Kegg Pathway: Long-term depression

Drugs Today (Barc). 2009 Aug; 45(8): 599-608
Owen RT

Agomelatine is a melatonin analogue which represents a novel class of antidepressants. It acts as an agonist at melatonin MT(1) and MT(2) receptors and as a specific antagonist at 5-HT(2C) receptors. It is rapidly absorbed orally and mainly metabolized via CYP1A2 hepatic isoenzymes, has no active metabolites and an elimination half-life of 1-2 hours. Short-term trials (6-8 weeks) have confirmed the compound's antidepressant effect in major depressive disorder at doses of 25-50 mg/day. It has comparable antidepressant activity to venlafaxine (75-150 mg/day) and in one trial, showed statistical superiority to sertraline 50-100 mg/day. In Long-term studies agomelatine was superior to placebo for relapse prevention at 10 months and treatment adherence rates were higher than with venlafaxine and sertraline over 6 months. The drug has anxiolytic properties and a beneficial effect on sleep without affecting rapid eye movement (REM) activity. Although agomelatine is generally well tolerated with low adverse event discontinuation rates, it currently requires monitoring of liver function because a small number of patients had raised liver enzyme activities in the trial program. The compound has fewer effects on sexual function than venlafaxine and, unlike paroxetine, it causes minimal discontinuation symptoms upon abrupt withdrawal. Agomelatine is currently being investigated for other indications such as seasonal affective disorder, generalized anxiety disorder and bipolar depression.

Pharmacol Rev. 2009 Nov 19;
Gladding CM, Fitzjohn SM, Molnár E

The ability to modify synaptic transmission between neurons is a fundamental process of the nervous system that is involved in development, learning, and disease. Thus, synaptic plasticity is the ability to bidirectionally modify transmission, where Long-term potentiation and Long-term depression (LTD) represent the best characterized forms of plasticity. In the hippocampus, two main forms of LTD coexist that are mediated by activation of either N-methyl-d-aspartic acid receptors (NMDARs) or metabotropic glutamate receptors (mGluRs). Compared with NMDAR-LTD, mGluR-LTD is less well understood, but recent advances have started to delineate the underlying mechanisms. mGluR-LTD at CA3:CA1 synapses in the hippocampus can be induced either by synaptic stimulation or by bath application of the group I selective agonist (R,S)-3,5-dihydroxyphenylglycine. Multiple signaling mechanisms have been implicated in mGluR-LTD, illustrating the complexity of this form of plasticity. This review provides an overview of recent studies investigating the molecular mechanisms underlying hippocampal mGluR-LTD. It highlights the role of key molecular components and signaling pathways that are involved in the induction and expression of mGluR-LTD and considers how the different signaling pathways may work together to elicit a persistent reduction in synaptic transmission.

Eur Psychiatry. 2009 Nov 17;
Preiss M, Kramska L, Dockalova E, Holubova M, Kucerova H

BACKGROUND: The capacity to focus and concentrate or to direct attention supports many aspects of cognitive functioning including short-term memory and higher-level cognitive functions. The purpose was to assess attentional networks in euthymic patients with unipolar depression using the Attentional Network Test (ANT). MATERIALS AND METHODS: We investigated performance of attention by virtue of ANT during remission from unipolar depressive disorder and tested a hypothesis that there are no differences between outpatient group (euthymic patients, N=32) and matched controls in attentional variables, the relationship of attentional networks and everyday cognitive failures. RESULTS: No differences between the groups in attentional networks were found and no relationship between attentional networks and cognitive failures was found. LIMITATIONS: One assessment during remission could be insufficient to recognize Long-term pattern of cognitive functions. CONCLUSIONS: These data show non-impaired attentional networks possibly explained by sufficient level of remission and ameliorated influence of high education on cognition.

