Neurons turnover rate

The turnover rate of a transmitter can be calculated from measurement of either the rate at which it is synthesised or the rate at which it is lost from the endogenous store. Transmitter synthesis can be monitored by administering [ H]- or [ " C]-labelled precursors in vivo these are eventually taken up by neurons and converted into radiolabelled product (the transmitter). The rate of accumulation of the radiolabelled transmitter can be used to estimate its synthesis rate. Obviously, the choice of precursor is determined by the rate-limiting step in the synthetic pathway for instance, when measuring catecholamine turnover, tyrosine must be used instead of /-DOPA which bypasses the rate-limiting enzyme, tyrosine hydroxylase. 

Figure 4.1 Turnover of classical neurotransmitters. At normal rates of neuronal activity, endogenous stores of neurotransmitter are maintained at constant (steady-state) levels, indicating that the supply of new neurotransmitter (through synthesis) meets the demand (determined by release and metabolism). Consequently, the rate of the depletion (A) of the endogenous store of transmitter after inhibition of its synthesis indicates turnover rate and is described by the equation ...

NOS-positive neurones and activated neuroglial cells were the most prominent citruUine-positive structures (Keilhoff et al. 2000). Lack of citruUine-immunoreaction in neurones of nNOS knockout mice emphasised the dependency of cit-ruUine positivity on NOS activity, and likewise there was no citrulline staining after application of the NOS inhibitors 7-nitroindazole and l-N -(1-iminoethyl)lysine. The inhibition of argininosuc-cinate synthetase by a-methyl-DL-aspartate increased the number of citrulline-positive cells, apparently due to the reduction of the turnover rate of citrulline. Cells positive for NOS but negative for citrulline may indicate that the enzyme is either not activated or inhibited by cellular control mechanisms. The fact that not all citrulline-positive cells were NOS positive may be explained by an insufficient detection sensitivity or by disparate sites of citrulline production and recycling. 

Imipramine blocked the uptake of dopamine at central aminergic neurons in the rat Lithium inhibited the electrically-induced release of NE and 5" in brain slices 3 and did not interfere with the transfer rate of Ma from blood to brain tissue. Data were reported which suggested that the therapeutic effect of electroshock treatment may be due to increased levels of brain amines 5 or to an increase in NE turnover rate . In a study of catecholamine turnover rates in mouse brain it was found that neuroleptics have a predominant influence on dopamine metabolism while antidepressants selectively affect NE metabolism, a higher rate of NE synthesis was found in the forebrain of "mouse-killing" rats over that of controls Imipramine blocked the muricidal behaviour9 and also lowered NE turnover . 

With respect to the first process, cell turnover rates range from that of the intestinal epithelium which is very high, the cells being replaced in a matter of hours, to that of the neurons which, once formed, never divide or are replaced. However, although exempt from the first process, the cellular constituents of neurons, like those of all other cells, are subject to continuous breakdown and replacement. 

Acetylcholine serves as a neurotransmitter. Removal of acetylcholine within the time limits of the synaptic transmission is accomplished by acetylcholinesterase (AChE). The time required for hydrolysis of acetylcholine at the neuromuscular junction is less than a millisecond (turnover time is 150 ps) such that one molecule of AChE can hydrolyze 6 105 acetylcholine molecules per minute. The Km of AChE for acetylcholine is approximately 50-100 pM. AChE is one of the most efficient enzymes known. It works at a rate close to catalytic perfection where substrate diffusion becomes rate limiting. AChE is expressed in cholinergic neurons and muscle cells where it is found attached to the outer surface of the cell membrane. 

The VTA (AlO) neurons innervating the cortex certainly show features that distinguish them from those in A9. They have a faster basal discharge rate (10 Hz, cf. 3 Hz in A9), a higher turnover of DA, fewer autoreceptors and are less easily inhibited by DA agonists (Bannon and Roth 1983 Farde et al. 1989). 

There are two distinct pools of HA in the brain (1) the neuronal pool and (2) the non-neuronal pool, mainly contributed by the mast cells. The turnover of HA in mast cells is slower than in neurons it is believed that the HA contribution from the mast cells is limited and that almost all brain histaminergic actions are the result of HA released by neurons (Haas Panula, 2003). The blood-brain barrier is impermeable to HA. HA in the brain is formed from L-histidine, an essential amino acid. HA synthesis occurs in two steps (1) neuronal uptake of L-histidine by L-amino acid transporters and (2) subsequent decarboxylation of l-histidine by a specific enzyme, L-histidine decarboxylase (E.C. 4.1.1.22). It appears that the availability of L-histidine is the rate-limiting step for the synthesis of HA. The enzyme HDC is selective for L-histidine and its activity displays circadian fluctuations (Orr Quay, 1975). HA synthesis can be reduced by inhibition of the enzyme HDC. a-Fluoromethylhistidine (a-FMH) is an irreversible and a highly selective inhibitor of HDC a single systemic injection of a-FMH (10-50 mg/kg) can produce up to 90% inhibition of HDC activity within 60-120 min (Monti, 1993). Once synthesized, HA is taken up into vesicles by the vesicular monoamine transporter and is stored until released. 

Peng, X., Gerzanich, V., Anand, R., Whiting, P, Lindstrom, J. Nicotine-induced increase in neuronal nicotinic receptor results from a decrease in the rate of receptor turnover. Mol. Pharmacol. 46 523, 1994. 

Cholesterol transport and regulation in the central nervous system is distinct from that of peripheral tissues. Blood-borne cholesterol is excluded from the CNS by the blood-brain barrier. Neurons express a form of cytochrome P-450, 46A, that oxidizes cholesterol to 24(S)-hydroxycholesterol [11] and may oxidize it further to 24,25 and 24,27-dihydroxy products [12]. In other tissues hydroxylation of the alkyl side chain of cholesterol at C22 or C27 is known to produce products that diffuse out of cells into the plasma circulation. Although the rate of cholesterol turnover in mature brain is relatively low, 24-hydroxylation may be a principal efflux path to the liver because it is not further oxidized in the CNS [10]. 

In most regions of the CNS there is little or no turnover of neurons during the life of the animal and following trauma to the adult CNS recruitment of new neurons is extremely limited. This may reflect the low proliferation rate of neural stem cells or the inability of stem cell... 

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