Alteration of the Centromedial Amygdala Glutamatergic Synapses by the BDNF Val66Met Polymorphism

Fear expression is mediated by an activation of the centromedial amygdala (CEm), the major output nucleus of the amygdaloid complex. Consistently, fear extinction is associated with an increased synaptic inhibition as well as a suppression of the excitability of the CEm neurons. However, little is known about the role of CEm glutamatergic synapses in fear regulation and anxiety-like behaviors. The BDNF Val66Met, a single-nucleotide polymorphism in the human BDNF gene, impairs fear extinction and leads to anxiety-like symptoms. To determine whether the BDNF Val66Met polymorphism affects the CEm excitatory synapses, we examined basal glutamatergic synaptic transmission and plasticity in the CEm neurons of BDNF Val66Met knock-in (BDNF^Met/Met) mice. The BDNF Val66Met single-nucleotide polymorphism exerted an opposite effect on non-NMDA and NMDA receptor transmission with a potentiation of the former and a suppression of the latter. In addition, the decay time of NMDA currents was decreased in BDNF^Met/Met mice, suggesting a modification of NMDA receptor subunit composition. Unlike the wild-type mice that exhibited a potentiation of non-NMDA receptor transmission following fear conditioning and a depotentiation upon fear extinction, BDNF^Met/Met mice failed to show this experience-dependent synaptic plasticity in the CEm neurons. Our results suggest that the elevated non-NMDA receptor transmission, the suppression of NMDA receptor transmission, and an impairment of synaptic plasticity in the CEm neurons might contribute to the fear extinction deficit and increased anxiety-like symptoms in BDNF Val66Met carriers.     

Impaired CD8 T cell memory and CD4 T cell primary responses in IL-7R alpha mutant mice

Loss of interleukin (IL)-7 or the IL-7 receptor alpha (IL-7Ralpha, CD127) results in severe immunodeficiencies in mice and humans. To more precisely identify signals governing IL-7 function in vivo, we have disrupted the IL-7Ralpha Y449XXM motif in mice by knock-in mutagenesis (IL-7Ralpha(449F)). Thymic precursors were reduced in number in IL-7Ralpha(449F) mice, but in marked contrast to IL-7Ralpha(-/-) knockout mice, thymocytes and peripheral T cells developed normally. Strikingly, Listeria infection revealed that CD4 and CD8 T cells had different requirements for IL-7Ralpha signals. CD4 T cells failed to mount a primary response, but despite normal CD8 primary responses, maintenance of CD8 memory was impaired in IL-7Ralpha(449F) mice. Furthermore, we show that Bcl-2 is IL-7Ralpha Y449 independent and insufficient for IL-7-mediated maintenance of CD8 memory.     

Acute disseminated encephalomyelitis due to abrus precatorius poisoning – A case report

Abrus precatorius, commonly known as ‘Rosary pea’ or ‘Jequirity pea’ and known as ‘Shisham, Batrah-Hindi or Ain Alfreeth’ in the Middle East, grows wild in the tropical and subtropical areas of the world. The seeds of the plant contain one of the most potent toxins known to man. Poisoning with abrus seeds is a rare occurrence as the harder outer coat of the seeds generally resists digestion and such reports are scarce in the literature. We present here a case of a 22 year old lady who developed severe vomiting, diarrhoea and malena at the initial stages and later seizures and acute disseminated encephalomyelitis due to deliberate chewing and swallowing of abrus seeds. She was rescued with several sessions of membrane plasmapheresis and supportive care. The neuropathological process of acute disseminated encephalomyelitis due to abrus poisoning was reversed by plasmapheresis.     

Social anxiety disorder and the neurobiology of social relationships

Social anxiety disorder (SAD) is a prevalent anxiety disorder with the potential for considerable impairment. A patient with SAD is presented and treatment options are discussed. Novel concepts guiding our understanding of the neurobiology of SAD are presented, including the concept of sensory maps of the body, which is used to speculate on the nature of internal representations of relationships and their potential role in triggering anxiety in SAD. Understanding the neural circuitry mediating social relationships and its role in the threat response in SAD may be important for the development of new treatments for this disorder.     

New goals in the treatment of depression: moving toward recovery

Depression is associated with marked suffering, morbidity, and high risk of recurrence and/or chronicity. As a result, the disorder represents a considerable public health problem and economic burden on society. Treatment of patients with depression to a state of remission is associated with a significantly improved long-term outcome, including a reduced risk of relapse and improved functioning. Thus, remission (which can be defined as attainment of a total score < or = 7 on the Hamilton Rating Scale for Depression) should be the goal of the acute phase of pharmacotherapy. Although it is widely assumed that available antidepressants are comparably effective, comparisons of the efficacy of antidepressants in clinical trials are flawed by a number of factors. Most notable problems are higher-than-expected placebo effects and low statistical power. Double-blind, comparative studies are also compromised by relatively high attrition rates and the often underestimated effects of patient nonadherence. Large study groups (in the order of 300 patients per treatment group) are needed to differentiate between a good and a potentially better antidepressant. The statistical technique of meta-analysis has been used to examine the results of studies of various antidepressants; these meta-analyses have shown that the selective serotonin reuptake inhibitors (SSRIs) have overall "within group" comparability and, overall, an efficacy profile comparable to the previous standard, tricyclic antidepressants (TCAs). However, in studies of hospitalized patients, TCAs affecting both serotonergic and noradrenergic systems (eg, amitriptyline or clomipramine) have been found to have greater efficacy when compared with SSRIs. Results of some individual studies, as well as a pooled analysis of the outcomes of more than 2,000 depressed patients, indicate that venlafaxine, a selective serotonin and norepinephrine reuptake inhibitor, may have a similar advantage relative to SSRIs across a broader range of patients. These findings suggest antidepressants that affect both serotonergic and noradrenergic neurotransmission may be more likely to accomplish the goal of remission. Compared with TCAs, the better safety profile of venlafaxine has established the drug as a more appropriate first-line treatment option.     

Report by the ACNP Task Force on response and remission in major depressive disorder.

This report summarizes recommendations from the ACNP Task Force on the conceptualization of remission and its implications for defining recovery, relapse, recurrence, and response for clinical investigators and practicing clinicians. Given the strong implications of remission for better function and a better prognosis, remission is a valid, clinically relevant end point for both practitioners and investigators. Not all depressed patients, however, will reach remission. Response is a less desirable primary outcome in trials because it depends highly on the initial (often single) baseline measure of symptom severity. It is recommended that remission be ascribed after 3 consecutive weeks during which minimal symptom status (absence of both sadness and reduced interest/pleasure along with the presence of fewer than three of the remaining seven DSM-IV-TR diagnostic criterion symptoms) is maintained. Once achieved, remission can only be lost if followed by a relapse. Recovery is ascribed after at least 4 months following the onset of remission, during which a relapse has not occurred. Recovery, once achieved, can only be lost if followed by a recurrence. Day-to-day functioning and quality of life are important secondary end points, but they were not included in the proposed definitions of response, remission, recovery, relapse, or recurrence. These recommendations suggest that symptom ratings that measure all nine criterion symptom domains to define a major depressive episode are preferred as they provide a more certain ascertainment of remission. These recommendations were based largely on logic, the need for internal consistency, and clinical experience owing to the lack of empirical evidence to test these concepts. Research to evaluate these recommendations empirically is needed.