Cerebral cortex tissue was obtained at autopsy from neonatal Poll Hereford calves with clinically confirmed maple syrup urine disease (MSUD), neonatal Holstein‐Friesian calves with clinically confirmed citrullinemia, and matched controls. From this, synaptosomes were prepared for studies of neurotransmitter amino acid uptake and stimulus‐induced release, and synaptic plasma membranes were obtained for studies of associated postsynaptic receptor binding sites. As well as having abnormal brain tissue concentrations of the pathognomic plasma amino acids (markedly increased levels of the branched‐chain compounds valine, isoleucine, and leucine in MSUD; marked elevation of citrulline levels in citrullinemia), both groups of diseased animals showed reduced, brain tissue concentrations of each of the transmitter amino acids glutamate, aspartate, and γ‐aminobutyric acid (GABA). Nontransmitter amino acids were generally unaffected in either disease. Citrullinemic calves showed a marked increase in brain glutamine concentration; in calves with MSUD, the glutamine concentration was raised, but to a much lesser extent. The Na+‐dependent synaptosomal uptake of both glutamate and GABA was markedly reduced (to <50% of control values in both cases) in citrullinemic calves but was unaltered in calves with MSUD. Whereas synaptosomes from normal calves showed the expected stimulus‐coupled release of transmitter amino acids, especially glutamate and aspartate, and no response to stimulus of nontransmitter amino acids, there was no increased release of transmitter amino acids in response to depolarization in synaptosomes from citrullinemic calves. This was in part because the extracellular concentrations of these compounds in citrullinemic control incubations were already high, especially for glutamate—basal extrasynaptosomal glutamate concentrations were some 20‐fold higher than those found with synaptosomes from normal calves—so that further stimuluscoupled enhancement was not possible. Calves with MSUD showed a marked loss in number of postsynaptic GABAA receptors (to ∼‐50% of normal values), as assessed from [³H]diazepam binding studies. In contrast, there was no loss of this receptor site in citrullinemic calves. Calves with citrullinemia showed a marked reduction in the affinity and density of postsynaptic glutamate N‐methyl‐D‐aspartate receptors as assessed from [³H]MK‐801 binding studies. In contrast, calves with MSUD showed no change in this parameter. These studies show that two major recessively inherited diseases of cattle have similar, but distinct, neurochemical pathologies. The MSUD encephalopathy appears to be driven by a diminution of GABA‐mediated inhibitory neurotransmission, whereas in citrullinemia the equivalent proconvulsive state may be driven by a relative increase in glutamate‐mediated excitatory activity.