Autism-Associated Neuroligin-3 Mutations Commonly Impair Striatal Circuits to Boost Repetitive Behaviors

Abstract

Summary In humans, neuroligin-3 mutations are associated with autism, while in mice the corresponding mutations produce robust synaptic and behavioral changes. However, different neuroligin-3 mutations cause largely distinct phenotypes in mice, and no causal relationship links a specific synaptic dysfunction to a behavioral change. Using rotarod motor learning as a proxy for acquired repetitive behaviors in mice, we found that different neuroligin-3 mutations uniformly enhanced formation of repetitive motor routines. Surprisingly, neuroligin-3 mutations caused this phenotype not via changes in the cerebellum or dorsal striatum, but via a selective synaptic impairment in the nucleus accumbens/ventral striatum. Here, neuroligin-3 mutations increased rotarod learning by specifically impeding synaptic inhibition onto D1-dopamine receptor-expressing but not D2-dopamine receptor-expressing medium spiny neurons. Our data thus suggest that different autism-associated neuroligin-3 mutations cause a common increase in acquired repetitive behaviors by impairing a specific striatal synapse, and thereby provide a plausible circuit substrate for autism pathophysiology.

Deletion of Fmr1 results in sex‐specific changes in behavior

“…However, one previous investigation has indicated that female wild‐type mice show improved performance on the accelerating rotarod task across multiple strains (McFadyen, Kusek, Bolivar, & Flaherty, 2003). Phenotypic analyses of another monogenic model of ASD, the neuroligin‐3 ( NLGN‐3 ) knockout mouse, have noted enhanced motor learning in the rotarod task, similar to our Fmr1 KO females (Rothwell Patrick et al., 2014). The authors from Rothwell Patrick et al., 2014 suggested that several components of the motor routine become less variable with training such that latency to falling in this task could be considered an indicator of acquired repetitive behavior.…”

“…Phenotypic analyses of another monogenic model of ASD, the neuroligin‐3 ( NLGN‐3 ) knockout mouse, have noted enhanced motor learning in the rotarod task, similar to our Fmr1 KO females (Rothwell Patrick et al., 2014). The authors from Rothwell Patrick et al., 2014 suggested that several components of the motor routine become less variable with training such that latency to falling in this task could be considered an indicator of acquired repetitive behavior. In accordance with these results, we suggest that perhaps female Fmr1 KOs display increases in acquired repetitive behavior in this task.…”

“…More recently, it has also been proposed that changes in repetitive behavior are also indicative of acquired repetitive behavior (Rothwell Patrick et al., 2014). The apparatus consisted of a rotating rod that accelerated from 5 to 40 RPM over a 5‐minute trial (Series 8 Rotorod; IITC Inc., Woodland Hills, CA, USA).…”

Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons

“…S4 D-G), all striatal-dependent symptoms observed in Fmr1 −/y mice (25)(26)(27)(28). Stereotypic behavior is indicated by an enhanced learning on the accelerating rotarod (24), mainly at late stages of learning (Fig. 4E).…”

“…Remarkably, these alterations are similar to the one observed in FXS mouse model (6). Approximately 50% of patients with FXS also carry an autism diagnosis, and recent research on hallmark autistic symptoms point toward striatal dysfunction (23,24). To test whether Dgkκ loss of function could contribute to FXS phenotype, AAV9-delivered shRNA-Dgkκ was injected bilaterally into the striatum of wild-type mice.…”