Background Although major depressive disorder (MDD) has low heritability, a genome-wide association study in humans has recently implicated type 3 adenylyl cyclase (AC3, ADCY3) in MDD. Moreover, the expression level of AC3 in blood has been considered as a MDD biomarker in humans, but there is lack of supporting evidence from animal study. Methods We employed multiple approaches to experimentally evaluate if AC3 is a contributing factor for major depression using mouse models lacking Adcy3 gene. Results We found that conventional AC3 KO mice exhibited phenotypes associated with MDD in behavioral assays. Electroencephalography/electromyography (EEG/EMG) recordings indicated that AC3 KO mice also have altered sleep patterns characterized by increased percentage of REM sleep. Sholl analysis revealed that cultured cortical neurons from AC3 KO mice have reduced dendritic arborization. Furthermore, synaptic activity at CA3-CA1 synapses was significantly lower in KO mice and they also exhibited attenuated long-term potentiation as well as deficits in spatial navigation. To confirm that theses defects are not secondary responses to anosmia or developmental defects, we generated a conditional AC3 floxed mouse strain. This enabled us to inactivate AC3 function selectively in the forebrain and to inducibly ablate it in adult mice. Both AC3 forebrain-specific and AC3 inducible knockout mice exhibited pro-depression phenotypes without anosmia. Conclusion This study demonstrates that loss of AC3 in mice leads to decreased neuronal activity, altered sleep pattern, and depression-like behaviors, providing strong evidence supporting AC3 as a candidate gene for MDD.

The insulin and insulin like growth factor (IGF) signaling systems are implicated in breast cancer biology. Thus, disrupting IGF/insulin signaling has been shown to have promise in a number of preclinical models. However, human clinical trials have been less promising. Despite evidence of some activity in early phase trials, randomized phase III studies have thus far been unable to show a benefit of blocking IGF signaling in combination with conventional strategies. In breast cancer, combination anti IGF/insulin signaling agents with hormone therapy has not yet proven to have benefit. This inability to translate the preclinical findings into useful clinical strategies calls attention to the need for a deeper understanding of this complex pathway. Development of predictive biomarkers and optimal inhibitory strategies of the IGF/insulin system should yield better clinical strategies. Furthermore, unraveling the interaction between the IGF/insulin pathway and other critical signaling pathways in breast cancer biology, namely estrogen receptor-α (ERα) and epidermal growth factor receptor (EGFR) pathways, provides additional new concepts in designing combination therapies. In this review, we will briefly summarize the current strategies targeting the IGF/insulin system, discuss the possible reasons of success or failure of the existing therapies, and provide potential future direction for research and clinical trials.

Rats and mice have been demonstrated to show episodic-like memory, a prototype of episodic memory, as defined by an integrated memory of the experience of an object or event, in a particular place and time. Such memory can be assessed via the use of spontaneous object exploration paradigms, variably designed to measure memory for object, place, temporal order and object-location inter-relationships. We review the methodological properties of these tests, the neurobiology about time and discuss the evidence for the involvement of the medial prefrontal cortex (mPFC), entorhinal cortex (EC) and hippocampus, with respect to their anatomy, neurotransmitter systems and functional circuits. The systematic analysis suggests that a specific circuit between the mPFC, lateral EC and hippocampus encodes the information for event, place and time of occurrence into the complex episodic-like memory, as a top-down regulation from the mPFC onto the hippocampus. This circuit can be distinguished from the neuronal component memory systems for processing the individual information of object, time and place.

