Cognitive flexibility and long-term depression (LTD) are impaired following β-catenin stabilization in vivo

Abstract

Significance Complex learning and memory are believed to require the weakening or elimination of synapses in the brain, a process mediated by adhesion molecules, which maintain synapse strength and stability. In the present study, we examine in vivo the effects of stabilization of β-catenin, an intracellular protein that is a component of the cadherin adhesion complex. We find that stabilization of β-catenin in the brain prevents normal activity-dependent downscaling of synapse strength, resulting in a striking impairment in cognitive flexibility. These results demonstrate that β-catenin plays an important role in learning and memory and that aberrant increases in synaptic adhesion can have detrimental effects on cognitive function.

Deletion of CTNNB1 in inhibitory circuitry contributes to autism-associated behavioral defects

“…Interestingly, the results that CTNNB1 PV-KO mice failed to recognize the second novel object in the NOR test and the second stranger mouse in the SIT, as well as to extinguish fear memory, indicate a deficit in the ability to acquire new information and to replace previous memories. This cognitive inflexibility is seen in autistic patients (63,64) and is consistent with phenotypes of mice expressing stabilized CTNNB1 during reversal learning tasks (24). Intriguingly, our mouse model showed enhanced spatial memory, which is consistent with other autistic mouse models with defect in Shank1 (49) and neuroligin-3 (45), but not with others (46,65).…”

“…Consistently, mutations of CTNNB1 were identified in patients with ASD (6) and ID (9). Previous studies did not identify autistic-like behaviors, including anxiety, social interaction deficit and repetitive behaviors, on mouse models with CTNNB1 KO in excitatory neurons (22,24,25,60). Our study reveals that CTNNB1 KO in PV interneurons leads to cognitive and autistic-like phenotypes, suggesting that CTNNB1 defects in PV interneurons are responsible for the core symptoms of autistic-like behaviors.…”

The sodium-activated potassium channel Slack is required for optimal cognitive flexibility in mice

“…The cellular mechanisms affected by the lack of Slack during reversal learning and cognitive flexibility are far from understood. In general, impaired reversal learning has been found in mice with defective long-term depression (LTD) (Nicholls et al 2008;Kim et al 2011;Mills et al 2014), whereas other studies point to an predominant role of depotentiation of previously strengthened synapses (after long-term potentiation (LTP) induction) for normal spatial reversal learning and memory extinction (Serrano et al 2008;Zhang et al 2011;Zhang and Wang 2013). Moreover, there is also some evidence that the balance between LTP and synaptic depotentiation is essential for behavioral flexibility (Errico et al 2008;Zhang and Wang 2013).…”

Cadherins and catenins in dendrite and synapse morphogenesis

“…Consistent with the key roles of these proteins in morphological and functional alterations associated with higher level behavior, mouse models of these proteins have aberrations in learning and other forms of higher level behavior including cognitive dysfunction, 74 memory consolidation and cognitive flexibility. 75 …”