Amino Acid Transmitters

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A central question regards the identity of any classical, low molecular weight transmitters that may be costored with Hcrt and MCH. In general, the expression of neuropeptides in a neuron is accompanied by at least one classical transmitter.64 It would appear likely that the LHA neurons, similar to what has been shown for most of the central nervous system, signal either via the excitatory amino acid glutamate (alternatively, aspartate) or via the inhibitory amino acid y-amino-butyric acid (GABA; alternatively, glycine). Notably, in the medial hypothalamus, when signalling via these transmitters is blocked, fast, miniature, and evoked synaptic activity is almost completely abolished, in accordance with histochemical data.65,66 Accumulating evidence suggests that Hcrt neurons contain an excitatory amino acid transmitter. Hcrt colocalizes with glutamate-LI67 as well as immunoreactivity for excitatory amino acid transporter 3 and, to a smaller extent, vesicular glutamate transporters 1 and 2, membrane proteins responsible for glutamate reuptake.68,74 In contrast, staining for glutamic acid decarboxylase-67 (GAD-67), a key enzyme in GABA biosynthesis, is completely absent from Hcrt neurons.69 Lending further support to an excitatory phenotype, Hcrt-ir terminals form asymmetrical synaptic contacts both in rat27 and cat.82 Thus, it appears likely that Hcrt (in line with its excitatory electrophysiological actions27) coexists with glutamate. The identity of a cotransmitter for MCH is more controversial. Similar to the Hcrt neurons, both glutamate and glutamate transporters have been immunohistochemically detected in MCH cells.67,68 However, the presence of GAD-67 mRNA in a large proportion of CART neurons in the LHA and zona incerta has also been reported.40 Since CART coexists with MCH in these regions (see above), it would appear that at least a portion of MCH neurons have an inhibitory phenotype. Such a population of neurons could correspond to a previously described GABAergic projection from the zona incerta to the cerebral cortex. Further research is needed to determine to what extent, if any, MCH neurons constitute a mixed population of inhibitory and excitatory cells.

Figure 2. Schematic depiction of colocalization patterns of signalling molecules in the LHA. Hypocretin (Hcrt) and melanin-concentrating hormone (MCH)-expressing neurons form two mutually exclusive cell groups. A near total colocalisation has been reported between Hcrt and dynorphin (Dyn) and secretogranin II (Sgr II). These cells are also believed to be glutamatergic. A few Hcrt neurons contain galanin (Gal). MCH neurons, on the other hand, contain cholinergic receptors (MC 3R) as well as acetylcholine esterase (AChE). These cells also label for markers of a glutamatergic phenotype. A large subpopulation of these cells express cocaine- and amphetamine-regulated transcript (CART) and the neurokinin 3 receptors (NK 3R). Of these, a considerable proportion also contains GABAergic markers. A minor degree of MCH/Substance P (SP) colocalisation has been reported. Both Hcrt and MCH overlap with the serotonin 5-HT1A receptor. There may also be additional overlap between Hcrt and MCH and other neuromodulatory molecules. The possibilities of Hcrt coexisting with neurotensin (NT) or the neurokinin 1 receptor (NK 1R), of MCH coexisting with thyrotropin-releasing hormone (TRH), or of somatostatin (Som) coexisting with either Hcrt and/or MCH, remain to be investigated (indicated by "?"). Neurons that signal via nitric oxide (NO) and express the neuropeptide Y Y1 receptor form a population distinct from both Hcrt and MCH cells. See text for details and references. Box sizes are not scaled to sizes of the cell populations.

Figure 2. Schematic depiction of colocalization patterns of signalling molecules in the LHA. Hypocretin (Hcrt) and melanin-concentrating hormone (MCH)-expressing neurons form two mutually exclusive cell groups. A near total colocalisation has been reported between Hcrt and dynorphin (Dyn) and secretogranin II (Sgr II). These cells are also believed to be glutamatergic. A few Hcrt neurons contain galanin (Gal). MCH neurons, on the other hand, contain cholinergic receptors (MC 3R) as well as acetylcholine esterase (AChE). These cells also label for markers of a glutamatergic phenotype. A large subpopulation of these cells express cocaine- and amphetamine-regulated transcript (CART) and the neurokinin 3 receptors (NK 3R). Of these, a considerable proportion also contains GABAergic markers. A minor degree of MCH/Substance P (SP) colocalisation has been reported. Both Hcrt and MCH overlap with the serotonin 5-HT1A receptor. There may also be additional overlap between Hcrt and MCH and other neuromodulatory molecules. The possibilities of Hcrt coexisting with neurotensin (NT) or the neurokinin 1 receptor (NK 1R), of MCH coexisting with thyrotropin-releasing hormone (TRH), or of somatostatin (Som) coexisting with either Hcrt and/or MCH, remain to be investigated (indicated by "?"). Neurons that signal via nitric oxide (NO) and express the neuropeptide Y Y1 receptor form a population distinct from both Hcrt and MCH cells. See text for details and references. Box sizes are not scaled to sizes of the cell populations.

Thus, using the various transmitter combinations, several subpopulations of LHA neurons can now be distinguished (see Fig. 2 for schematic summary). Future investigations will likely add to the complexity of neurochemical phenotypes in this region, and it will be of interest to correlate the transmitter content to projection patterns. It should, however, be cautioned that the total number of cells that make up the LHA has been estimated to ca. 250,000.71 This figure may be compared with available estimates of the Hcrt population (slightly above 1000)32 and the MCH neurons (circa 90,000).72 Needless to say, calculations of absolute neuron numbers have their inherent limitations. Yet, these figures serve as a useful reminder that the LHA may still harbour large clusters of cells whose transmitter and circuitry phenotype remains unaccounted for, and which may shed further light on the phenotype resulting from lateral hypothalamic ablations.

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