Principal neurons encode information by varying their firing rate and patterns precisely fine-tuned through GABAergic interneurons. Dysregulation of inhibition can lead to neuropsychiatric disorders, yet little is known about the molecular basis underlying inhibitory control. Here, we find that excessive GABA release from basket cells (BCs) attenuates the firing frequency of Purkinje neurons (PNs) in the cerebellum of Fragile X Mental Retardation 1 (Fmr1) knockout (KO) mice, a model of Fragile X Syndrome (FXS) with abrogated expression of the Fragile X Mental Retardation Protein (FMRP). This over-inhibition originates from increased excitability and Ca transients in the presynaptic terminals, where Kv1.2 potassium channels are downregulated. By paired patch-clamp recordings, we further demonstrate that acutely introducing an N-terminal fragment of FMRP into BCs normalizes GABA release in the Fmr1-KO synapses. Conversely, direct injection of an inhibitory FMRP antibody into BCs, or membrane depolarization of BCs, enhances GABA release in the wild type synapses, leading to abnormal inhibitory transmission comparable to the Fmr1-KO neurons. We discover that the N-terminus of FMRP directly binds to a phosphorylated serine motif on the C-terminus of Kv1.2; and that loss of this interaction in BCs exaggerates GABA release, compromising the firing activity of PNs and thus the output from the cerebellar circuitry. An allosteric Kv1.2 agonist, docosahexaenoic acid, rectifies the dysregulated inhibition in vitro as well as acoustic startle reflex and social interaction in vivo of the Fmr1-KO mice. Our results unravel a novel molecular locus for targeted intervention of FXS and perhaps autism.

The cyclic adenosine monophosphate (cAMP), mitogen-activated protein kinase (MAPK) and cAMP response element-binding protein (CREB) transcriptional pathway is required for consolidation of hippocampus-dependent memory. In mice, this pathway undergoes a circadian oscillation required for memory persistence that reaches a peak during the daytime. Since mice exhibit polyphasic sleep patterns during the day, this suggested the interesting possibility that cAMP, MAPK activity and CREB phosphorylation may be elevated during sleep. Here, we report that cAMP, phospho-p44/42 MAPK and phospho-CREB are higher in rapid eye movement (REM) sleep compared to awake mice but are not elevated in non-rapid eye movement (NREM) sleep. This peak of activity during REM sleep does not occur in mice lacking calmodulin-stimulated adenylyl cyclases, a mouse strain that learns but cannot consolidate hippocampus-dependent memory. We conclude that a preferential increase in cAMP, MAPK activity and CREB phosphorylation during REM sleep may contribute to hippocampus-dependent memory consolidation.

Insulin-like growth factors (IGFs) stimulate cell growth in part by increasing amino acid uptake. xCT (SLC7A11) encodes the functional subunit of the cell surface transport system xC− which mediates cystine uptake, a pivotal step in glutathione synthesis and cellular redox control. In this study, we show that IGF-I regulates cystine uptake and cellular redox status by activating the expression and function of xCT in estrogen receptor-positive (ER+) breast cancer cells by a mechanism that relies on the IGF receptor substrate-1 (IRS-1). Breast cancer cell proliferation mediated by IGF-I was suppressed by attenuating xCT expression or blocking xCT activity with the pharmacological inhibitor sulfasalazine (SASP). Notably, SASP sensitized breast cancer cells to inhibitors of the IGF-I receptor in a manner reversed by the ROS scavenger N-acetyl-L-cysteine. Thus, IGF-I promoted the proliferation of ER+ breast cancer cells by regulating xC− transporter function to protect cancer cells from ROS in an IRS-1 dependent manner. Our findings suggest that inhibiting xC− transporter function may synergize with modalities that target the IGF-I receptor to heighten their therapeutic effects.

The expression of this downregulation depends on ongoing synaptic activity, and is attenuated by a dynamin peptide (D15) that blocks clathrindependent internalization. We further demonstrated that the same induction paradigm specifically reduces NMDAR-dependent plateau potential and aberrant spike firings during repetitive activity. Together, our results suggest that coincident activation of mGluRs and NMDARs during intense synaptic activity may lead to selective endocytosis of NMDARs in the perisynaptic/extrasynaptic domain, and implicate that mGluRs are potentially important for gating development of high-fidelity neurotransmission at this synapse.

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