mTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity.

Postmortem studies have revealed increased density of excitatory synapses in the brains of individuals with autism spectrum disorder (ASD), with a putative link to aberrant mTOR-dependent synaptic pruning. ASD is also characterized by atypical macroscale functional connectivity as measured with resting-state fMRI (rsfMRI). These observations raise the question of whether excess of synapses causes aberrant functional connectivity in ASD. Using rsfMRI, electrophysiology and in silico modelling in Tsc2 haploinsufficient mice, we show that mTOR-dependent increased spine density is associated with ASD -like stereotypies and cortico-striatal hyperconnectivity. These deficits are completely rescued by pharmacological inhibition of mTOR. Notably, we further demonstrate that children with idiopathic ASD exhibit analogous cortical-striatal hyperconnectivity, and document that this connectivity fingerprint is enriched for ASD-dysregulated genes interacting with mTOR or Tsc2. Finally, we show that the identified transcriptomic signature is predominantly expressed in a subset of children with autism, thereby defining a segregable autism subtype. Our findings causally link mTOR-related synaptic pathology to large-scale network aberrations, revealing a unifying multi-scale framework that mechanistically reconciles developmental synaptopathy and functional hyperconnectivity in autism.

Behavioral flexibility in a mouse model for obsessive-compulsive disorder: Impaired Pavlovian reversal learning in SAPAP3 mutants.

Obsessive-compulsive disorder (OCD) is characterized by obsessive thinking, compulsive behavior and anxiety, and is often accompanied by cognitive deficits. The neuropathology of OCD involves dysregulation of cortical-striatal circuits. Similar to OCD patients, SAPAP3 knockout mice 3 (SAPAP3-/- ) exhibit compulsive behavior (grooming), anxiety and dysregulated cortical-striatal function. However, it is unknown whether SAPAP3-/- display cognitive deficits and how these different behavioral traits relate to one another. SAPAP3-/- and wild-type (WT) littermates were trained in a Pavlovian conditioning task pairing visual cues with the delivery of sucrose solution. After mice learned to discriminate between a reward-predicting conditioned stimulus (CS+) and a non-reward stimulus (CS-), contingencies were reversed (CS+ became CS- and vice versa). Additionally, we assessed grooming, anxiety and general activity. SAPAP3-/- acquired Pavlovian approach behavior similarly to WT, albeit less vigorously and with a different strategy. However, unlike WT, SAPAP3-/- were unable to adapt their behavior after contingency reversal, exemplified by a lack of re-establishing CS+ approach behavior (sign tracking). Surprisingly, such behavioral inflexibility, decreased vigor, compulsive grooming and anxiety were unrelated. This study shows that SAPAP3-/- are capable of Pavlovian learning, but lack flexibility to adapt associated conditioned approach behavior. Thus, SAPAP3-/- not only display compulsive-like behavior and anxiety, but also cognitive deficits, confirming and extending the validity of SAPAP3-/- as a suitable model for the study of OCD. The observation that compulsive-like behavior, anxiety and behavioral inflexibility were unrelated suggests a non-causal relationship between these traits and may be of clinical relevance for the treatment of OCD.