Eur Psychiatry. 2009 Nov 17;
Ozyıldırım I, Cakır S, Yazıcı O

OBJECTIVE: In this study, we aimed to compare the clinical features and response patterns to the Long-term prophylaxis of bipolar patients with or without psychotic features. METHOD: The life charts of patients with bipolar I disorder were evaluated. Two hundred and eighty-one patients who suffer with bipolar disorder for at least 4 years and who had at least three mood episodes were included to the study. The patients whose all episodes are psychotic (psychotic group) and the patients who never experienced psychotic episode (non-psychotic group) were assigned as comparison groups. The clinical features and the response to Long-term prophylaxis were compared across the groups. RESULTS: The psychotic group consists of 43 patients; non-psychotic group consists of 54 patients. The history of bipolar disorder among the first-degree relatives was remarkably more prevalent in non-psychotic group (p=0.032). The predominance of manic/hypomanic episodes was significantly higher in psychotic group than non-psychotic group; and the rate of depressive episodes were higher in non-psychotic group than psychotic group (p=0.013). Episodes were more severe (p<0.001) and hospitalization rates were higher (p=0.023) in psychotic group. The response to lithium monotherapy was better in non-psychotic group (p<0.001). CONCLUSION: The well identified psychotic subtype of bipolar patients may give important predictions about long term course and prophylaxis of bipolar disorder.

Nutr Neurosci. 2009 Dec; 12(6): 281-288
da Silva Tenório A, da Silva Moura FR, de Lima Silva LP, Guedes RC

Early malnutrition interferes with the formation of somatosensory pathways and reduced sensory input activity during brain development can induce morphological and physiological changes in the cerebral cortex, altering their response properties in the Long-term. Here, we investigated cortical spreading depression (CSD) propagation in male adult rats submitted to unilateral vibrissae removal, at postnatal days 2-3, and malnourished during lactation followed by nutritional recovery until adulthood (90-120 days), when CSD was recorded. Compared to nutrition-matched non-lesioned controls, CSD-propagation was increased in the hemisphere contralateral to the vibrissae removal. The findings indicate that vibrissae removal during brain development enhances CSD-propagation, and early malnutrition did not modify this effect. Considering that CSD-facilitation persisted until adulthood, we suggest that this effect is permanent. The data might contribute to the understanding of the mechanisms by which sensory input deprivation-induced plasticity modifies cerebral electrophysiological responses in the developing brain.

Acta Psychiatr Scand. 2009 Nov 18;
Fichter MM, Quadflieg N, Fischer UC, Kohlboeck G

Fichter MM, Quadflieg N, Fischer UC, Kohlboeck G. Twenty-five-year course and outcome in anxiety and depression in the Upper Bavarian Longitudinal Community Study.Objective: Assessment of 25-year course of pure and mixed anxiety and depression in a community sample. Method: Participants were grouped into pure anxiety, pure depression, mixed anxiety and depression, and no anxiety or depressive syndrome at baseline. Assessments consisted of a: i) baseline survey, ii) 5-year follow-up, iii) 25-year follow-up. Self-rating scales as well as expert-rating interviews yielded data on social and psychopathological risk factors and outcome measures. Results: Baseline prevalence for mixed anxiety and depressive syndrome was 8.7%. Subjects with combined anxiety and depressive syndrome were more predisposed towards later adverse mental health outcomes and reduced functionality. The transition from anxiety syndrome (pure and mixed) to depressive syndrome over the 25-year study is more likely than the reverse. Logistic regression analysis emphasized the impact of early anxiety syndromes on later depression. Conclusion: Results underscore the Long-term risks of suffering from a combined anxiety and depressive syndrome.

