Neuronal splice site selection events control multiple brain functions. Here, we report their involvement in stress-modulated hippocampal plasticity and errors of cognitive performance. Under stress, alternative splicing changes priority from synaptic acetylcholinesterase (AChE-S) to the normally rare, soluble and monomeric AChE-R variant, which facilitates hippocampal long-term potentiation (LTP) and intensifies fear-motivated learning. To explore the adaptive value of changes in AChE splicing, we compared hippocampal plasticity and errors of executive function in TgS and TgR transgenic mice overexpressing AChE-S or AChE-R, respectively. Hippocampal slices from TgS and TgR mice presented delayed and facilitated transition to LTP maintenance, respectively, compared with strain-matched FVB/N controls. TgS slices further showed failed recruitment of both the α-amino-3-hydroxy-5-methylisoxazole-4-propionate and N-methyl-d-aspartate components of LTP, refractory response to cholinergic enhancement and suppressed protein kinase C (PKC) levels. Stable LTP could, however, be rescued by phorbol ester priming, attributing the TgS deficits to disrupted signal transduction. In serial maze tests, TgS mice displayed more errors of conflict and executive function than did FVB/N controls, reflecting maladaptive performance under chronic AChE-S overexpression. In contrast, TgR mice displayed enhanced serial maze performance, suggesting that chronic AChE-R overexpression facilitates adaptive reactions. Our findings are compatible with the notion that changes in the alternative splicing of AChE pre-mRNA and consequent alterations in PKC signalling are causally involved in modulating hippocampal plasticity and cognitive performance.