Guanidinoacetate Methyl Transferase (GAMT) deficiency is a rare disease characterized by neurodevelopmental derangements, epilepsy, and movement disorders. The condition arises from the combined effect of postnatal brain creatine (Cr) depletion and guanidinoacetate (GAA) toxicity. Consequently, current treatment relies on Cr supplementation and metabolic management to reduce GAA accumulation by limiting its synthesis through ornithine supplementation and precursor reduction. Although effective in preventing the severe GAMT phenotype, the therapy is limited in normalizing these metabolites’ concentrations. Recently, interest has been growing in approaches aimed at restoring the mutant enzyme as the primary step toward a cure. Some of these approaches have been investigated at the preclinical level and are here summarized. Interestingly, a mouse model that replicates most of the patients’ features is now available in various labs, and the strong commitment of the Association for Creatine Deficiency has fostered the coordination and support of many of these models’ initiatives. This review introduces readers to the complexity of this ultrarare condition, describes current therapeutic approaches, provides information about the most accurate methods for an early diagnosis, and outlines the main features of the available animal models. Finally, some current preclinical investigations are described, along with some preliminary expectations of emerging data.

The brain employs distinct circuitries to encode positive and negative valence stimuli, and dysfunctions of these neuronal circuits have a key role in the etiopathogenesis of many psychiatric disorders. The Dorsal Raphè Nucleus (DRN) is involved in various behaviors and drives the emotional response to rewarding and aversive experiences. Whether specific subpopulations of neurons within the DRN encode these behaviors with different valence is still unknown. Notably, microRNA expression in the mammalian brain is characterized by tissue and neuronal specificity, suggesting that it might play a role in cell and circuit functionality. However, this specificity has not been fully exploited. Here, we demonstrate that microRNA-34a (miR-34a) is selectively expressed in a subpopulation of GABAergic neurons of the ventrolateral DRN. Moreover, we report that acute exposure to both aversive (restraint stress) and rewarding (chocolate) stimuli reduces GABA release in the DRN, an effect prevented by the inactivation of DRN miR-34a or its genetic deletion in GABAergic neurons in aversive but not rewarding conditions. Finally, miR-34a inhibition selectively reduced passive coping with severe stressors. These data support a role of miR-34a in regulating GABAergic neurotransmitter activity and behavior in a context-dependent manner and suggest that microRNAs could represent a functional signature of specific neuronal subpopulations with valence-specific activity in the brain.

Mouse models of genetic diseases are important research tools. However, the genetic background of the mouse strain can significantly influence how a genetic mutation is expressed. Studies on preclinical models of phenylketonuria (PKU), an inherited metabolic disorder, have used two strains, BTBR and C57Bl/6, created via a chemically induced point mutation in the gene encoding the enzyme phenylalanine hydroxylase (BTBR^enu2 and C57^enu2, respectively). Despite having the same levels of hyperphenylalaninemia (HPA), published results indicate differences in neural and behavioral phenotypes between the two backgrounds. To explore this difference further, the current study examines the genome-wide transcriptome of the prefrontal cortex (pFC), the brain region which is the most vulnerable to the negative effects of HPA. Regardless of the strain, the enu2 mutation upregulated the expression of several aminoacyl-tRNA synthetases and eukaryotic translation initiation factors, suggesting an essential modification in the protein translation process and supporting the downregulation of gene programs related to myelination. Accordingly, we deepened the exploration of cognitive dysfunctions in C57^enu2− mice, showing a previously unreported working memory impairment under increasing information load. These findings identify convergent pFC molecular and cognitive alterations induced by HPA across distinct genetic backgrounds, providing clinically relevant insights into mechanisms that may contribute to executive dysfunctions in PKU.