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In this section, the elements involved in developing the neuron-vascular control mechanism hypothesis are presented in a logical sequence, with each step evaluated by considering what purpose is served by the particular process or metabolic step involved. Indeed, what follows is more of a description of events than a hypothesis, a description that leads to the conclusions that form the basis of a possible understanding the roles of NAA and NAAG in the brain.

2.1. Neuron requirements for energy and for waste metabolic product removal

The basic function of a neuron is to communicate, and they do this by generating intracellular electrophysiological signals in the form of action potentials or spikes. The spikes are then translated into intercellular neurochemical signals transmitted to other neurons at synapses, and subsequently interpreted at some level in the CNS neural network (Clifford and Ibbotson, 2000). These energy-dependent spike trains are both ephemeral and transient in nature, and a neuron must be able to quickly indicate its needs for increased energy supplies, and for waste metabolic product removal in order to sustain this spiking activity. Signal transmission is also a metabolically expensive process with energy demands tightly coupled to encoding of information (Smith et al., 2002).

The timeframe in which normal information processing activities must operate is short, and is bounded by the time between neuronal action potentials measured in ms (Clifford and Ibbotson, 2000; Mackel and Brink, 2003) and changes in rate of energy supply and waste removal in seconds (Vanzetta and Grinvald, 1999). Within this timeframe, dynamic metabolic feedback interactions between neurons and the vascular system, changes in rates of neuronal energy supply and ATP production, and energy-dependent neuronal re-polarization all occur. Since the ATP energy required by neurons increases directly with spike frequency, use of stores of ATP to generate an increase in spiking must be replaced by an equivalent increase in Glc oxidation and ATP production. Without a timely replenishment of ATP supplies, it can be anticipated that neuron re-polarization and absolute refractory periods would increase, reducing the maximum spike frequency and thus altering information processing. On the global level, this could be associated with a loss of cognitive ability. The waste metabolic products of Glc oxidation are CO2, which can exit neurons down its gradient, and water, which must be removed against a water gradient.

2.2. Measures of neuron-vascular system interactions

As neurostimulation is a metabolically expensive process, it requires the continuous supply of energy in the form of Glc and oxygen from the vascular compartment. One method used to evaluate neurostimulated areas of the brain is by measuring changes in vascular oxygen levels. This can be measured locally using magnetic resonance (MR), based on magnetic properties of blood, which are in turn dependent on the oxygenation state of hemoglobin (Thomas et al., 2000). Blood oxygen exists in two states, a dissolved but freely diffusible gas, and a bound form associated with hemoglobin in red blood cells. As oxygen gas diffuses down its gradient out of the vascular system, additional bound oxygen in the vascular compartment is dissociated from hemoglobin.

Since deoxygenated hemoglobin is more paramagnetic than oxygenated hemoglobin, it can then act as an intravascular paramagnetic contrast agent. Thus, hemoglobin deoxygenation results in an increased magnetic susceptibility difference resulting in a signal loss in vascular water, caused by changes in the apparent proton transverse relaxation time (T2*). It has also been observed that in addition to measuring a vascular water T2 * signal loss, these MR changes in intravascular magnetic susceptibility can also be calibrated to obtain values for focal changes in the cerebral metabolic rate of O2 consumption (Smith et al., 2002; Hyder et al., 2002).

Because the changes in blood oxygenation levels affect the water signal, and are also associated with neurostimulation, this MR imaging technique (MRI) is used to visualize areas of the brain that appear to be stimulated as a function of brain activation tasks. The acronym for these functional MRI (fMRI) measurements is "BOLD" imaging, which stands for blood oxygen level dependent-imaging. The basis of the fMRI induced BOLD signal has been recently reviewed (Logothetis, 2003). An initial BOLD effect phase in 12 s, which is a measure of the change in oxygenation level of hemoglobin in the vascular system, is separate from a second BOLD phase within 3-12 s, which is linked to hyperemia due to vascular expansion (Logothetis, 2003). However, since both are associated with neurostimulation, the interrelationship and balance between these two parameters are incorporated into most BOLD measurements (Zarahn, 2001).

Using another technique, based on temporal data obtained using an oxygen-dependent phosphorescence quenching method of an exogenous indicator, it has also been observed that the first event after sensory stimulation was a localized increase in O2 consumption, and this was followed by hyperemia and a more regional increase in blood flow (Vanzetta and Grinvald, 1999). Therefore, it has been suggested that fMRI focused on the earliest initial phase after stimulation would better co-localize with the actual site of neurostimulation.

To summarize, the BOLD effect in response to focal neurostimulation, while complex in origin, reflects two basic elements; an initial increase in deoxyhemoglobin as a result of increased O2 demand, and a subsequent increase in blood flow to meet this demand. This focal neurostimulation-vascular system interaction serves two purposes for neurons. It increases the vascular sink capacity for waste metabolic water and, at the same time, increases the available supply of energy in areas where it is required by increased neuronal activity, both factors which are important to maintenance of neuron function.

2.3. Synthesis of NAA and NAAG by neurons

NAA is an amino acid that is present in the vertebrate brain, and in human brain, at about 10 mM, its concentration is among the highest of all free amino acids. Although NAA is synthesized and stored primarily in neurons, it cannot be hydrolyzed in these cells. However, neuronal NAA is dynamic in that it turns over more than once each day by virtue of its continuous efflux down a steep gradient, in a regulated inter-compartmental cycling via extracellular fluids (ECF), between neurons and a second compartment, primarily in oligodendrocytes (Madhavarao et al., 2004), where it is rapidly deacetylated.

