Angelman syndrome is a rare disorder severely affecting AS probands’ and their parents’ quality of life. Cognitive impairment, ataxic gait, absence of speech and occurrence of seizures are the main features of the syndrome that no therapy is available to ameliorate.
Our study reports that taurine dissolved in drinking water may restore motor deficits and learning impairment of a
Ube3am−/p+ C57BL/6J mouse when administered daily, while the same treatment has no effect on motor and cognitive behavior of a wild type
Ube3am+/p+ mouse. As the best period to obtain a rescue of behavioral deficits in the AS model seems to be the postnatal period [
24], we started the treatment in the juvenile period of life (three weeks) as soon as the pups were able to feed by themselves. During the statistical evaluation, genders were considered separately to ensure a better homogeneity in the test groups and the amelioration appeared substantially overlapping, with the exception of the Open Field test. The rescue of motor deficit demonstrated by rotarod assay appeared since the first set of tests at the 7th week suggesting a strong effect of taurine on these skills; this point is supported by the performances at total distance walked in the OF test, a measure of ataxia attenuation, with significant improvement in the female group and a trend to improvement in males. A slight decrease of female performance at the last time-point may suggest that dosage could need to be adjusted during such a long chronic treatment. Variations among sex might be due to some environmental factors, as reported by Kovacs [
30] in C57BL/6J mice. Memory and learning skills, as shown by NORT, results raised toward those of control animals, since the last two sets of evaluations, indicating the need of a longer treatment to achieve visible improvement of learning disability. Apparently, the prolonged administration of 1 g/Kg/day taurine did not reveal any toxicity [
15]. Taurine is well known to increase neurogenesis of adult neural stem cells [
18,
31] and to promote neuroprotection preventing (i) glutamate-induced excitotoxicity through modulation of intracellular calcium homeostasis [
32]; (ii) mitochondrial dysfunction by exerting an antioxidant activity; and (iii) apoptosis, by downregulating molecules that drive apoptotic events [
16,
17,
33,
34]. Potential beneficial effects of taurine in brain disorders, as Alzheimer’s [
15], schizophrenia [
16] and neurodevelopment disorder as fragile X syndrome have been reported [
23,
35]. Out of the multiple functions of taurine in the mammalian body, a key one is modulation of GABA neurotransmission. A defect in tonic GABAergic inhibition shared by fragile X and Angelman syndrome has been suggested to contribute to expression of the disease phenotype [
11], raising the option to use agonists of GABA receptors as a winning strategy to restore the decrease in GABAergic inhibition [
12]. Interestingly, taurine is considered an endogenous ligand of GABA extrasynaptic receptors [
36]. Our study first investigates and proves the beneficial effect of taurine administration in ameliorating AS features of
Ube3am−/p+ mice supporting the concept that GABA receptor agonist strategy may be effective. Neurological deficits in Angelman syndrome have been associated with an increased level of Arc (activity-regulated cytoskeletal-associated protein) which has the consequence to impair the Long Term Potentiation (LTP) and alter the recruitment of the scaffold protein PSD-95 (PostSynaptic Density-95), a marker of synaptic dysfunction [
26]. Furthermore, UBE3A loss enhances the ERK1/2 (Extracellular Signal-Regulated Kinase) signaling pathway [
27], which plays a relevant role in several biological processes including synaptic activity with a stimulatory effect on the proliferation of neural stem cells rather than in the following differentiation [
37]. Our biochemical analyses confirmed the activation of ERK1/2 pathway and a major expression of the synaptic protein PSD-95 as a consequence of UBE3A deficit in the
Ube3am−/p+ mice and demonstrated that taurine may restore a normal activity of both markers. We could speculate that the therapeutic effect of taurine in the AS model might be achieved for a restoration of both extrasynaptic GABAergic activity, with taurine being an agonist of the GABA receptor, and synaptic pathway as shown by our data on ERK1/2 activity and PSD-95. The dosage of taurine in the whole brain remained the same in treated and untreated animals while in serum we observed an a 4–6 folds increase. This finding is not completely unexpected considering the occurrence of active transport of taurine in brain, mediated by a specific saturable TauT transporter [
16]. Sved D.W. et al. [
29] investigated the absorption and tissue distribution when taurine was orally administered to rats using
14C taurine and observed that some tissues as brain, heart, muscles showed a slow increase of
14C taurine during the first 24 h and a small decrease during the following 168 h without changing the total amount of brain taurine. The authors supposed that after taurine passed the blood–brain barrier (BBB), it became part of an endogenous pool regulated by a Na
+/Cl
− saturable transport within brain cells, which makes the taurine concentration in brain not proportional to plasma concentration. The same behavior has been described in muscles where despite a very high dosage of taurine being administered to a Duchenne dystrophy model, high performance liquid chromatography (HPLC) quantification revealed a higher concentration only in serum and in liver [
38], while muscles maintained a constant concentration.