Reversing Autism in Mice: Autism comprises a heterogeneous group of neurodevelopmental disorders characterized by defects in communication and social inter action. A group of nonsyndromic forms of autism is associated with mutations in the neuroligin genes, which encode postsynaptic adhesion molecules. Using a reversible knockout approach, Baudouin et al. (p. 128 , published online 13 September) investigated the in vivo functions of neuroligin-3 in the mouse cerebellum. Mutant mice showed a major defect in metabotropic glutamate receptor–dependent, long-term potentiation; disrupted heterosynaptic competition; and ectopic synapse formation in vivo. These synaptic defects could be rescued by reactivation of the neuroligin gene in the adult.

Despite the pivotal functions of the NMDA receptor (NMDAR) for neural circuit development and synaptic plasticity, the molecular mechanisms underlying the dynamics of NMDAR trafficking are poorly understood. The cell adhesion molecule neuroligin-1 (NL1) modifies NMDAR-dependent synaptic transmission and synaptic plasticity, but it is unclear whether NL1 controls synaptic accumulation or function of the receptors. Here, we provide evidence that NL1 regulates the abundance of NMDARs at postsynaptic sites. This function relies on extracellular, NL1 isoform-specific sequences that facilitate biochemical interactions between NL1 and the NMDAR GluN1 subunit. Our work uncovers NL1 isoform-specific cis -interactions with ionotropic glutamate receptors as a key mechanism for controlling synaptic properties.

In most mammals, including humans, the postnatal acquisition of normal social and nonsocial behavior critically depends on interactions with peers. Here we explore the possibility that mixed-group housing of mice carrying a deletion ofNlgn3, a gene associated with autism spectrum disorders, and their wild-type littermates induces changes in each other’s behavior. We have found that, when raised together, maleNlgn3knockout mice and their wild-type littermates displayed deficits in sociability. Moreover, social submission in adult maleNlgn3knockout mice correlated with an increase in their anxiety. Re-expression ofNlgn3in parvalbumin-expressing cells in transgenic animals rescued their social behavior and alleviated the phenotype of their wild-type littermates, further indicating that the social behavior ofNlgn3knockout mice has a direct and measurable impact on wild-type animals’ behavior. Finally, we showed that, unlike male mice, female mice lackingNlgn3were insensitive to their peers’ behavior but modified the social behavior of their littermates. Altogether, our findings show that the environment is a critical factor in the development of behavioral phenotypes in transgenic and wild-type mice. In addition, these results reveal that the social environment has a sexually dimorphic effect on the behavior of mice lackingNlgn3, being more influential in males than females.

A novel idea is emergxsing that a large molecular repertoire is common to the nervous and immune systems, which might reflect the existence of novel neuronal functions for immune molecules in the brain. Here, we show that the transmembrane adaptor signaling protein CD3ζ, first described in the immune system, has a previously uncharacterized role in regulating neuronal development. Biochemical and immunohistochemical analyses of the rat brain and cultured neurons showed that CD3ζ is mainly expressed in neurons. Distribution of CD3ζ in developing cultured hippocampal neurons, as determined by immunofluorescence, indicates that CD3ζ is preferentially associated with the somatodendritic compartment as soon as the dendrites initiate their differentiation. At this stage, CD3ζ was selectively concentrated at dendritic filopodia and growth cones, actin-rich structures involved in neurite growth and patterning. siRNA-mediated knockdown of CD3ζ in cultured neurons or overexpression of a loss-of-function CD3ζ mutant lacking the tyrosine phosphorylation sites in the immunoreceptor tyrosine-based activation motifs (ITAMs) increased dendritic arborization. Conversely, activation of endogenous CD3ζ by a CD3ζ antibody reduced the size of the dendritic arbor. Altogether, our findings reveal a novel role for CD3ζ in the nervous system, suggesting its contribution to dendrite development through ITAM-based mechanisms.

Deletions in the 15q11.2 region of the human genome are associated with neurobehavioral deficits, and motor development delay, as well as in some cases, symptoms of autism or schizophrenia. The cytoplasmic FMRP-interacting protein 1 (CYFIP1) is one of the four genes contained within this locus and has been associated with other genetic forms of autism spectrum disorders (ASD). In mice, Cyfip1 haploinsufficiency leads to alteration of dendritic spine morphology and defects in synaptic plasticity, two pathophysiological hallmarks of mouse models of ASD. At the behavioral level, however, Cyfip1 haploinsufficiency leads to minor phenotypes, not directly relevant for 15q11.2 deletion syndrome or ASD. A fundamental question is whether neuronal phenotypes caused by the mutation of Cyfip1 are relevant for the human condition. Here, we describe a synaptic cluster of ASD-associated proteins centered on CYFIP1 and the adhesion protein Neuroligin-3. Cyfip1 haploinsufficiency in mice led to decreased dendritic spine density and stability associated with social behavior and motor learning phenotypes. Behavioral training early in development resulted in alleviating the motor learning deficits caused by Cyfip1 haploinsufficiency. Altogether, these data provide new insight into the neuronal and behavioral phenotypes caused by Cyfip1 mutation and proof-of-concept for the development of a behavioral therapy to treat phenotypes associated with 15q11.2 syndromes and ASD.