Amyotroph Lateral Scler. 2009; 10(5-6): 448-455
Rabkin JG, Albert SM, Rowland LP, Mitsumoto H

Our objective was to assess the impact of personal, situational and patient characteristics on mood, and changes over time, among ALS caregivers. Seventy-one patient-caregiver pairs were interviewed once and 51 (72%) monthly until endpoints of death or tracheostomy for Long-term mechanical ventilation (LTMV). Depressive symptoms and DSM-IV disorders, coping strategies, caregiver burden, satisfaction with care-giving, and patient disease severity were assessed. At baseline, 13% of caregivers had major depression, and 10% had minor depression. Rates declined at last visit before death or LTMV (median interval three months), as did depressive symptoms. Correlates of caregiver depression included reliance on avoidance, perceived burden, fatigue, and feeling that the patient was critical and unappreciative. Half of the 14 caregivers of patients who planned LTMV were depressed at baseline, declining to 8% at endpoint, versus 16% (9/57) among caregivers of patients who died, declining non-significantly to 11%. While few personal or situational factors were correlated with caregiver distress, patients' plans and degree of supportiveness influenced caregiver mood. Verbal comments of caregivers clarified the distinction between sadness and psychiatric depression. The high baseline rate of depression among caregivers of patients who planned tracheostomy decreased as caregivers instituted major changes in patient care or personal counseling.

World J Biol Psychiatry. 2009; 10(4): 269-275
Mendlewicz J

depression is increasingly prevalent in Western countries. It has severe consequences and is associated with increased rates of disability, morbidity, and mortality. Despite numerous therapeutic options, a great number of depressed patients do not achieve full remission. In addition, despite good short-term outcomes, Long-term therapeutic results remain disappointing and associated with a poor prognosis, raising significant concern in terms of public health. Impaired sleep - especially insomnia - may be at least partly responsible for this problem. Very close relationships between major depressive disorder (MDD) and sleep disorders have been observed. In particular, residual symptoms of sleep disturbance in a remitted patient may predict a relapse of the disease. However, most currently available antidepressants do not always take into consideration the sleep disturbances of depressed patients; some agents long used in clinical practice even appear to worsen them by their sleep-inhibiting properties. But some other new medications were shown to relieve early sleep disturbance in addition to alleviating other depression-related symptoms. This positive impact should promote compliance with medication and psychological treatments, and increase daytime performance and overall functioning. Complete remission of MDD appears therefore to depend on the relief of sleep disturbances, a core symptom of MDD that should be taken into consideration and treated early in depressed patients.

Exp Brain Res. 2009 Nov 17;
Kamal A, Van der Harst JE, Kapteijn CM, Baars AJ, Spruijt BM, Ramakers GM

Chronic stress causes insensitivity to rewards (anhedonia) in rats, reflected by the absence of anticipatory behavior for a sucrose-reward, which can be reversed by antidepressant treatment or repeated announced transfer to an enriched cage. It was, however, not clear whether the highly rewarding properties of the enriched cage alone caused this reversal or whether the anticipation of this reward as such had an additional effect. Therefore, the present study compared the consequences of the announcement of a reward to the mere effect of a reward alone with respect to their efficacy to counteract the consequences of chronic stress. Two forms of synaptic plasticity, Long-term potentiation and Long-term depression were investigated in area CA1 of the hippocampus. This was done in socially stressed rats (induced by defeat and subsequent Long-term individual housing), socially stressed rats that received a reward (short-term enriched housing) and socially stressed rats to which this reward was announced by means of a stimulus that was repeatedly paired to the reward. The results were compared to corresponding control rats. We show that announcement of enriched housing appeared to have had an additional effect compared to the enriched housing per se as indicated by a significant higher amount of LTP. In conclusion, announced short-term enriched housing has a high and long-lasting counteracting efficacy on stress-induced alterations of hippocampal synaptic plasticity. This information is important for counteracting the consequences of chronic stress in both human and captive rats.

Wien Klin Wochenschr. 2009 Oct; 121(19-20): 604-614
Balint EE, Falkay G, Balint GA

