RESEARCH HIGHLIGHTS

AUTISM Pinpointing common deficits Two mutations in the encoding deficits differ between the two accumbens (NAc) but was expressed 3 (NLGN3) — a post‑ lines. Thus, to search for an ASD- in low levels in both cell types in with training, synaptic adhesion molecule — have relevant behavioural change that the dorsal striatum. Furthermore, the motor been associated with spec‑ was common to both lines, the the injection of an adeno-associated trum disorders (ASDs). How these authors examined another ASD virus expressing Cre into striatal routines of mutations elicit behavioural changes symptom domain, namely repetitive subcompartments in Nlgn3‑cKO Nlgn3‑KO remains unknown, not least because behaviours. mice revealed that of Nlgn3 animals in the it has been difficult to ascribe The authors tested Nlgn3‑KO and specifically in the NAc enhanced rotarod task common behavioural and synaptic Nlgn3‑R451C mice in the accelerating performances on the rotarod task. deficits to these mutations in mice. rotarod task, which requires mice This suggests that D1‑MSNs in the became less Now, Rothwell, Fuccillo et al. reveal to develop and maintain repetitive NAc — which is typically associated variable than that both mutations impair striatal motor activity: the mutant mice learnt with reward-related behaviours those of wild- circuits in mice and that these the task more quickly than wild-type rather than motor function — have impairments may promote repetitive animals and managed to complete tri‑ an important role in the observed type mice behaviours, a feature of ASDs. als involving greater ‘terminal’ speeds repetitive behaviour. The two mutations linked to of rod rotation. Moreover, with train‑ Finally, the authors examined ASDs are the deletion of NLGN3 ing, the motor routines of Nlgn3‑KO the effect of NLGN3 on synaptic and the R451C , animals in the rotarod task became function in the NAc. They could which reduces NLGN3 levels. less variable than those of wild-type not detect any changes in spon‑ Nlgn3‑knockout (Nlgn3‑KO) mice mice. Together, these data suggest taneous miniature excitatory and mice harbouring the point that the Nlgn3 mutations promote the postsynaptic currents in D1‑MSNs mutation (Nlgn3‑R451C mice) development of repetitive behaviours. or D2‑MSNs in Nlgn3‑KO mice; exhibit social interaction deficits, To examine which brain areas are however, they found that the fre‑ typically found in ASDs, but these involved in generating the repetitive quency of spontaneous miniature Jennie Vallis/NPG behaviours, the authors created mice inhibitory postsynaptic currents in in which Nlgn3 could be condition‑ NAc D1‑MSNs was decreased in ally knocked out (Nlgn3‑cKO mice) Nlgn3‑KO and Nlgn3‑R451C mice. with Cre recombinase expression Moreover, the ratio of the peak and crossed these animals with mice GABA receptor-mediated current to expressing Cre in specific neuronal the peak AMPA receptor-mediated subpopulations. One brain area that current was reduced in D1‑MSNs was targeted using this approach in Nlgn3‑KO mice. Thus, the loss of was the striatum, which is known to NLGN3 seems to be associated with influence the acquisition of repetitive an alteration in the balance between and stereotyped behaviours. Indeed, synaptic excitation and inhibition in knocking out Nlgn3 expression in this cell type. striatal medium spiny projection This study reveals that ASD- (MSNs) that express D1 associated NLGN3 mutations dopamine receptors (D1‑MSNs), but promote repetitive behaviour in mice not in D2‑MSNs, recapitulated the and pinpoints a specific synaptic motor phenotypes of the Nlgn3‑KO deficit in the striatal circuitry that and Nlgn3‑R451C mice, suggesting underlies this phenotype. that the Nlgn3 mutations target Darran Yates D1‑MSN function.

Quantitative RT-PCR showed ORIGINAL RESEARCH PAPER Rothwell, P. E. that Nlgn3 mRNA was expressed at et al. Autism-associated neuroligin‑3 mutations high levels in D1‑MSNs compared commonly impair striatal circuits to boost repetitive behaviors. Cell 158, 198–212 (2014) with D2‑MSNs in the nucleus

NATURE REVIEWS | NEUROSCIENCE VOLUME 15 | AUGUST 2014

© 2014 Macmillan Publishers Limited. All rights reserved