Excessive UBE3A dosage impairs retinoic acid signaling and synaptic plasticity in autism spectrum disorders.

The autism spectrum disorders (ASDs) are a collection of human neurological disorders with heterogeneous etiologies. Hyperactivity of E3 ubiquitin (Ub) ligase UBE3A, stemming from 15q11-q13 copy number variations, accounts for 1%-3% of ASD cases worldwide, but the underlying mechanisms remain incompletely characterized. Here we report that the functionality of ALDH1A2, the rate-limiting enzyme of retinoic acid (RA) synthesis, is negatively regulated by UBE3A in a ubiquitylation-dependent manner. Excessive UBE3A dosage was found to impair RA-mediated neuronal homeostatic synaptic plasticity. ASD-like symptoms were recapitulated in mice by overexpressing UBE3A in the prefrontal cortex or by administration of an ALDH1A antagonist, whereas RA supplements significantly alleviated excessive UBE3A dosage-induced ASD-like phenotypes. By identifying reduced RA signaling as an underlying mechanism in ASD phenotypes linked to UBE3A hyperactivities, our findings introduce a new vista of ASD etiology and facilitate a mode of therapeutic development against this increasingly prevalent disease.

Conditioning-strength dependent involvement of NMDA NR2B subtype receptor in the basolateral nucleus of amygdala in acquisition of auditory fear memory.

It is known that N-methyl-D-aspartate (NMDA) receptor in the basolateral nucleus of amygdala (BLA) is essential for fear memory formation. NMDA NR2B and NR2A subtype receptors exhibit difference in electrophysiological and signaling properties. However, it is unclear whether these two subtype receptors have different roles in fear memory formation. Here, we provide evidence, using pharmacological blockade and genetic interference, that NR2B is involved in acquisition of auditory fear memory in a conditioning-strength dependent way. Pre-conditioning intra-BLA infusion of the NR2B selective antagonist ifenprodil or Ro25-6981 impaired 48-h auditory fear memory (AFM) induced by five but not one CS-US pairing protocol, while similar treatment with the NR2A antagonist NVP-AAM077 disrupted memory for both protocols. Consistently, genetic over-expression of NR2B C-terminal in the BLA, which interferes with the C-terminal mediated intracellular signaling, produced a severe deficit in 48-h AFM for five but not one CS-US pairing protocol, whereas over-expression of NR2A C-terminal impaired memory for both protocols. Furthermore, pre-conditioning infusion of ifenprodil down-regulated the elevated phosphorylation level of extracellular signal-regulated kinase (ERK) induced by five CS-US pairing protocol. Thus, the involvement of BLA NR2B in AFM acquisition depends on conditioning strength.