A Dual Shaping Mechanism for Postsynaptic Ephrin‐B3 as a Receptor that Sculpts Dendrites and Synapses
As the neural network becomes wired, postsynaptic signaling molecules are thought to control the growth of dendrites and synapses. However, how these molecules are coordinated to sculpt postsynaptic structures is less well understood. Henkemeyer and colleagues found that ephrin‐B3, a transmembrane ligand for Eph receptors, serves as a postsynaptic receptor to transduce reverse signals into developing dendrites of hippocampal neurons (Nat Neurosci 2011;14:1421–1429). Both tyrosine phosphorylation‐dependent GRB4 SH2/SH3 adaptor‐mediated signals and PSD‐95‐discs large‐zona occludens‐1 (PDZ) domain‐dependent signals are required to inhibit the branching of dendrite, whereas only PDZ interaction is necessary for spine formation and excitatory synaptic function. PICK1 and syntenin, two PDZ domain proteins, participate together with ephrin‐B3 in these postsynaptic activities. PICK1 has a specific role in spine and synapse formation; syntenin promotes both dendrite pruning and synapse formation to build postsynaptic structures that are essential for neural circuits. The study dissected ephrin‐B reverse signaling into three distinct intracellular pathways and protein–protein interactions that mediate the maturation of postsynaptic neurons.
Activation of Central Orexin/Hypocretin Neurons by Dietary Amino Acids
Hypothalamic orexin/hypocretin (orx/hcrt) neurons regulate energy balance, wakefulness, and reward; loss of these neurons could lead to narcolepsy and weight gain. Glucose can lower the activity of orx/hcrt cells, but whether other dietary macronutrients have similar effects is unclear. Burdakov and colleagues showed that orx/hcrt cells could be stimulated by nutritionally relevant mixtures of amino acids (AAs), both in brain slice patch‐clamp experiments, and in c‐Fos expression assays following systemic administration or local injection of AAs into the brain of mice (Neuron 2011;72:616–629). A physiologically relevant mixture of AAs electrically excited orx/hcrt cells through a dual mechanism of inhibiting KATP channels and activating system‐A amino acid transporters. Nonessential AAs were more potent in activating orx/hcrt cells than essential AAs. The presence of physiological concentrations of AAs also suppressed the glucose responses of orx/hcrt cells. These results suggest a new mechanism of hypothalamic integration of macronutrient signals and imply that orx/hcrt cells sense macronutrient balance, rather than net energy value, in extracellular fluid.
Nicotinamide Phosphoribosyltransferase Protects against Ischemic Stroke through SIRT1‐Dependent Adenosine Monophosphate‐Activated Kinase Pathway
Miao and colleagues investigated whether nicotinamide phosphoribosyltransferase (Nampt), the rate‐limiting enzyme regulating mammalian nicotinamide adenine dinucleotide (NAD+) biosynthesis, contributes to ischemic stroke (Ann Neurol 2011;69:360–374). They found inhibiting Nampt with FK866 could aggravate brain infarction in a rat model of cerebral ischemia. In contrast, ischemic damage was attenuated by Nampt overexpression in the brain or the Nampt enzymatic product nicotinamide mononucleotide. They also showed that neuroprotection of Nampt is abolished in neurons lacking AMP‐activated protein kinase‐α2 (AMPKα2−/–). Nampt increased NAD+ levels and, by doing so, controlled silent mating type information regulation 2 homolog 1 (SIRT1) activity of the neurons. SIRT1 coprecipitated with Sarine/threominekinase II (LKB1), an upstream kinase of AMPK, and promoted LKB1 deacetylation in neurons. Nampt‐induced LKB1 deacetylation and AMPK activation were absent in SIRT1−/– neurons. Ca2+/calmodulin‐dependent protein kinase kinase‐β, another upstream kinase of AMPK, was not involved in the neuroprotection of Nampt. More importantly, Nampt‐induced neuroprotection was abolished in SIRT1+/− and AMPKα2−/– mice. Collectively, their findings identified a new neuroprotective cascade “Nampt‐NAD+‐SIRT1‐AMPK” and suggested that Nampt could be a new therapeutic target for stroke.
DJ‐1 Modulates the Expression of Cu/Zn‐Superoxide Dismutase‐1 through the Erk1/2‐Elk1 Pathway in Neuroprotection
Loss of function mutations of Park7/DJ‐1 gene increases the susceptibility of dopaminergic cells to reactive oxygen species and cause familial Parkinson disease (PD). Ding and colleagues found that the interaction of DJ‐1 with Erk1/2 is required for nuclear translocation of Erk1/2 upon oxidative stimulation. The translocation of Erk1/2 activated Elk1 and subsequently promoted superoxide dismutase1 (SOD1) expression. The nuclear translocation of Erk1/2, the activation of Elk1, and the ensuing upregulation of SOD1 in response to oxidative insult were all suppressed in DJ‐1 knockdown cells and DJ‐1 null mice. Reintroduction of SOD1 into DJ‐1 knockdown cells protected them against oxidative stress. They also found close correlation between the protein levels of DJ‐1 and SOD1 in the saliva samples in PD patients. These results suggested that DJ‐1 is protective against oxidative insult via regulating SOD1 expression through the Erk1/2‐Elk1 pathway (Ann Neurol 2011;70:591–599).