Khat (Catha edulis) is a shrub or tree whose leaves have been chewed for centuries by people who live in the Eastern part of Africa and the Arabian Peninsula. It has recently turned up in North America and Europe, particularly among emigrants and refugees from countries such as Somalia, Ethiopia and Yemen. Khat contains a number of chemicals, among which are two controlled substances, cathinone (Schedule I) and cathine (Schedule IV). Both chemicals are stimulant drugs with effects similar to amphetamine. Chewing the leaves makes people feel more alert and talkative, and suppresses appetite. Chewing khat leaves releases cathinone, a stimulant that produces the feeling of euphoria. When cathinone is broken down in the body, it produces chemicals including cathine and norephedrine, which have a similar structure to amphetamine and adrenaline (epinephrine). Regular khat use is associated with a rise in arterial blood pressure and pulse rate, corresponding with levels of cathinone in the plasma. Moreover, regular khat chewers have gingivitis and loose teeth, but there appears to be no convincing unusual incidence of oral cancer. Among khat users in Yemen there is, however, a higher incidence of esophageal cancer compared with gastric cancer. Long term use or abuse can cause insomnia, anorexia, gastric disorders, depression, liver damage and cardiac complications, including myocardial infarction. Manic and delusional behavior, violence, suicidal depression, hallucinations, paranoia and khat-induced psychosis have also been reported. On the basis of the scientific data it seems clear that khat use has negative consequences on the economic development of a country and on the health of the society.

J Aging Health. 2009 Nov 17;
Kim J, Pai M

OBJECTIVE: The purpose of this study was twofold: (1) to examine the association between volunteering and trajectories of depression; and (2) to evaluate whether this relationship varies by age. METHOD: Data come from three waves of the Americans' Changing Lives (ACL) study. ACL is a nationally representative sample of adults 25 years of age or older who lived in the United States. RESULTS: Latent growth model analysis indicates that although volunteering is associated with lower levels of baseline depression, it does not predict trajectories of depression. Nevertheless, further analyses reveal an age variation in the relationship between volunteering and trajectories of depression. Specifically, we find that volunteering affects the decline of depression for individuals above age 65; yet there is no effect of volunteering on trajectories of depression for younger and middle-aged adults. DISCUSSION: Overall findings highlight the importance of assessing the Long-term health impact of volunteering and doing so under diverse social structural contexts.

Addiction. 2009 Nov 12;
Morgan CJ, Muetzelfeldt L, Curran HV

Background 'Recreational' use of ketamine is spreading rapidly among young people. In healthy individuals an acute dose of the N-methyl D-aspartate (NMDA) receptor antagonist ketamine induces marked psychosis-like effects and cognitive impairments, but little is known about the Long-term effects of the drug. Aims To evaluate the Long-term neuropsychiatric or cognitive consequences. Methods A total of 150 individuals were assessed, 30 in each of five groups: frequent ketamine users, infrequent ketamine users, abstinent users, polydrug controls and non-users of illicit drugs. Twelve months later, 80% of these individuals were re-tested. Results Cognitive deficits were mainly observed only in frequent users. In this group, increasing ketamine use over the year was correlated with decreasing performance on spatial working memory and pattern recognition memory tasks. Assessments of psychological wellbeing showed greater dissociative symptoms in frequent users and a dose-response effect on delusional symptoms, with frequent users scoring higher than infrequent, abstinent users and non-users, respectively. Both frequent and abstinent using groups showed increased depression scores over the 12 months. Conclusions These findings imply that heavy use of ketamine is harmful to aspects of both cognitive function and psychological wellbeing. Health education campaigns need to raise awareness among young people and clinicians about these negative consequences of ketamine use.

Br J Health Psychol. 2009 Nov 13;
Kennedy P, Lude P, Elfström ML, Smithson E

Study design Longitudinal, multi-wave design. Objectives To investigate the contribution of sense of coherence (SOC), appraisals, and behavioural responses when predicting psychological outcomes to spinal cord injury (SCI). Method Patients (N=237) sustaining a SCI aged 17 or above were recruited from specialist spinal injuries centres across six European countries. Measures of SOC, appraisals, coping strategies, and psychological well-being were administered at 6 and 12 weeks post-injury and at a 1 year follow-up. Results People scoring high on SOC at 6 weeks post-injury showed significantly better psychological outcomes at 1 year post-injury and SOC showed significant relationships with appraisals at 12 weeks post-injury and coping strategies 1 year post-injury. Significant relationships were found between appraisals at 12 weeks post-injury and psychological outcomes, adaptive coping strategies were significantly related to psychological well-being at 1 year post-injury. Regression analyses found SOC, appraisals, and coping behaviours to explain 61.8% of the variance in psychological quality of life, 66.5% of the variance in depression, and 37.7% of the variance in anxiety at 1 year post-injury. Conclusion This study provides further evidence in support of previous findings which suggest SOC to have a primary role in Long-term psychological well-being. The relationship described here - from SOC to the appraisal of injury and subsequent behavioural responses - suggests SOC to be an influential factor in the Long-term adjustment of people with SCI.

