Enhanced Hippocampal Long-Term Potentiation and Fear Memory in Btbd9 Mutant Mice

Polymorphisms in BTBD9 have recently been associated with higher risk of restless legs syndrome (RLS), a neurological disorder characterized by uncomfortable sensations in the legs at rest that are relieved by movement. The BTBD9 protein contains a BTB/POZ domain and a BACK domain, but its function is unknown. To elucidate its function and potential role in the pathophysiology of RLS, we generated a line of mutant Btbd9 mice derived from a commercial gene-trap embryonic stem cell clone. Btbd9 is the mouse homolog of the human BTBD9. Proteins that contain a BTB/POZ domain have been reported to be associated with synaptic transmission and plasticity. We found that Btbd9 is naturally expressed in the hippocampus of our mutant mice, a region critical for learning and memory. As electrophysiological characteristics of CA3-CA1 synapses of the hippocampus are well characterized, we performed electrophysiological recordings in this region. The mutant mice showed normal input-output relationship, a significant impairment in pre-synaptic activity, and an enhanced long-term potentiation. We further performed an analysis of fear memory and found the mutant mice had an enhanced cued and contextual fear memory. To elucidate a possible molecular basis for these enhancements, we analyzed proteins that have been associated with synaptic plasticity. We found an elevated level of dynamin 1, an enzyme associated with endocytosis, in the mutant mice. These results suggest the first identified function of Btbd9 as being involved in regulating synaptic plasticity and memory. Recent studies have suggested that enhanced synaptic plasticity, analogous to what we have observed, in other regions of the brain could enhance sensory perception similar to what is seen in RLS patients. Further analyses of the mutant mice will help shine light on the function of BTBD9 and its role in RLS

Microarray-Based Transcriptomic Analysis of Differences between Long-Term Gregarious and Solitarious Desert Locusts

Desert locusts (Schistocerca gregaria) show an extreme form of phenotypic plasticity and can transform between a cryptic solitarious phase and a swarming gregarious phase. The two phases differ extensively in behavior, morphology and physiology but very little is known about the molecular basis of these differences. We used our recently generated Expressed Sequence Tag (EST) database derived from S. gregaria central nervous system (CNS) to design oligonucleotide microarrays and compare the expression of thousands of genes in the CNS of long-term gregarious and solitarious adult desert locusts. This identified 214 differentially expressed genes, of which 40% have been annotated to date. These include genes encoding proteins that are associated with CNS development and modeling, sensory perception, stress response and resistance, and fundamental cellular processes. Our microarray analysis has identified genes whose altered expression may enable locusts of either phase to deal with the different challenges they face. Genes for heat shock proteins and proteins which confer protection from infection were upregulated in gregarious locusts, which may allow them to respond to acute physiological challenges. By contrast the longer-lived solitarious locusts appear to be more strongly protected from the slowly accumulating effects of ageing by an upregulation of genes related to anti-oxidant systems, detoxification and anabolic renewal. Gregarious locusts also had a greater abundance of transcripts for proteins involved in sensory processing and in nervous system development and plasticity. Gregarious locusts live in a more complex sensory environment than solitarious locusts and may require a greater turnover of proteins involved in sensory transduction, and possibly greater neuronal plasticity

Neddylation inhibition impairs spine development, destabilizes synapses and deteriorates cognition

Neddylation is a ubiquitylation-like pathway that controls cell cycle and proliferation by covalently conjugating Nedd8 to specific targets. However, its role in neurons, nonreplicating postmitotic cells, remains unexplored. Here we report that Nedd8 conjugation increased during postnatal brain development and is active in mature synapses, where many proteins are neddylated. We show that neddylation controls spine development during neuronal maturation and spine stability in mature neurons. We found that neddylated PSD-95 was present in spines and that neddylation on Lys202 of PSD-95 is required for the proactive role of the scaffolding protein in spine maturation and synaptic transmission. Finally, we developed Nae1 CamKIIα-CreERT2 mice, in which neddylation is conditionally ablated in adult excitatory forebrain neurons. These mice showed synaptic loss, impaired neurotransmission and severe cognitive deficits. In summary, our results establish neddylation as an active post-translational modification in the synapse regulating the maturation, stability and function of dendritic spines.Fil: Vogl, Annette M.. Instituto Max Planck de Psiquiatria de Munich; AlemaniaFil: Brockmann, Marisa M.. Instituto Max Planck de Psiquiatria de Munich; AlemaniaFil: Giusti, Sebastian Alejandro. Instituto Max Planck de Psiquiatria de Munich; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: MacCarrone, Giuseppina. Instituto Max Planck de Psiquiatria de Munich; AlemaniaFil: Vercelli, Claudia Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Bauder, Corinna A.. Instituto Max Planck de Psiquiatria de Munich; AlemaniaFil: Richter, Julia S.. Instituto Max Planck de Psiquiatria de Munich; Alemania. Instituto Max Planck de Psiquiatria de Munich; AlemaniaFil: Roselli, Francesco. Universita Degli Studi Di Bari; ItaliaFil: Hafner, Anne-Sophie. Universite de Bordeaux; FranciaFil: Dedic, Nina. Instituto Max Planck de Psiquiatria de Munich; AlemaniaFil: Wotjak, Carsten T.. Instituto Max Planck de Psiquiatria de Munich; AlemaniaFil: Vogt Weisenhorn, Daniela M.. Institute Of Developmental Genetics; AlemaniaFil: Choquet, Daniel. Universite de Bordeaux; FranciaFil: Turck, Christoph W.. Instituto Max Planck de Psiquiatria de Munich; AlemaniaFil: Stein, Valentin. Universitaet Bonn; AlemaniaFil: Deussing, Jan M.. Instituto Max Planck de Psiquiatria de Munich; AlemaniaFil: Refojo, Damian. Instituto Max Planck de Psiquiatria de Munich; Alemani