Current Concepts and State of Knowledge

Platelets as Peripheral Markers of Neurotransmitter Dysfunction

Human platelets have been repeatedly considered as potentially useful tools for modeling neurochemical dysfunctions in neurological and psychiatric patients. In fact, although the main function of the platelet is related to hemostasis, they are implicated with various signaling molecules that operate into the CNS as well. More specifically, platelets store, release, and ► uptake several neurotransmitters, such as serotonin, dopamine, glutamate, and GABA, frequently expressing cognate functional receptor molecules.

Considering that most of the neuropsychiatric disorders do not allow to study in details the involved patho-mechanisms directly into the nervous system, platelets offer the advantage of being readily accessible upon a simple blood withdrawal. Hence, in this chapter we will consider them as ► peripheral markers of neurotransmit-ter dysfunction in neuropsychiatry.

However, as a final caveat we should remember that technical factors and reproducibility obviously play an extremely important role and influence the characterization of any suitable peripheral neurochemical marker. Platelets unfortunately display quite a strong tendency to activation, changing shape, and releasing granule contents, if careful procedures are not used when performing blood sampling and platelet separation. As an example, a generous needle gage and avoiding the tourniquet use might be critical issues for circumventing these phenomena, especially when measuring granule contents or performing electron microscopy procedures (see Fig. 1A, with respect to a less activated platelet shown in B).

Serotonin Uptake and Release

Human platelets are capable of producing very little amounts of ► serotonin (5-hydoxytryptamine, 5-HT) but represent the major storage site for this neurotrans-mitter outside the central nervous system. Platelets actively uptake serotonin, store it in electron-dense granules and release it, together with other platelet factors, in response to a number of signals (Paasonen 1965). Specific transporter molecules (SERT) located on platelet membranes are responsible for the highly selective uptake of serotonin, although there is some affinity for the other ► monoamines (e.g., norepinephrine, dopamine) (Omenn and Smith 1978). Molecular cloning has revealed

Platelets. Fig. 1. Bar = 500 nm. Electron microscopy photographs courtesy of Virginia Rodriguez-Menendez.

that the amino acid sequence of the human platelet SERT protein is identical to the neuronal SERT, and platelet high-affinity uptake system for serotonin displays kinetic and pharmacological characteristics similar to those reported in brain synaptosomes. All this makes platelets good model systems for investigating alterations of mono-amine neurotransmission occurring in neuropsychiatric diseases.

Platelet SERTs have been studied in psychiatric and neurological patients, both as ► binding of radioligands on platelet plasma membranes, and as activity in intact platelets (Mellerup and Plenge 1986). Platelet serotonin uptake was demonstrated to be decreased in depressed patients, both adult and children, with respect to controls, before and during antidepressant treatment, although not all the studies agree (Fisar and Raboch 2008). No significant correlations were found between serotonin uptake kinetics and the severity of the depressive disorder. Abnormalities of platelet serotonin uptake have been reported also in patients with Down's syndrome and ► Huntington's disease, and a reduced platelet content of this neurotransmitter has also been demonstrated, again, in Down's syndrome.

The use of specific serotonin receptor antagonists has shown the presence on platelet surface of the 5-HT2A receptor subtype involved in the amplification of platelet aggregation by recruiting additional platelets once the process has been initiated. Using [3H]-ketanserin as a radioligand, a significant decrease in the affinity of platelet 5-HT2A receptors was observed in patients affected by migraine, and a significant reduction in the number of binding sites was found in tension-type headache as well. Interestingly, a role for platelet-released serotonin in the

Platelets. Table 1. Monoamine functions in human platelets in neuropsychiatric diseases. ADHD, attention deficit/ hyperactivity disorder; BPD, borderline personality disorder; DP, depression; DS, Down syndrome; HD, Huntington's disease; M, migraine; N/A, not investigated; PD, Parkinson's disease; PSG, platelet storage granules; SZ, schizophrenia; TH, tension-type headache.

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