Dorsolateral and Ventromedial Prefrontal Cortex Orchestrate Normative Choice
Humans are capable to override self‐interest in favor of normatively valued goals. Fehr and colleagues examined the neural circuitry that is causally involved in normative, fairness‐related decisions by generating a temporarily diminished capacity for costly normative behavior, a ‘deviant’ case, through noninvasive brain stimulation (repetitive transcranial magnetic stimulation) and compared normal subjects’ functional magnetic resonance imaging signals with those of the deviant subjects. When fairness and economic self‐interest were in conflict, normal subjects (who make costly normative decisions at a much higher frequency) displayed significantly higher activity in, and connectivity between, the right dorsolateral prefrontal cortex (DLPFC) and the posterior ventromedial prefrontal cortex (pVMPFC). In contrast, when there was no conflict between fairness and economic self‐interest, both types of subjects displayed identical neural patterns and behaved identically. These findings suggest that a parsimonious prefrontal network, the activation of right DLPFC and pVMPFC, and the connectivity between them, facilitates subjects’ willingness to incur the cost of normative decisions (Nat Neurosci 2011;14:1468–1474).
Interaction between FEZ1 and DISC1 in Regulation of Neuronal Development and Risk for Schizophrenia
Disrupted‐in‐schizophrenia 1 (DISC1), a susceptibility gene for major mental disorders, encodes a scaffold protein that has a multifaceted impact on neuronal development. Ming and colleagues showed that fasciculation and elongation protein zeta‐1 (FEZ1) interacts with DISC1 to synergistically regulate dendritic growth of newborn neurons in the adult mouse hippocampus (Neuron 2011;72:559–571). This pathway complements a parallel DISC1–NDEL1 interaction that regulates cell positioning and morphogenesis of newborn neurons. Genetic association analysis of two independent cohorts of schizophrenic patients and healthy controls revealed an epistatic interaction between FEZ1 and DISC1, but not between FEZ1 and nuclear distribution proteinnude‐like (NDEL1), for risk of schizophrenia. These findings supported a model in which DISC1 regulates distinct aspects of neuronal development through interaction with different intracellular partners to increase risk for schizophrenia.
Dysbindin‐1, a Schizophrenia‐Related Protein, Facilitates Neurite Outgrowth by Promoting the Transcriptional Activity of P53
Dysbindin‐1 regulates synaptic activity and neuronal development. The gene encoding dysbindin‐1 (DTNBP1) is a risk factor in the pathogenesis of schizophrenia. Wang and colleagues identified necdin as a binding partner of dysbindin‐1 using a yeast two‐hybrid screening system (Mol Psychiatry 2011;16:1105–1116). Dysbindin‐1 recruits necdin to the cytoplasm, thereby attenuating the repressive effects of necdin on p53 transcriptional activity. Similar to p53 knockdown, knockdown of dysbindin‐1 dramatically decreased the expressions of the p53 target genes coronin 1b and rab13, which in turn are required for neurite outgrowth. Overexpression of p53 restored the neurite outgrowth in neurons with dysbindin‐1 knockdown. In brains of dysbindin‐1 null mice (the sandy strain), p21, Coronin 1b, and Rab13 levels were reduced. Primary culture of cortical neurons from the sandy mice displayed neurite outgrowth defects when compared with wild‐type control. These data provided evidence that dysbindin‐1 has an important role in neurite outgrowth through regulating p53's transcriptional activity.
PI3Kγ is required for NMDA Receptor‐Dependent Long‐Term Depression and Behavioral Flexibility
Phosphatidylinositol 3‐kinase (PI3K) is implicated in synaptic plasticity. Kaang and colleagues investigated the role of PI3Kγ in hippocampal‐dependent synaptic plasticity and cognitive functions (Nat Neurosci 2011;14:1447–1454). They found that PI3Kγ has a crucial and specific role in NMDA receptor (NMDAR)‐mediated synaptic plasticity in mouse Schaffer collateral–commissural synapses. Both genetic deletion and pharmacological inhibition of PI3Kγ disrupted NMDAR long‐term depression (LTD) while leaving other forms of synaptic plasticity intact. Most strikingly, the impairment of NMDAR LTD by PI3Kγ blockade resulted in gross deficits in behavioral flexibility. These findings suggest that PI3Kγ is critical for NMDAR LTD as well as some cognitive function. To extrapolate from these findings, PI3K isoforms may have distinct roles in different types of synaptic plasticity and may therefore influence various kinds of behavior.
Bidirectional Regulation of Dendritic Voltage‐Gated Potassium Channels by the Fragile X Mental Retardation Protein
How transmitter receptors modulate neuronal signaling by regulating voltage‐gated ion channel expression remains an open question. Jan and colleagues reported dendritic localization of mRNA of Kv4.2 voltage‐gated potassium channel (Neuron 2011;72:630–642). Translational regulation of Kv4.2 by fragile X mental retardation protein (FMRP). FMRP suppression of Kv4.2 was revealed by elevation of Kv4.2 in neurons from fmr1 knockout (KO) mice and in neurons expressing Kv4.2–3’UTR that binds to FMRP. Treatment of hippocampal slices from fmr1 KO mice with a Kv4 channel blocker restored long‐term potentiation induced by moderate stimuli. Surprisingly, recovery of Kv4.2 after N‐methyl‐D‐aspartate receptor (NMDAR)‐induced degradation also required FMRP, likely due to NMDAR‐induced FMRP dephosphorylation. The study of FMRP regulation of Kv4.2 reveals a FMRP target of potential relevance to fragile X syndrome.
(Provided by Dr Jian‐Guang Yu)