EPAC Null Mutation Impairs Learning and Social Interactions via Aberrant Regulation of miR‐124 and Zif268 Translation
EPAC (exchange proteins directly activated by cAMP) proteins are guanine nucleotide exchange factors that act as intracellular receptors for cyclic AMP. Two variants of the EPAC genes (e.g., EPAC1 and EPAC2) are expressed throughout the brain. But, their functions in the brain remain unknown. Yang et al. genetically deleted EPAC1 (EPAC1−/−), EPAC2 (EPAC2−/−), or both EPAC1 and EPAC2 genes (EPAC−/−) in the forebrain of mice. They observed that EPAC null mutation impairs long‐term potentiation (LTP). This impairment is paralleled with severe deficits in spatial learning and social interactions and is mediated in a direct manner by miR‐124 transcription and Zif268 translation. Knockdown of miR‐124 restores Zif268 and reverses all aspects of the EPAC−/− phenotypes, whereas expression of miR‐124 or knockdown of Zif268 reproduces effects similar to EPAC null mutation. Thus, EPAC proteins control miR‐124 transcription in the brain for processing spatial learning and social interactions (Neuron 2012;73:774–788).
Reduced Conduction Failure of the Main Axon of Polymodal Nociceptive C‐Fibres Contributes to Painful Diabetic Neuropathy
It is generally believed that the number of nociceptive primary afferent firings is determined at the free nerve endings, whereas the main axon of unmyelinated C‐fibres are only involved in propagation of firing series to the central terminals. Sun et al. challenged this classic view by showing that conduction of action potential can fail to occur when they travel down the main axon of polymodal nociceptive C‐fibres. Quantitative analysis of conduction failure revealed that the degree of conduction failure displays a frequency‐dependent manner. Following streptozotocin‐induced diabetes, a subset of polymodal nociceptive C‐fibres exhibited high‐firing frequency to suprathreshold mechanical stimulation, of which the conduction failure significantly reduced. These results revealed a novel mechanism underlying diabetic hyperalgesia (Brain 2012;135:359–375).
Activin C in Nociceptive Afferent Neurons is Required for Suppressing Inflammatory Pain
Suppressive modulators released from nociceptive afferent neurons contribute to pain regulation. Liu et al. observed that activin C in small dorsal root ganglion neurons is required for suppressing inflammation‐induced nociceptive responses (Brain 2012;135:391–403). The expression of activin C in small dorsal root ganglion neurons of rats was markedly down‐regulated during the early days of peripheral inflammation induced by intraplantar injection of complete Freund's adjuvant. Intrathecal treatment with a small interfering RNA targeting activin βC or an antibody against activin C could enhance the formalin‐induced nociceptive responses, and impair the recovery from complete Freund's adjuvant‐induced thermal hyperalgesia. In contrast, intrathecally applied activin C could reduce nociceptive responses induced by formalin or complete Freund's adjuvant. Activin C also inhibited inflammation‐induced phosphorylation of extracellular signal‐regulated kinase in the dorsal root ganglia and the dorsal spinal cord. Thus, activin C functions as an endogenous suppressor of inflammatory nociceptive transmission and may have a therapeutic potential for inflammatory pain.
Activity Recall in a Visual Cortical Ensemble
Cue‐triggered recall of learned temporal sequences is an important cognitive function, and has been attributed to higher brain areas. Xu et al. found that in both anesthetized and awake rats, after repeated stimulation with a moving spot that evoked sequential firing of an ensemble of primary visual cortex (V1) neurons, a brief flash at the starting point of the motion path was sufficient to evoke a sequential firing pattern that reproduced the activation order evoked by the moving spot. The speed of recalled spike sequences reflected the internal dynamics of the network rather than the motion speed. Such a recall was observed in awake rats during a synchronized (“quiet wakeful”) brain state having large‐amplitude, low‐frequency local field potential (LFP) but not in a desynchronized (“active”) state having low‐amplitude, high‐frequency LFP. The authors concluded that conditioning‐enhanced, cue‐evoked sequential spiking of a V1 ensemble may contribute to experience‐based perceptual inference in a brain state‐dependent manner (Nat Neurosci 2012;15:449–455).
SMAD3 Contributes to Metabolic Side Effects of Antipsychotics
Many antipsychotics are associated with metabolic side effects. Cohen et al. revealed that SMAD3 contributes to metabolic side effects of antipsychotics (Mol Psychiatry 2012; doi:10.1038/mp.2011.186). Previously, this group of researchers found that phenothiazine antipsychotics could modulate human insulin promoter through high‐throughput screening. Recently, they extended their initial finding to structurally diverse typical and atypical antipsychotics. They found that antipsychotics could activate SMAD3, a downstream effector of the transforming growth factor beta (TGFβ) pathway, through a receptor distinct from the TGFβ receptor family and known neurotransmitter receptor targets of antipsychotics. Of note, antipsychotics that do not cause metabolic side effects did not activate SMAD3. Analysis of gene expression in the brain of human subjects treated with antipsychotics demonstrated altered expression of SMAD3 responsive genes. This work suggested a possible way to separate beneficial CNS activity of antipsychotics from metabolic influence.
