Neuroligin-1 regulates excitatory synaptic transmission, LTP and EPSP-spike coupling in the dentate gyrus in vivo.

Neuroligins are transmembrane cell adhesion proteins with a key role in the regulation of excitatory and inhibitory synapses. Based on previous in vitro and ex vivo studies, neuroligin-1 (NL1) has been suggested to play a selective role in the function of glutamatergic synapses. However, the role of NL1 has not yet been investigated in the brain of live animals.

Juvenile manifestation of ultrasound communication deficits in the neuroligin-4 null mutant mouse model of autism.

Neuroligin-4 (Nlgn4) is a member of the neuroligin family of postsynaptic cell adhesion molecules. Loss-of-function mutations of NLGN4 are among the most frequent, known genetic causes of heritable autism. Adult Nlgn4 null mutant (Nlgn4(-/-)) mice are a construct valid model of human autism, with both genders displaying a remarkable autistic phenotype, including deficits in social interaction and communication as well as restricted and repetitive behaviors.

Divergent dysregulation of gene expression in murine models of fragile X syndrome and tuberous sclerosis.

Background: Fragile X syndrome and tuberous sclerosis are genetic syndromes that both have a high rate of comorbidity with autism spectrum disorder (ASD). Several lines of evidence suggest that these two monogenic disorders may converge at a molecular level through the dysfunction of activity-dependent synaptic plasticity.

Methods: To explore the characteristics of transcriptomic changes in these monogenic disorders, we profiled genome-wide gene expression levels in cerebellum and blood from murine models of fragile X syndrome and tuberous sclerosis.

Neurobiology of autism gene products: towards pathogenesis and drug targets.

Rationale: The genetic heterogeneity of autism spectrum disorders (ASDs) is enormous, and the neurobiology of proteins encoded by genes associated with ASD is very diverse. Revealing the mechanisms on which different neurobiological pathways in ASD pathogenesis converge may lead to the identification of drug targets.

Objective: The main objective is firstly to outline the main molecular networks and neuronal mechanisms in which ASD gene products participate and secondly to answer the question how these converge.

The adhesion protein IgSF9b is coupled to neuroligin 2 via S-SCAM to promote inhibitory synapse development.

Synaptic adhesion molecules regulate diverse aspects of synapse formation and maintenance. Many known synaptic adhesion molecules localize at excitatory synapses, whereas relatively little is known about inhibitory synaptic adhesion molecules. Here we report that IgSF9b is a novel, brain-specific, homophilic adhesion molecule that is strongly expressed in GABAergic interneurons.

Evidence for a common endocannabinoid-related pathomechanism in autism spectrum disorders.

In this issue of Neuron, Földy et al. (2013) report that endocannabinoid-mediated signaling at inhibitory synapses is dysregulated in mouse models of autism-associated Neuroligin-3 mutations. These findings carry implications regarding the pathophysiology of autism spectrum disorders and the development of treatment strategies.

Development of an autism severity score for mice using Nlgn4 null mutants as a construct-valid model of heritable monogenic autism.

Autism is the short name of a complex and heterogeneous group of disorders (autism spectrum disorders, ASD) with several lead symptoms required for classification, including compromised social interaction, reduced verbal communication and stereotyped repetitive behaviors/restricted interests. The etiology of ASD is still unknown in most cases but monogenic heritable forms exist that have provided insights into ASD pathogenesis and have led to the notion of autism as a 'synapse disorder'. Among the most frequent monogenic causes of autism are loss-of-function mutations of the NLGN4X gene which encodes the synaptic cell adhesion protein neuroligin-4X (NLGN4X).

The role of neurexins and neuroligins in the formation, maturation, and function of vertebrate synapses.

Neurexins (NXs) and neuroligins (NLs) are transsynaptically interacting cell adhesion proteins that play a key role in the formation, maturation, activity-dependent validation, and maintenance of synapses. As complex alternative splicing processes in nerve cells generate a large number of NX and NLs variants, it has been proposed that a combinatorial interaction code generated by these variants may determine synapse identity and network connectivity during brain development. The functional importance of NXs and NLs is exemplified by the fact that mutations in NX and NL genes are associated with several neuropsychiatric disorders, most notably with autism.

Cognitive dysfunction and prefrontal synaptic abnormalities in a mouse model of fragile X syndrome.

Among the hallmark phenotypes reported in individuals with fragile X syndrome (FXS) are deficits in attentional function, inhibitory control, and cognitive flexibility, a set of cognitive skills thought to be associated with the prefrontal cortex (PFC). However, despite substantial clinical research into these core deficits, the PFC has received surprisingly little attention in preclinical research, particularly in animal models of FXS. In this study, we sought to investigate the molecular, cellular, and behavioral consequences of the loss of the fragile X mental retardation protein in the PFC of Fmr1 KO mice, a mouse model of FXS.

