Synaptic transmission and plasticity: mechanisms of antidepressants Synaptic plasticity encompasses all forms of neuroplasticity that specifically occur at synapses; both functional and structural forms of plasticity have been described (Table II). In many cases this term is referred to activity -dependent modifications of the strength or efficacy of synaptic transmission at glutamate synapses; the most common forms Inhibitors,research,lifescience,medical of long-lasting activity-dependent changes in synaptic strength are long-term potentiation (LTP) and longterm depression (LTD).56 It has been repeatedly shown

that, both stress and antidepressant treatments change synaptic plasticity (reviewed in refs 3,18,57,58). Beyond the monoamine hypothesis: the role of glutamate Recent, neuroimaging Inhibitors,research,lifescience,medical and histopathological studies in brain of depressed and bipolar patients revealed the presence of morphometric/functional modifications, including ventricular enlargement, hippocampal and cortical volumetric reduction, and of reduced neurons and glial density.59-61 In many of the areas implicated, glutamatergic neurons and synapses predominate, suggesting Inhibitors,research,lifescience,medical an involvement. of glutamate neurotransmission

in the pathophysiology of mood disorders. Indeed, in the last few years numerous lines of evidence have accumulated in favor of a role for glutamate in psychiatric pathophysiology, including the following: (i) higher levels of glutamate in plasma and brain of patients with mood disorders62-63; (ii) abnormal elevation of glutamate neurotransmission and glutamate levels in cortical/limbic brain areas of depressed patients16,64; (iii) atrophy of apical dendrites in Inhibitors,research,lifescience,medical CA3 hippocampal neurons induced by chronic stress, a major factor in pathogenesis of mood disorders17; (iv) increased amplitude

and reduced decay kinetics of NMDA current, induced by chronic stress65; (v) impaired long-term potentiation (ITP) and FHPI manufacturer facilitated depression (LTD) induced by stress.66 Conversely, antidepressant treatments were also shown Inhibitors,research,lifescience,medical to affect glutamate neurotransmission: Thalidomide (i) antidepressants downregulate NMDA receptor subunits and dampen NMDA function67; (ii) antidepressants may overcome the effects of stress on LTP68-69; (iii) chronic antidepressants reduce depolarization-evoked release of glutamate in hippocampus by modifying presynaptic protein interactions regulating exocytotic release.70 Several compounds that modulate glutamate receptors or glutamate neurotransmission at various levels are under development for the treatment of mood disorders (depression, bipolar disorder, anxiety).71 Some of these putative drugs may work by stabilizing glutamate release when its synaptic level becomes too high, a feature that, is now considered as part of the pathophysiology of mood disorders.3,15,58,72,73 Recently, it.