Primary Cilia Regulates Glutamatergic Synaptic Integration of Adult‐Born Neurons
Sequential synaptic integration of adult‐born neurons has been widely examined in rodents, but the mechanisms regulating the integration remain largely unknown. The primary cilium, a microtubule‐based signaling center, is essential for vertebrate development, including the development of the CNS. Kumamoto et al. examined the assembly and function of the primary cilium in the synaptic integration of adult‐born mouse hippocampal neurons, and observed that primary cilia were absent in young adult‐born neurons, but assembled precisely at the stage when newborn neurons approach their final destination, further extend dendrites and form synapses with entorhinal cortical projections. Conditional deletion of cilia from adult‐born neurons induced severe defects in dendritic refinement and synapse formation. Deletion of primary cilia led to enhanced Wnt and β‐catenin signaling, which may account for these developmental defects. Taken together, their findings identify the assembly of primary cilia as a critical regulatory event in the dendritic refinement and synaptic integration of adult‐born neurons (Nat Neurosci 2012;15:399–405).
Human Cerebral Cortex Development from Pluripotent Stem Cells to Functional Excitatory Synapses
Efforts to study the development and function of the human cerebral cortex in health and disease have been limited by the availability of model systems. Recently, Shi et al. developed a robust, multistep process for human cortical development from pluripotent stem cells: directed differentiation of human embryonic stem (ES) and induced pluripotent stem (iPS) cells to cortical stem and progenitor cells, followed by an extended period of cortical neurogenesis, neuronal terminal differentiation to acquire mature electrophysiological properties, and functional excitatory synaptic network formation. The authors found that induction of cortical neuroepithelial stem cells from human ES cells and human iPS cells is dependent on retinoid signaling. Furthermore, human ES cell and iPS cell differentiation to cerebral cortex recapitulated in vivo development to generate all classes of cortical projection neurons in a fixed temporal order (Nat Neurosci 2012;15:477–486).
Gamma Oscillations are Generated in Optic Tectum In Vitro
The optic tectum (OT), a midbrain structure implicated in sensorimotor processing and attention, exhibits gamma oscillations. However, the origin and mechanisms of these oscillations remain unknown. Goddard et al. discovered that persistent (>100 ms) epochs of large amplitude gamma oscillations that closely resemble those recorded in vivo can be evoked in acute slices of the avian OT. They found that cholinergic, glutamatergic, and GABAergic mechanisms differentially regulate the structure of the oscillations at various timescales. These persistent oscillations originate in the multisensory layers of the OT and are broadcast to visual layers via the cholinergic nucleus Ipc, providing a potential mechanism for enhancing the processing of visual information within the OT. These findings suggest that the OT could use its own oscillatory code to route signals to forebrain networks (Neuron 2012;73:567–580).
Dysfunctional Astrocytic Regulation of Glutamate Transmission in Depression
Depression is usually associated with alterations in the monoaminergic system. However, new evidences suggest the involvement of the glutamatergic system in the aetiology of depression. Gómez‐Galán et al. explored the glutamatergic system in a rat model of depression (i.e., the flinders sensitive line [FSL]). They found a dramatically elevated level of baseline glutamatergic synaptic transmission by whole‐cell recordings as well as impairment in long‐term potentiation (LTP) induced by high‐frequency stimulation in hippocampal slices from FSL rats compared with Sprague‐Dawley rats. At behavioural level, FSL rats displayed recognition memory impairment in a novel object recognition test. Enantioselective chromatography analysis revealed lower levels of D‐serine in the hippocampus of FSL rats and both synaptic plasticity and memory impairments were restored by administration of D‐serine. The researchers also observed dysfunctional astrocytic glutamate regulation including downregulation of the glia glutamate transporter GLAST. One possibility is that dysfunctional astrocytic glutamate reuptake triggers a succession of events, including the reduction of D‐serine production as a safety mechanism to avoid NMDA receptor overactivation, which in turn causes the synaptic plasticity and memory impairments. These findings open up new brain targets for the development of more potent and efficient antidepressant drugs (Mol Psychiatry 2012;doi: 10.1038/mp.2012.10).
(Provided by Dr. Jian‐Guang Yu and Dr. Yan Sun)