Toward fulfilling the promise of molecular medicine in fragile X syndrome.

Fragile X syndrome (FXS) is the most common inherited form of mental retardation and a leading known cause of autism. It is caused by loss of expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein that negatively regulates protein synthesis. In neurons, multiple lines of evidence suggest that protein synthesis at synapses is triggered by activation of group 1 metabotropic glutamate receptors (Gp1 mGluRs) and that many functional consequences of activating these receptors are altered in the absence of FMRP.

Hypersensitivity to mGluR5 and ERK1/2 leads to excessive protein synthesis in the hippocampus of a mouse model of fragile X syndrome.

Fragile X syndrome (FXS) is caused by loss of the FMR1 gene product FMRP (fragile X mental retardation protein), a repressor of mRNA translation. According to the metabotropic glutamate receptor (mGluR) theory of FXS, excessive protein synthesis downstream of mGluR5 activation causes the synaptic pathophysiology that underlies multiple aspects of FXS. Here, we use an in vitro assay of protein synthesis in the hippocampus of male Fmr1 knock-out (KO) mice to explore the molecular mechanisms involved in this core biochemical phenotype under conditions where aberrant synaptic physiology has been observed.

Activation of mGluR5 induces rapid and long-lasting protein kinase D phosphorylation in hippocampal neurons.

Metabotropic glutamate receptors (mGluRs), including mGluR5, play a central role in regulating the strength and plasticity of synaptic connections in the brain. However, the signaling pathways that connect mGluRs to their downstream effectors are not yet fully understood. Here, we report that stimulation of mGluR5 in hippocampal cultures and slices results in phosphorylation of protein kinase D (PKD) at the autophosphorylation site Ser-916.

Prior chronic cocaine exposure in mice induces persistent alterations in cognitive function.

Chronic cocaine use has been proposed to induce long-lasting alterations in cognitive functions dependent on the prefrontal cortex, and these alterations may contribute to the development of addiction. However, the underlying cellular mechanisms remain largely unknown, in part because of the lack of suitable animal models of cocaine-induced cognitive dysfunction that are amenable to molecular manipulations. Here, we characterized the effects of repeated cocaine administration on multiple aspects of cognitive function in C57BL/6 mice.

Expression of PKC substrate proteins, GAP-43 and neurogranin, is downregulated by cAMP signaling and alterations in synaptic activity.

Growth-associated protein 43 (GAP-43) and neurogranin are protein kinase C substrate proteins that are thought to play an important role in synaptic plasticity, but little is currently known about the mechanisms that may regulate their function at the synapse. In this study, we show that long-term elevation of intracellular cAMP levels in rat primary cortical cultures results in a persistent downregulation of GAP-43 and neurogranin, most likely at the transcriptional level. This effect may be at least partially mediated by protein kinase A, but is independent of protein kinase C activation.

Orbitofrontal cortex and cognitive-motivational impairments in psychostimulant addiction: evidence from experiments in the non-human primate.

Addiction is characterized by compulsive drug use despite adverse consequences. The precise psychobiological changes that underlie the progression from casual use to loss of control over drug-seeking and drug-taking behavior are not well understood. Here we report that short-term cocaine exposure in monkeys is sufficient to produce both selective deficits in cognitive functions dependent on the orbitofrontal cortex (OFC) concurrent with enhancements in motivational processes involving limbic-striatal regions.

Recent advances in neuroproteomics.

The last few years have seen a rapid growth in the use of proteomic methods to study normal brain function. In addition, such methods have been used to analyze changes in protein expression associated with the onset and progression of neuronal disease. The field of neuroproteomics faces special challenges given the complex cellular and sub-cellular architecture of the central nervous system.

Assessment of cognitive function in the heterozygous reeler mouse.

Rationale: The heterozygous reeler mouse has been proposed as a genetic mouse model of schizophrenia based on several neuroanatomical and behavioral similarities between these mice and patients with schizophrenia. However, the effect of reelin haploinsufficiency on one of the cardinal symptoms of schizophrenia, the impairment of prefrontal-cortex-dependent cognitive function, has yet to be determined.

Objective: Here, we investigated multiple aspects of cognitive function in heterozygous reeler mice that are known to be impaired in schizophrenic patients.

Identification of multiple HLA-DR-restricted epitopes of the tumor-associated antigen CAMEL by CD4+ Th1/Th2 lymphocytes.

CD4(+) Th cells play an important role in the induction and maintenance of adequate CD8(+) T cell-mediated antitumor responses. Therefore, identification of MHC class II-restricted tumor antigenic epitopes is of major importance for the development of effective immunotherapies with synthetic peptides. CAMEL and NY-ESO-ORF2 are tumor Ags translated in an alternative open reading frame from the highly homologous LAGE-1 and NY-ESO-1 genes, respectively.