is apparently also necessary.379 460 Without this stimulation the excitatory glutamatergic neurons of the developing brain undergo apoptosis. 

Table 1. Location of H3 heteroreceptors inhibiting the release of monoamines, acetylcholine and glutamate in the brain. To prove or disprove the presynaptic location of H3 receptors, transmitter release was studied in isolated nerve endings (synaptosomes) or in brain slices superfused with K+-rich Ca2+-free medium containing tetrodotoxin (TTX) (in the latter case, transmitter release was evoked by introduction of Ca2+ ions into the medium). The experimental approaches used in the electrophysiological study to show the presynaptic location of H3 receptors on glutamatergic neurones are described in the text.

Czyrak A, Czepiel K, Mackowiak M, Chocyk A, Wedzony K. Serotonin 5-HT1A receptors might control the output of cortical glutamatergic neurons in rat cingulate cortex. Brain Res 2003 989 42-51. 

Dysbindin-1 is expressed by glutamatergic neurons and by their targets cells in brain areas affected in schizophrenia, including the DLPFC, hippocampal formation, and striatum (see Sections 2.2.6.3.2.3.4— 2.2.6.3.2.3.6). Reduced dysbindin-1 levels in such cells and their targets is likely to contribute to glutamatergic dysfunction in schizophrenia, because dysbindin-1 knockdown in cerebrocortical cells reduces stimulus-induced release of glutamate (Numakawa et al., 2004) and because dysbindin-1 loss in sdy mice leads to reduced NMDA-mediated currents in the rodent homolog of the primate DLPFC (Andrew et al.,... 

Squires RF, Lajtha A, Saederup E, Palkovits M. 1993. Reduced [3H]flunitrazepam binding in cingulate cortex and hippocampus of postmortem schizophrenic brains Is selective loss of glutamatergic neurons associated with major psychoses Neurochem Res 18 219-223. 

As indicated above, Glu is not only a neurotransmitter but is also involved in a variety of metabolic functions in the brain. The metabolism of Glu is complicated and involves neurons as well as glial cells. Transmitter Glu may be synthesized through different metabolic pathways, and different populations of glutamatergic neurons may differ in certain aspects of Glu metabolism. The first part of this chapter will provide an update on the metabolism of Glu and related compounds in the brain. 

Sibson NR, Dhankhar A, Mason GF. Rothman DL, Behar KL, Shulman RG (1998) Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity, Proc Natl Acad Sci USA 95 316-321. 

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