Loss of UBE3A from TH-expressing neurons suppresses GABA co-release and enhances VTA-NAc optical self-stimulation

Motivated reward-seeking behaviours are governed by dopaminergic ventral tegmental area projections to the nucleus accumbens. In addition to dopamine, these mesoaccumbal terminals co-release other neurotransmitters including glutamate and GABA, whose roles in regulating motivated behaviours are currently being investigated. Here we demonstrate that loss of the E3-ubiquitin ligase, UBE3A, from tyrosine hydroxylase-expressing neurons impairs mesoaccumbal, non-canonical GABA co-release and enhances reward-seeking behaviour measured by optical self-stimulation

Effects of the neuroactive steroid allopregnanolone on intracranial self-stimulation in C57BL/6J Mice

RATIONALE: The neuroactive steroid (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP, allopregnanolone) has effects on reward-related behaviors in mice and rats that suggest that it may activate brain reward circuits. Intracranial self-stimulation (ICSS) is an operant behavioral technique that detects changes in the sensitivity of brain reward circuitry following drug administration. OBJECTIVE: to examine the effects of the neuroactive steroid allopregnanolone on ICSS and to compare these effects to those of cocaine. METHODS: Male C57BL/6J mice implanted with stimulating electrodes implanted into the medial forebrain bundle responded for reinforcement by electrical stimulation (brain stimulation reward, BSR). Mice received cocaine (n=11, 3.0 – 30.0 mg/kg, i.p.) or the neuroactive steroid allopregnanolone (n=11, 3.0 – 17.0 mg/kg, i.p.). BSR thresholds (θ(0)) and maximum operant response rates (MAX) after drug treatments were compared to those after vehicle injections. RESULTS: Cocaine and allopregnanolone dose dependently lowered BSR thresholds relative to vehicle injections. Cocaine was maximally effective (80 % reduction) in the second 15 minutes following the 30 mg/kg dose, while allopregnanolone was maximally effective (30% reduction) 15-45 minutes after the 17 mg/kg dose. Neither drug had significant effects on MAX response rates. CONCLUSIONS: The effects of allopregnanolone on BSR thresholds are consistent with the previously reported effects of benzodiazepines and alcohol suggesting that positive modulation of GABA(A) receptors can facilitate reward-related behaviors in C57BL/6J mice

UBE3A reinstatement as a disease-modifying therapy for Angelman syndrome

Half a century ago, Harry Angelman reported three patients with overlapping clinical features, now well known as Angelman syndrome. Angelman syndrome is caused by mutations affecting the maternally inherited UBE3A gene, which encodes an E3-ubiquitin ligase that is critical for typical postnatal brain development. Emerging evidence indicates that UBE3A plays a particularly important role in the nucleus. However, the critical substrates that are controlled by UBE3A remain elusive, which hinders the search for effective treatments. Moreover, given the multitude of signalling mechanisms that are derailed, it is unlikely that targeting a single pathway is going to be very effective. Therefore, expectations are very high for approaches that aim to restore UBE3A protein levels. A particular promising strategy is an antisense oligonucleotide approach, which activates the silenced paternal UBE3A gene. When successful, such treatments potentially offer a disease-modifying therapy for Angelman syndrome and several other neurodevelopmental disorders

Angelman Syndrome

In this review we summarize the clinical and genetic aspects of Angelman syndrome (AS), its molecular and cellular underpinnings, and current treatment strategies. AS is a neurodevelopmental disorder characterized by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, and frequent seizures. AS is caused by disruption of the maternally expressed and paternally imprinted UBE3A, which encodes an E3 ubiquitin ligase. Four mechanisms that render the maternally inherited UBE3A nonfunctional are recognized, the most common of which is deletion of the maternal chromosomal region 15q11-q13. Remarkably, duplication of the same chromosomal region is one of the few characterized persistent genetic abnormalities associated with autistic spectrum disorder, occurring in >1–2 % of all cases of autism spectrum disorder. While the overall morphology of the brain and connectivity of neural projections appear largely normal in AS mouse models, major functional defects are detected at the level of context-dependent learning, as well as impaired maturation of hippocampal and neocortical circuits. While these findings demonstrate a crucial role for ubiquitin protein ligase E3A in synaptic development, the mechanisms by which deficiency of ubiquitin protein ligase E3A leads to AS pathophysiology in humans remain poorly understood. However, recent efforts have shown promise in restoring functions disrupted in AS mice, renewing hope that an effective treatment strategy can be found. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13311-015-0361-y) contains supplementary material, which is available to authorized users

Dopamine D2/3 receptor antagonism reduces activity-based anorexia

Anorexia nervosa (AN) is an eating disorder characterized by severe hypophagia and weight loss, and an intense fear of weight gain. Activity-based anorexia (ABA) refers to the weight loss, hypophagia and paradoxical hyperactivity that develops in rodents exposed to running wheels and restricted food access, and provides a model for aspects of AN. The atypical antipsychotic olanzapine was recently shown to reduce both AN symptoms and ABA. We examined which component of the complex pharmacological profile of olanzapine reduces ABA. Mice received 5-HT(2A/2C), 5-HT(3), dopamine D(1)-like, D(2), D(3) or D(2/3) antagonist treatment, and were assessed for food intake, body weight, wheel running and survival in ABA. D(2/3) receptor antagonists eticlopride and amisulpride reduced weight loss and hypophagia, and increased survival during ABA. Furthermore, amisulpride produced larger reductions in weight loss and hypophagia than olanzapine. Treatment with either D(3) receptor antagonist SB277011A or D(2) receptor antagonist L-741,626 also increased survival. All the other treatments either had no effect or worsened ABA. Overall, selective antagonism of D(2) and/or D(3) receptors robustly reduces ABA. Studies investigating the mechanisms by which D(2) and/or D(3) receptors regulate ABA, and the efficacy for D(2/3) and/or D(3) antagonists to treat AN, are warranted