In 1965, Dr. Harry Angelman, a British pediatrician, described a neuro-genetic disorder characterized by intellectual and developmental deficits, minimal verbal communication, disturbed sleep, seizures, jerky movements (especially hand-flapping), frequent laughter or smiling, and, usually, a happy disposition. The disorder had been known by several names (a few of them pejorative), but, because Angelman first described it, it is now more acceptably known as Angelman syndrome (AS). Some AS symptoms are very much like Parkinson’s, which is commonly treated with L-DOPA, a precursor of the neurotransmitter dopamine. Because L-DOPA significantly ameliorated tremors and rigidity (two AS phenotypes) in a case study of two AS patients (Harbord et al. 2001), it moved on to clinical trials as a potential AS treatment (NIH 2012). However, L-DOPA’s mechanism of action in ameliorating AS is not known. To define it, a group of researchers led by Drs. C.J. Malanga and Benjamin Philpot, from the University of North Carolina, Chapel Hill, began characterizing dopamine-signaling pathways in the AS mouse model B6.129S7-Ube3atm1Alb/J (Ube3am–/p+, 016590). They found that dopamine signaling in this mouse is not only abnormal but is distinctly so in different brain regions (Riday et al. 2012). Their findings indicate that dopamine-signaling pathways are very complex and must be better understood before dopamine-based therapies are used to treat AS.
Angelman syndrome is a rare disease, with an estimated prevalence of one in 10,000 to 20,000 births. It is characterized by a deleted or defective maternally inherited ubiquitin ligase E3A (UBE3A) allele on chromosome 15. The paternal copy of the allele, which may be normal, is imprinted – silenced in the brain. This is a classic example of genomic imprinting. In fruit flies, UBE3A regulates the synthesis of the neurotransmitter dopamine (Ferdousy et al. 2011), and it is thought to have a similar/related function in other species. The Malanga/ Philpot team suspected that abnormal dopamine signaling in “dopaminergic pathways” – neural pathways that transmit dopamine from one brain region to another – cause some AS phenotypes. They focused on two dopaminergic pathways that are likely important but little understood in AS – the mesolimbic pathway, thought to play a role in reward/pleasure, and the nigrostriatal pathway, thought to play a role in movement.
Ube3am–/p+ mice are deficient for the maternally inherited Ube3a allele. They produce 64-73% less UBEA3 protein than wild-type C57BL/6J (B6J, 000664) mice in heart, liver, and kidney tissues, and no detectable amounts in hippocampal neurons and Purkinje cells. They exhibit low motor coordination, tremor, ataxia, impaired long-term potentiation, defective neocortical plasticity, fluid consumption defects (abnormal licking behavior), and context-dependent learning abnormalities. Depending on the background strain, they may be abnormally susceptible to handling-induced tonic clonic seizures.
In one of the tests to determine if UBE3A deficiency alters AS-relevant dopaminergic pathways, the Malanga/Philpot team trained some Ube3am–/p+ mice and C57BL/6J (B6J, 000664) controls to spin a wheel that stimulates electrodes implanted in the medial forebrain bundle, one of the major connections between parts of the brain that perceive reward or pleasure. They found that Ube3am–/p+ mice exhibit a lower stimulation threshold (need less electrical charge) than do B6J controls to elicit a pleasure response, and that Ube3am–/p+ mice work longer than B6J controls to maintain their stimulation. However, drugs that increase extracellular dopamine has less effect on the speed and intensity of the pleasure response induced in Ube3am–/p+ than it does in B6J mice. One of the drugs, cocaine, also increases the locomotor activity of Ube3am–/p+ mice less than it does in B6J controls. Unexpectedly, Ube3am–/p+ mice release excess dopamine in the mesolimbic pathway but an abnormally low amount in the nigrostriatal pathway.
In summary, the Malanga/Philpot team found that Ube3am–/p+ mice do exhibit abnormal dopamine signaling – they release abnormally high amounts of dopamine in the pleasure/reward-regulating mesolimbic dopaminergic pathway and abnormally low amounts of dopamine in the movement-regulating nigrostriatal dopaminergic pathway. Additionally, the behavior of these mice is markedly less sensitive to drugs that enhance extracellular dopamine availability. The abnormal signaling doesn’t appear to be due to a deficiency of dopaminergic neurons, impaired dopamine synthesis, or differences in dopamine clearance: these are all comparable in Ube3am–/p+ mice and B6J controls. These findings demonstrate that dopaminergic pathways are very complex and brain-region specific. To maximize the efficacy of dopamine-based therapies for AS, these pathways need to be more clearly understood.