EBRI Issue Brief. 2009 Oct; 1-65
VanDerhei J, Holden S, Alonso L

Because 401(k) balances can fluctuate with market returns from year to year, meaningful analysis of 401(k) plans must examine how participants' accounts have performed over the long term. Looking at consistent participants in the EBRI/ICI 401(k) database over the five-year period from 2003 to 2008 (which included one of the worst bear markets for stocks since the Great depression), the study found: After rising in 2003 and for the next four consecutive years, the average 401(k) retirement account fell 24.3 percent in 2008. The average 401(k) account balance moved up and down with stock market performance, but over the entire five-year time period increased at an average annual growth rate of 7.2 percent, attaining $86,513 at year-end 2008. The median (mid-point) 401(k) account balance increased at an average annual growth rate of 11.4 percent over the 2003-2008 period to $43,700 at year-end 2008. THE BULK OF 401(K) ASSETS CONTINUED TO BE INVESTED IN STOCKS. On average, at year-end 2008, 56 percent of 401(k) participants' assets were invested in equity securities through equity funds, the equity portion of balanced funds, and company stock. Forty-one percent was in fixed-income securities such as stable-value investments and bond and money market funds. THREE-QUARTERS OF 401(K) PLANS INCLUDED LIFECYCLE FUNDS IN THEIR INVESTMENT LINEUP AT YEAR-END 2008. At year-end 2008, nearly 7 percent of the assets in the EBRI/ICI 401(k) database were invested in lifecycle funds and 31 percent of 401(k) participants held lifecycle funds. Also known as "target-date" funds, they are designed to simplify investing and automate account rebalancing. NEW EMPLOYEES CONTINUED TO USE BALANCED FUNDS, INCLUDING LIFECYCLE FUNDS. Across all age groups, more new or recent hires invested their 401(k) assets in balanced funds, including lifecycle funds. At year-end 2008, 36 percent of the account balances of recently hired participants in their 20s were invested in balanced funds, compared with 28 percent in 2007, and about 7 percent in 1998. At year-end 2008, almost 23 percent of the account balances of recently hired participants in their 20s were invested in lifecycle funds, compared with almost 19 percent at year-end 2007. 401(K) PARTICIPANTS CONTINUED TO SEEK DIVERSIFICATION OF THEIR INVESTMENTS. The share of 401(k) accounts invested in company stock continued to shrink, falling by nearly 1 percentage point (to 9.7 percent) in 2008. That continued a steady decline that started in 1999. Recently hired 401(k) participants contributed to this trend: they were less likely to hold employer stock. PARTICIPANTS' 401(K) LOAN ACTIVITY WAS STABLE. In 2008, 18 percent of all 401(k) participants eligible for loans had a loan outstanding against their 401(k) account, the same percentage as at year-end 2007 and year-end 2006. Loans outstanding amounted to 16 percent of the remaining account balance, on average, at year-end 2008; this is similar to the year-end 2002 level.

