Pathway-specific dopaminergic deficits in a mouse model of Angelman syndrome

Abstract

Angelman syndrome (AS) is a neurodevelopmental disorder caused by maternal deletions or mutations of the ubiquitin ligase E3A (UBE3A) allele and characterized by minimal verbal communication, seizures, and disorders of voluntary movement. Previous studies have suggested that abnormal dopamine neurotransmission may underlie some of these deficits, but no effective treatment currently exists for the core features of AS. A clinical trial of levodopa (l-DOPA) in AS is ongoing, although the underlying rationale for this treatment strategy has not yet been thoroughly examined in preclinical models. We found that AS model mice lacking maternal Ube3a (Ube3a m-/p+ mice) exhibit behavioral deficits that correlated with abnormal dopamine signaling. These deficits were not due to loss of dopaminergic neurons or impaired dopamine synthesis. Unexpectedly, Ube3a m-/p+ mice exhibited increased dopamine release in the mesolimbic pathway while also exhibiting a decrease in dopamine release in the nigrostriatal pathway, as measured with fast-scan cyclic voltammetry. These findings demonstrate the complex effects of UBE3A loss on dopamine signaling in subcortical motor pathways that may inform ongoing clinical trials of l-DOPA therapy in patients with AS.

Different Contributions of Dopamine D1 and D2 Receptor Activity to Alcohol Potentiation of Brain Stimulation Reward in C57BL/6J and DBA/2J Mice

“…Quinpirole elevated but did not lower BSR threshold in DBA mice, suggesting that this strain may have enhanced D2 autoreceptor and/or decreased postsynaptic D2 sensitivity, consistent with previous findings that D2-like receptor binding and mRNA expression are greater in the VTA and substantia nigra pars compacta and lower in the striatum of DBA compared with C57 mice (Ng et al, 1994;Cabib et al, 1998). In both strains, raclopride elevated thresholds and reduced MAX in a dose range similar to previous studies in C57 mice (Riday et al, 2012), and more potently in C57 than DBA mice, which is inconsistent with data on haloperidol-induced catalepsy (Kanes et al, 1993) and suppression of sucrose drinking by raclopride (Dym et al, 2009). Taken together, the differences in responses to quinpirole and raclopride suggest that, regarding reward-related behavior in both C57 and DBA strains, D2 receptors may contribute more than D1 receptors.…”

Dissociation of locomotor and cerebellar deficits in a murine Angelman syndrome model

“…Other candidate brain areas that could contribute to these locomotor deficits are the motor cortex and the nigrostriatal pathway, in which both UBE3A and αCaMKII are highly expressed. Notably, a recent study showed that AS mice exhibited behavioral deficits that correlated with abnormal dopamine signaling (47). Specifically, AS mice exhibited changes in dopamine release in both the mesolimbic and nigrostriatal pathways (47), whereas another study reported increased dopamine levels in the striatum, midbrain, and frontal cortex of AS mice (48).…”

“…Notably, a recent study showed that AS mice exhibited behavioral deficits that correlated with abnormal dopamine signaling (47). Specifically, AS mice exhibited changes in dopamine release in both the mesolimbic and nigrostriatal pathways (47), whereas another study reported increased dopamine levels in the striatum, midbrain, and frontal cortex of AS mice (48). AS mice were also shown to have a reduced number of tyrosine hydroxylase-positive neurons in the substantia nigra (10).…”

Angelman Syndrome

“…Socially, Ube3a m-/p+ mice show reduced activity in social testing but not substantial social preference deficit [25,38]. Finally, Ube3a m-/p+ animals show pathway-specific misregulation of dopaminergic release, potentially contributing to both reward and motor phenotypes in these animals, and informing clinical trials for levodopa and the use of stimulants in patients with AS [44]. These animals are also prone to seizures depending on the background strain [35].…”