<p>Tumor cell plasticity in novel microenvironments is central to the integration and subsequent growth of metastatic cells. However, the functional consequences of tumor cell integration with central neurons remains understudied. Here, we address this question using small cell lung cancer (SCLC), which has an extraordinary propensity to metastasize to the brain in humans. Transcriptomic and electrophysiological analysis of SCLC cells in neuronal microenvironments reveal a heterogeneous population of synapse-forming SCLC cells with neurons. While a proportion of neuron-SCLC synapses are blocked by AMPA receptor antagonists, we also find a sensitivity of these synapses to GABA_A receptor inhibition. The functional integration of SCLC with central neurons induced multiplicative synaptic upscaling between neurons and dysregulated neuronal excitability. Aberrant excitation in human neurons with SCLC was sustained by synaptic NMDA receptor activation and can be reduced by the FDA approved NMDA receptor blocker memantine. These findings reveal strategies to normalize tumor-induced exacerbation of aberrant neuronal activity.</p>