Stress Disorders, Post-Traumatic Clinical Trial
Official title:
Neuroimmunological Model of Traumatic Memory
Traumatic events may lead to strong emotional episodic memories common in Post- Traumatic
Stress Disorder(PTSD). Intense affect may inhibit efficacy of glutamatergic
neurotransmission in two particular areas of the limbic system that have been implicated in
the processing of emotionally charged memories: the amygdala and the hippocampus(1,2).
Dysfunction of glutamatergic neurotransmission is associated with disbalance of long-term
potentiation (LTP) and long-term depression (LTD)- two underlying mechanisms that cooperate
to achieve synaptic plasticity and its expressations- learning and memory(3). LTP- the long
lasting enhancement of synaptic function includes changes in the amount of neurotransmitter
glutamate released into a synapse, changes in the levels of key proteins in synapses,
protein phosphorylation and changes the density of receptors on their synaptic membranes.
LTD is the inverse of LTP, a long lasting reduction in synaptic transmission (4).
Interactions among the different forms of plasticity underlie different forms of memories.
Normally these mechanisms are balanced.
In the current literature there is data that a class I major histocompatibility complex (MHC
class I) molecules, known to be important for immune responses to antigen, are expressed
also by neurons that undergo activity-dependence, long-term structural and synaptic
modifications (5). The brain produces its own immune molecules, the proteins MHC class I and
CD3-zeta (a component of receptors for MHC class I). In the immune system, the two proteins
act as part of a lock and key system to recognize and get rid of the body’s foreign
invaders. The CD3-zeta polypeptide is component of the T cell antigen receptor (TCR) which
contribute to its efficient cell surface expression and account for part of its transducing
capability (6).
In the brain, they may be part of a signaling system that recognizes and eliminates
inappropriate neural connections. Expression of MHC class I is regulated by the naturally
occurring electrical activity, and sensitive to both natural and pathological changes in the
activity. Electrical activity of neurons drives to an establishment of the final pattern of
connection. Changes in the strength of individual synapses such as potention and depression
leads to stabilization and withdrawal, respectively, of the affected connections. There are
data, that in mice with deficiency of MHC class I and CD3-zeta the LTP in the hippocampus is
enhanced significantly and LTD is absent. Thus, MHC class I is crucial for translating
activity into changes in synaptic strength and neuronal connectivity in vivo. He required
for normal activity dependent potentiation, depression, removal of inappropriate connection
and responding to injury in the CNS (6).
Glutamate receptors play critical roles in LTP/LTD mechanisms. Some researchers consider
that a key role in pathogenesis of PTSD is being played by excessive excitation of
NMDA-receptors in limbic system structures (1). The existing data allows to assume, that
equation of plasticity mechanisms depends on mutual relations between the MHC class I and
glutamate receptors.
T-cells, like neurons, express high levels of glutamate receptors that are identical to the
brain glutamate receptors. Presence of ionotropic and metabotropic glutamate receptors in
membranes of lymphocytes makes them sensitive to the same alarm molecules which operate
neuronal activity. Glutamate by itself triggers several T-cell activation which differs
quantitatively or qualitatively from that ones triggered by “classical’ T-cell activators
like antigens(7). There are data about influence of T cell receptor-CD3 complex- on the
expression of T-cells glutamate receptors (8). It is possible, that the key roles in this
function play CD3-zeta.
Status | Recruiting |
Enrollment | 40 |
Est. completion date | December 2007 |
Est. primary completion date | |
Accepts healthy volunteers | Accepts Healthy Volunteers |
Gender | Both |
Age group | 18 Years to 60 Years |
Eligibility |
Inclusion Criteria: - male and female between 18-60 years - PTSD Exclusion Criteria: - any immune system disease |
Observational Model: Defined Population, Primary Purpose: Screening, Time Perspective: Cross-Sectional
Country | Name | City | State |
---|---|---|---|
Israel | Sieff Government Hospital | Safed |
Lead Sponsor | Collaborator |
---|---|
Ziv Hospital |
Israel,
7. Mia Levite. Direct Bi-Directional Dialogues Between The Nervous System And The Immune System in health and disease. www.weizmann.ac.il/neuro 2006.
Bellone C, Lüscher C. mGluRs induce a long-term depression in the ventral tegmental area that involves a switch of the subunit composition of AMPA receptors. Eur J Neurosci. 2005 Mar;21(5):1280-8. — View Citation
Boulanger LM. MHC class I in activity-dependent structural and functional plasticity. Neuron Glia Biol. 2004 Aug;1(3):283-9. doi: 10.1017/S1740925X05000128. — View Citation
Gaiarsa JL, Caillard O, Ben-Ari Y. Long-term plasticity at GABAergic and glycinergic synapses: mechanisms and functional significance. Trends Neurosci. 2002 Nov;25(11):564-70. Review. — View Citation
Heresco-Levy U, Kremer I, Javitt DC, Goichman R, Reshef A, Blanaru M, Cohen T. Pilot-controlled trial of D-cycloserine for the treatment of post-traumatic stress disorder. Int J Neuropsychopharmacol. 2002 Dec;5(4):301-7. — View Citation
Malissen M, Gillet A, Rocha B, Trucy J, Vivier E, Boyer C, Köntgen F, Brun N, Mazza G, Spanopoulou E, et al. T cell development in mice lacking the CD3-zeta/eta gene. EMBO J. 1993 Nov;12(11):4347-55. — View Citation
van der Kolk BA. The body keeps the score: memory and the evolving psychobiology of posttraumatic stress. Harv Rev Psychiatry. 1994 Jan-Feb;1(5):253-65. Review. — View Citation
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