J Psychosom Res. 2009 Dec; 67(6): 497-501
Bloch MH, Leckman JF

OBJECTIVE: Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by multiple motor and vocal tics lasting at least a year in duration. Children with TS often experience comorbid conditions such as obsessive-compulsive disorder (OCD) and attention-deficit disorder. The goal of this article was to review the Long-term clinical course of tics and comorbid conditions in children with TS. METHOD: We conducted a traditional literature search to locate relevant articles regarding Long-term outcome and prognosis in TS and tic disorders. RESULTS: Tics typically have an onset between the ages of 4 and 6 years and reach their worst-ever severity between the ages of 10 and 12 years. On average, tic severity declines during adolescence. By early adulthood, roughly three-quarters of children with TS will have greatly diminished tic symptoms and over one-third will be tic free. Comorbid conditions, such as OCD and other anxiety and depressive disorders, are more common during the adolescence and early adulthood of individuals with TS than in the general population. CONCLUSION: Although tics are the sine qua non of TS, they are often not the most enduring or impairing symptoms in children with TS. Measures used to enhance self-esteem, such as encouraging strong friendships and the exploration of interests, are crucial to ensuring positive adulthood outcome in TS.

Eur J Health Econ. 2009 Nov 13;
Hamre HJ, Witt CM, Glockmann A, Ziegler R, Kienle GS, Willich SN, Kiene H

We studied costs of healthcare and productivity loss in 487 German outpatients starting anthroposophic treatment: Group 1 was treated for depression, Group 2 had depressive symptoms but were treated for another chronic disorder, while Group 3 did not have depressive symptoms. Costs were adjusted for socio-demographics, comorbidity, and baseline health status. Total costs in groups 1-3 averaged 7,129, 4,371, and 3,532 in the pre-study year (P = 0.008); 6,029, 3,522, and 3,353 in the first year (P = 0.083); and 4,929, 3,792, and 4,031 in the second year (P = 0.460). In the 2nd year, costs were significantly reduced in Group 1. This study underlines the importance of depression for health costs, and suggests that treatment of depression could be associated with Long-term cost reductions.

Am J Geriatr Psychiatry. 2009 Nov 10;
Raue PJ, Morales KH, Post EP, Bogner HR, Ten Have T, Bruce ML

OBJECTIVES:: The authors examined the impact of the wish to die on mortality over a 5-year period, stratified by baseline depressive status (i.e., major, minor, and no depression diagnosis). The authors also examined whether a depression care management intervention would minimize these relationships. DESIGN:: Longitudinal analyses of the practice-randomized Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT). SETTING:: Twenty primary care practices from New York City, Philadelphia, and Pittsburgh. PARTICIPANTS:: One thousand two hundred two participants were identified through two-stage, age-stratified (60-74 years; 75 years and older) depression screening of randomly sampled participants. INTERVENTION:: Practices randomized to Care Management Intervention or Usual Care conditions. MEASUREMENTS:: Vital status at 5 years using the National Death Index. RESULTS:: Rates of the wish to die were 29% (major depression), 11% (minor depression), and 7% (no depression). In Usual Care, the wish to die was associated with an increased risk of 5-year mortality across depressive status (adjusted hazard ratios ranging from 1.62 to 1.71). In intervention practices, this association was greater among the no depression (adjusted hazard ratio 1.64) compared with major depression group (adjusted hazard ratio 0.68). CONCLUSIONS:: The wish to die was associated with mortality in the usual care of elderly primary care patients, suggesting that the wish to die has clinical significance and may be worth assessing even in patients without other evidence of depression. This association was not observed among depressed patients located in primary care practices that implemented the PROSPECT intervention, suggesting potential Long-term benefits of treatment and management of depression.

Pain. 2009 Nov 10;
Achterberg WP, Gambassi G, Finne-Soveri H, Liperoti R, Noro A, Frijters DH, Cherubini A, Dell'aquila G, Ribbe MW

