Setd1a, a lysine-methyltransferase, is a key enzyme involved in histone H3 lysine 4 (H3K4) methylation. This methylation is crucial for chromatin-mediated regulation of gene expression, participating in various cellular processes such as cell cycle control, differentiation, and DNA damage repair [2,4]. It is also associated with multiple biological pathways and has overall significance in development and disease [3]. Genetic models, especially mouse models, have been valuable for studying its functions.

In Setd1a-deficient mice, which carry a heterozygous loss-of-function mutation, there are alterations in axonal branching and cortical synaptic dynamics, along with working memory deficits, recapitulating schizophrenia-related phenotypes [1]. Reinstating Setd1a expression in adulthood can rescue these cognitive deficits. Moreover, LSD1, identified as a major counteracting demethylase for Setd1a, and its pharmacological antagonism can fully rescue the behavioral and morphological deficits in these mice [1]. In Drosophila, the SETD1A orthologue is required in post-mitotic neurons of the fly brain for normal memory, suggesting its role in post-development neuronal function [2].

In conclusion, Setd1a is essential for normal neuronal function, as demonstrated through model-based research. The Setd1a-deficient mouse models have significantly contributed to understanding its role in schizophrenia-related phenotypes, providing insights into how Setd1a mutations may predispose to schizophrenia and pointing to potential therapeutic interventions [1].