A large-scale genetic association study in adolescents associated
NPTN with cortical thickness and intellectual ability
[57], suggesting a role for NPTN in cognition and learning and memory. Furthermore,
NPTN variants were recently related to creativity
[78].
In recent years, we have addressed the role of neuroplastin in learning and memory using several mouse mutants. When neuroplastin was missing from only glutamatergic neurons, achieved using an
Emx1-promoter driven Cre-recombinase, associative learning was slightly improved. However, the continuity of task execution was affected, suggesting altered striatum-dependent decision making
[79]. The complete loss of neuroplastin expression resulted in a complex phenotype, which included the inability to learn associative tasks
[51]. The comparison of
Nptn-ablation in glutamatergic versus all neurons suggests a particular role of neuroplastin, expressed by gabaergic interneurons for associative learning. When neuroplastin expression was specifically ablated in all types of neurons after a normal development, again, the anterograde memory was not formed for associative tasks
[51]. Furthermore, when the associative tasks were first acquired perfectly before neuroplastin ablation, the induced loss of neuroplastin resulted in specific retrograde amnesia for these associative memories but not for spatial memories
[51]. Interestingly, the β-blocker propranolol has retrograde amnestic side effects. Therefore, propranolol is applied as off-label use for the treatment of intrusive thoughts associated with post-traumatic stress disorder (PTSD) (for a review, see:
[80]). Propranolol also acts as an inhibitor of the PMCAs
[81], and thus its amnestic effects may be related to PMCA inhibition. In vivo, the absence of neuroplastin leads to dramatically reduced PMCA levels
[79][51], suggesting that the neuroplastin-PMCA assembly may be critical for associative learning and memory. If this hypothesis can be substantiated, it may provide an opportunity to address PTSD and other psychiatric conditions involving intrusive thoughts.