There have been very few and limited cross-national comparisons concerning pain among residents of Long-term care facilities in Europe. The aim of the present cross-sectional study has been to document the prevalence of pain, its frequency and severity as well as its correlates in three European countries: Finland (north), Italy (south) and the Netherlands (western central). Patients (aged 65years or above) were assessed with the Minimum Data Set 2.0 (MDS).The final sample comprised 5761 patients from 64 facilities in Finland, 2295 patients from 8 facilities in the Netherlands and 1959 patients from 31 facilities in Italy. The prevalence of pain - defined as any type of pain - varied between 32% in Italy, 43% in the Netherlands and 57% in Finland. In nearly 50% of cases, pain was present daily; there were no significant differences in pain prevalence between patients with cancer diagnosis and those with non-cancer diagnosis. Regardless of the different prevalence estimates, pain was moderate-to-severe in over 50% of cases in all the countries. In multivariate logistic regression models, clinical correlates of pain were substantially similar across countries: pain was positively correlated with more severe physical disability (ADL impairment), clinical depression and a diagnosis of osteoporosis. Pain was negatively correlated with a diagnosis of dementia and more severe degrees of cognitive deterioration. We conclude that pain is frequently encountered in Long-term care facilities in Europe and that, despite cultural and case-mix differences, pain speaks one language.

Biochim Biophys Acta. 2009 Nov 10;
Mukai H, Kimoto T, Hojo Y, Kawato S, Murakami G, Higo S, Hatanaka Y, Ogiue-Ikeda M

The hippocampus is a center for learning and memory as well as a target of Alzheimer's disease in aged humans. Synaptic modulation by estrogen is essential to understand the molecular mechanisms of estrogen replacement therapy. Because the local synthesis of estrogen occurs in the hippocampus of both sexes, in addition to the estrogen supply from the gonads, its functions are attracting much attention. Hippocampal estrogen modulates memory-related synaptic plasticity not only slowly but also rapidly. Slow actions of 17beta-estradiol (17beta-E2) occur via classical nuclear receptors (ERalpha or ERbeta), while rapid E2 actions occur via synapse-localized ERalpha or ERbeta. Elevation or decrease of the E2 concentration changes rapidly the density and morphology of spines in CA1-CA3 neurons. ERalpha, but not ERbeta, drives this enhancement/suppression of spinogenesis. Kinase networks are involved downstream of ERalpha. The Long-term depression but not the Long-term potentiation is modulated rapidly by changes of E2 level. Determination of the E2 concentration in the hippocampus is enabled by mass-spectrometry in combination with derivatization methods. The E2 level in the hippocampus is as high as approx. 8 nM for the male and 0.5-2 nM for the female, which is much higher than that in circulation. Therefore, hippocampus-derived E2 plays a major role in modulation of synaptic plasticity. Many hippocampal slice experiments measure the restorative effects of E2 by supplementation of E2 to E2-depleted slices. Accordingly, isolated slice experiments can be used as in vitro models of in vivo estrogen replacement therapy for ovariectomized female animals with depleted circulating estrogen.

Biochem Soc Trans. 2009 Dec; 37(Pt 6): 1364-8
Moult PR, Harvey J

It is well established that leptin is a circulating hormone that enters the brain and regulates food intake and body weight via its hypothalamic actions. However, it is also known that leptin receptors are widely expressed in the CNS (central nervous system), and evidence is accumulating that leptin modulates many neuronal functions. In particular, recent studies have indicated that leptin plays an important role in the regulation of hippocampal synaptic plasticity. Indeed leptin-insensitive rodents display impairments in hippocampal synaptic plasticity and defects in spatial memory tasks. We have also shown that leptin facilitates the induction of hippocampal LTP (Long-term potentiation) via enhancing NMDA (N-methyl-D-aspartate) receptor function and that leptin has the ability to evoke a novel form of NMDA receptor-dependent LTD (Long-term depression). In addition, leptin promotes rapid alterations in hippocampal dendritic morphology and synaptic density, which are likely to contribute to the effects of this hormone on excitatory synaptic strength. Recent studies have demonstrated that trafficking of AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptors is pivotal for activity-dependent hippocampal synaptic plasticity. However, little is known about how AMPA receptor trafficking processes are regulated by hormonal systems. In the present paper, we discuss evidence that leptin rapidly alters the trafficking of AMPA receptors to and away from hippocampal CA1 synapses. The impact of these leptin-driven changes on hippocampal excitatory synaptic function are discussed.