The neuronal membrane transport mechanism for NAA into ECF and its oligodendrocyte docking mechanism are presently unknown. In addition, the specific neuronal sites of NAA efflux are unclear. While the NAA synthetic enzyme has only been partially characterized (Madhavarao et al., 2003), the gene for its hydrolytic enzyme, amidohydrolase II (aspartoacylase), in oligodendrocytes has been cloned. The compartmental metabolism of NAA, between its anabolic compartment in neurons and its catabolic compartment in oligodendrocytes, and its possible physiological role in the brain has been reviewed (Birken and Oldendorf, 1989; Baslow, 1997, 2000, 2003).

NAAG, a dipeptide derivative of NAA and Glu, is also present in abundance in neurons as well as being present in oligodendrocytes and microglia, and at about 1 mM, it is one of the most abundant dipeptides in the vertebrate brain. NAAG is metabolically unusual in that there are three cell types involved in its metabolism. NAAG that is synthesized in neurons is first exported to astrocytes, via an as yet unknown transport mechanism, where it docks with a metabotropic Glu receptor, and then an astrocyte-specific enzyme located on the astrocyte surface, NAAG peptidase (GCP II,

NAALADase, NAAG peptidase I), hydrolyzes the Glu moiety, which is then taken up by the astrocytes and converted into glutamine (Gln), which is then transported back to neurons. The residual NAA metabolic product then diffuses to oligodendrocytes, where the cell-specific enzyme, amidohydrolase II, removes the acetate (Ac) moiety, which is then taken up by the oligodendrocytes. Finally, the ECF-liberated Asp diffuses back to neurons where it is taken up and subsequently used for recycling into NAA and then into NAAG, completing the cycle.

The nature of the NAAG synthase is presently unknown, but the NAAG peptidase (GCP II) has been cloned (Kozikowski et al., 2004), as has been a second membrane-bound brain astrocyte NAAG peptidase, NAAG peptidase II (GCP III) that has about 6% of the activity of NAAG peptidase I on NAAG (Bacich et al., 2002; Bzdega et al., 2004). The distribution and unusual metabolism of NAAG in brain has also been reviewed (Birken and Oldendorf, 1989; Coyle, 1997; Neale et al., 2000; Baslow, 2000; Karelson et al., 2003).

From these observations, it is clear that neurons synthesize and release NAA and NAAG for the purpose of interacting with oligodendrocytes and astrocytes respectively, and that these metabolic interactions are highly complex and cyclical in nature, with Asp continuously being recycled to neurons. What remains to be clarified are the reasons for this intercellular traffic.

2.4. NAA is structurally and metabolically coupled to Glc metabolism

Using MRS involving combined 13 C MRS and [1-13 C] glucose (Glc) infusion, the rate of NAA synthesis in the human brain has been measured in vivo, and it has been demonstrated that NAA synthesis is both structurally and metabolically coupled to Glc metabolism. The NAA carbon 6 (Ac moiety) is derived from acetyl-coenzyme A (AcCoA), which is derived in turn from [1-13 C] Glc metabolism (Moreno et al, 2001). This study connects both the structure, and the rate of synthesis of NAA directly with the rate of Glc energy metabolism in the human brain. Similar results have also been reported in rat brain (Choi and Gruetter, 2001; Henry et al., 2003; Karelson et al., 2003). The synthesis of NAA and oxidation of Glc are also physically connected in that their metabolism occurs in the same organelle, the mitochondrion. The NAA metabolic sequence starting from neuron Glc is unidirectional in nature and is only completed when Asp is regenerated by the action of oligodendrocyte amidohydrolase II.

There are two human inborn errors associated with the Glc-NAA metabolic sequence. One is Canavan disease (CD), a rare inborn error in which amidohydrolase II activity is lacking, and as a consequence, there is a buildup of NAA (hyperacetylaspartia) in brain (Baslow, 2003a). The second is a singular human case of hypoacetylaspartia, where brain NAA may not be synthesized at all (Boltshauser et al., 2004). In both cases the outcomes are profound. In CD, there is extensive neuron-oligodendrocyte and astrocyte pathology, along with severe cognitive dysfunction. In hypoacetylaspartia, the NAA metabolic deficit is also closely associated with cognitive dysfunction, but without any other striking cellular, electrophysiological, or brain macro-structural pathology. Thus, in this inborn error, neuron viability and spiking activity appear to be intact, but without meaningful information being processed. Similarly, in cultured neurons and organotypic brain slices of rats, which represent two levels of brain deconstruction, NAA levels are also significantly reduced or absent, but without evidence of loss of neuron viability or function (Baslow et al., 2003).

2.5. NAA and NAAG are structurally, metabolically and dynamically coupled

NAA and NAAG are also metabolically and structurally connected since Glc metabolism is the source of Ac in both molecules. In rat brain, NAAG is synthesized from NAA and Glu (Tyson and Sutherland, 1998) at a rate of about 0.06 |imol/g/h or about 1 molecule of NAAG for every 10 molecules of NAA synthesized, and under steady-state conditions they are maintained at this ratio. Based on its rate of synthesis, and a brain NAAG content of about 1 mM, the turnover time of NAAG at the calculated rate of 6.0 %/h is 16.7 h, a value very similar to the turnover rate of NAA (14.2 h) in the rat brain. Thus, even though brain NAAG content is lower than that of NAA, their turnover rates are similar, suggesting that there is also a dynamic connection. The NAAG metabolic sequence starting with neuron Glc is also unidirectional, and is also completed when Asp is regenerated from NAA by the action of amidohydrolase II, following the hydrolysis of NAAG to form NAA by astrocyte NAAG peptidase. The relationships between rates of NAA and NAAG synthesis, and rates of efflux and hydrolysis in rat brain are shown in Table 1.

Table 1. Rat brain NAA and NAAG dynamic values a

Symbol Function Units Measured/Derived

NAA b NAAG c

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