This study shows that mice with inborn hyperammonemia (LGS‐KO) display lower sensitivity of corticostriatal neurotransmission to histamine (significantly lower DDhist) without any significant changes of histamine‐induced corticostriatal plasticity (LLDhist) and in the striatal expression of genes relevant for synaptic plasticity, except for a slight reduction in H2R expression, which may impact DDhist. The gene discussed is HRH2; the disease is Hyperammonemia.