Retraction notice to "Chronic fluoxetine treatment in vivo enhances excitatory synaptic transmission in the hippocampus" [Neuropharmacology, 150 (15th May 2019) 38-45].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Authors. After publication, Scott M. Thompson found significant concerns about the data and duly notified The University of Maryland. The University of Maryland conducted an internal investigation which confirmed that the article was compromised. Namely in Figure 2B, the Investigation Committee determined that the western blots used to create the figure were not the ones used for the quantification and concluded that the figure was falsified to fit the hypothesis. In Figure 2C and D, the Investigation Committee determined that the densitometry data (pCaMKII, pS831, CamKII and GluA1) used to create the histogram were falsified to fit the hypothesis.

RETRACTED: Chronic fluoxetine treatment in vivo enhances excitatory synaptic transmission in the hippocampus.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Authors. After publication, Scott M. Thompson found significant concerns about the data and duly notified The University of Maryland. The University of Maryland conducted an internal investigation which confirmed that the article was compromised. Namely in Figure 2B, the Investigation Committee determined that the western blots used to create the figure were not the ones used for the quantification and concluded that the figure was falsified to fit the hypothesis. In Figure 2C and 2D, the Investigation Committee determined that the densitometry data (pCaMKII, pS831, CamKII and GluA1) used to create the histogram were falsified to fit the hypothesis.

Long-Term Potentiation Requires a Rapid Burst of Dendritic Mitochondrial Fission during Induction.

Synaptic transmission is bioenergetically demanding, and the diverse processes underlying synaptic plasticity elevate these demands. Therefore, mitochondrial functions, including ATP synthesis and Ca2+ handling, are likely essential for plasticity. Although axonal mitochondria have been extensively analyzed, LTP is predominantly induced postsynaptically, where mitochondria are understudied. Additionally, though mitochondrial fission is essential for their function, signaling pathways that regulate fission in neurons remain poorly understood. We found that NMDAR-dependent LTP induction prompted a rapid burst of dendritic mitochondrial fission and elevations of mitochondrial matrix Ca2+. The fission burst was triggered by cytosolic Ca2+ elevation and required CaMKII, actin, and Drp1, as well as dynamin 2. Preventing fission impaired mitochondrial matrix Ca2+ elevations, structural LTP in cultured neurons, and electrophysiological LTP in hippocampal slices. These data illustrate a novel pathway whereby synaptic activity controls mitochondrial fission and show that dynamic control of fission regulates plasticity induction, perhaps by modulating mitochondrial Ca2+ handling.

Mice lacking L-12/15-lipoxygenase show increased mortality during kindling despite demonstrating resistance to epileptogenesis.

OBJECTIVE: Studies have addressed the potential involvement of L-12/15-lipoxygenases (LOs), a polyunsaturated fatty acid metabolizing enzyme, in experimental models of acute stroke and chronic neurodegeneration; however, none to our knowledge has explored its role in epilepsy development. Thus, this study characterizes the cell-specific expression of L-12/15 -LO in the brain and examines its contribution to epileptogenesis. METHODS: L-12/15-LO messenger RNA (mRNA) and protein expression and activity were characterized via polymerase chain reaction (PCR), immunocytochemistry and enzyme-linked immunosorbent assay (ELISA), respectively. To assess its role in epileptogenesis, L-12/15 -LO-deficient mice and their wild-type littermates were treated with pentylenetetrazole (PTZ, ip) every other day for up to 43 days (kindling paradigm). The innate seizure threshold was assessed by the acute PTZ-induced seizure response of naive mice. RESULTS: L-12/15 -LO mRNA is expressed in hippocampal and cortical tissue from wild-type C57BL/6 mice. In addition, it is physically and functionally expressed by microglia, neurons, and brain microvessel endothelial cells, but not by astrocytes. Mice deficient in L-12/15 -LO were resistant to PTZ-induced kindling and demonstrated an elevated innate seizure threshold. Despite this, a significant increase in seizure-related mortality was observed during the kindling paradigm in L-12/15 -LO nulls relative to their wild-type littermates. SIGNIFICANCE: The present study is the first to detail the role of L-12/15-LO in the epileptogenic process. The results suggest that constitutive L-12/15-LO expression contributes to a lower innate set point for PTZ acute seizure generation, translating to higher rates of kindling acquisition. Nevertheless, increased seizure-related deaths in mice lacking activity of L-12/15-LO suggests that its products may influence endogenous mechanisms involved in termination of seizure activity.

Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS-FTD-linked UBQLN2 mutations.

Missense mutations in ubiquilin 2 (UBQLN2) cause ALS with frontotemporal dementia (ALS-FTD). Animal models of ALS are useful for understanding the mechanisms of pathogenesis and for preclinical investigations. However, previous rodent models carrying UBQLN2 mutations failed to manifest any sign of motor neuron disease. Here, we show that lines of mice expressing either the ALS-FTD-linked P497S or P506T UBQLN2 mutations have cognitive deficits, shortened lifespans, and develop motor neuron disease, mimicking the human disease. Neuropathologic analysis of the mice with end-stage disease revealed the accumulation of ubiquitinated inclusions in the brain and spinal cord, astrocytosis, a reduction in the number of hippocampal neurons, and reduced staining of TAR-DNA binding protein 43 in the nucleus, with concomitant formation of ubiquitin+ inclusions in the cytoplasm of spinal motor neurons. Moreover, both lines displayed denervation muscle atrophy and age-dependent loss of motor neurons that correlated with a reduction in the number of large-caliber axons. By contrast, two mouse lines expressing WT UBQLN2 were mostly devoid of clinical and pathological signs of disease. These UBQLN2 mouse models provide valuable tools for identifying the mechanisms underlying ALS-FTD pathogenesis and for investigating therapeutic strategies to halt disease.

Rapid Antidepressant Action and Restoration of Excitatory Synaptic Strength After Chronic Stress by Negative Modulators of Alpha5-Containing GABAA Receptors.

Selective serotonin reuptake inhibitors (SSRIs) are the primary pharmacological treatment for depression, but SSRIs are effective in only half of the patients and typically take several weeks to relieve symptoms. The NMDA receptor antagonist ketamine exerts a rapid antidepressant action, but has troubling side effects. We hypothesized that negative allosteric modulators of GABAA receptors would exert similar effects on brain activity as ketamine, but would not exert as many side effects if targeted only to GABAA receptors containing α5 subunits, which are enriched in the hippocampus and prefrontal cortex. Here, we show that the α5-selective negative modulator L-655,708 reversed the alterations in hedonic behavior in the sucrose preference and social interaction tests produced by two different chronic stress paradigms in rats within 24 h of systemic administration. Similar effects were observed with another α5-selective negative modulator, MRK-016. L-655,708 had no effect on hedonic or open-field behavior in unstressed animals. Within 24 h, L-655,708 injection also restored the strength of pathologically weakened excitatory synaptic transmission at the stress-sensitive temporoammonic-CA1 synapse, measured electrophysiologically, and increased levels of the GluA1 subunit of the AMPA receptor, measured with western blotting. We suggest that the ability of L-655,708 to restore excitatory synaptic strength rapidly may underlie its ability to restore stress-induced behavioral alterations rapidly, supporting evidence that dysfunction of multiple excitatory synapses in cortico-mesolimbic reward pathways contributes, in part, to the genesis of depression. Negative allosteric modulators of α5 subunit-containing GABAA receptors represent a promising novel class of fast-acting and clinically viable antidepressant compounds.

An excitatory synapse hypothesis of depression.

Depression is a common cause of mortality and morbidity, but the biological bases of the deficits in emotional and cognitive processing remain incompletely understood. Current antidepressant therapies are effective in only some patients and act slowly. Here, we propose an excitatory synapse hypothesis of depression in which chronic stress and genetic susceptibility cause changes in the strength of subsets of glutamatergic synapses at multiple locations, including the prefrontal cortex (PFC), hippocampus, and nucleus accumbens (NAc), leading to a dysfunction of corticomesolimbic reward circuitry that underlies many of the symptoms of depression. This hypothesis accounts for current depression treatments and suggests an updated framework for the development of better therapeutic compounds.