The Astrocyte-Neuron Lactate Shuttle model posits that lactate is transferred from astrocytes to neurons to fulfill energetic needs and act as a signal that regulates gene expression related to neuroprotection, neuronal excitability, synaptic plasticity, and memory. N6-methyladenosine (m6A), the most abundant internal modification of RNA, influences mRNA stability, translation, transport, localization, and alternative splicing. This dynamic epitranscriptomic mark is prevalent in the nervous system, impacting various processes, including those affected by lactate, such as neurogenesis, synaptic plasticity, learning and memory, and cognition. Moreover, m6A modifications are dysregulated in neurodegenerative disorders, which often exhibit altered energy metabolism. The potential interaction between lactate signaling and the m6A epitranscriptomic landscape, however, remains unexplored.Here, immunoprecipitation of m6A mRNA followed by deep sequencing (MeRIP-Seq) revealed that exposing primary cultured cortical neurons to exogenous lactate for 6 hours modified the m6A methylation profile. We identified 319 transcripts differentially methylated; 240 gained m6A marks while 79 lost the methylation. Overrepresentation and gene set enrichment analyses found that differentially expressed RNAs with altered m6A marks in response to lactate were significantly associated with genes critical for neurogenesis, neuronal development, trophic support, neuronal excitability, and synapse plasticity and organization. Current efforts aim to determine the effects of lactate-induced changes in m6A RNA marks on protein levels and their potential role in modulating synaptic plasticity.Our findings uncover a new regulatory layer by which lactate may influence synaptic plasticity and higher-order brain functions through modulation of the epitranscriptome, contributing to the broad actions of astrocytes on neuronal function.