EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation.

The mechanisms that promote excitatory synapse formation and maturation have been extensively studied. However, the molecular events that limit excitatory synapse development so that synapses form at the right time and place and in the correct numbers are less well understood. We have identified a RhoA guanine nucleotide exchange factor, Ephexin5, which negatively regulates excitatory synapse development until EphrinB binding to the EphB receptor tyrosine kinase triggers Ephexin5 phosphorylation, ubiquitination, and degradation. The degradation of Ephexin5 promotes EphB-dependent excitatory synapse development and is mediated by Ube3A, a ubiquitin ligase that is mutated in the human cognitive disorder Angelman syndrome and duplicated in some forms of Autism Spectrum Disorders (ASDs). These findings suggest that aberrant EphB/Ephexin5 signaling during the development of synapses may contribute to the abnormal cognitive function that occurs in Angelman syndrome and, possibly, ASDs.

The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc.

Angelman Syndrome is a debilitating neurological disorder caused by mutation of the E3 ubiquitin ligase Ube3A, a gene whose mutation has also recently been associated with autism spectrum disorders (ASDs). The function of Ube3A during nervous system development and how Ube3A mutations give rise to cognitive impairment in individuals with Angleman Syndrome and ASDs are not clear. We report here that experience-driven neuronal activity induces Ube3A transcription and that Ube3A then regulates excitatory synapse development by controlling the degradation of Arc, a synaptic protein that promotes the internalization of the AMPA subtype of glutamate receptors. We find that disruption of Ube3A function in neurons leads to an increase in Arc expression and a concomitant decrease in the number of AMPA receptors at excitatory synapses. We propose that this deregulation of AMPA receptor expression at synapses may contribute to the cognitive dysfunction that occurs in Angelman Syndrome and possibly other ASDs.

Dorsal Striatal Circuits for Habits, Compulsions and Addictions.

Here, we review the neural circuit bases of habits, compulsions, and addictions, behaviors which are all characterized by relatively automatic action performance. We discuss relevant studies, primarily from the rodent literature, and describe how major headway has been made in identifying the brain regions and neural cell types whose activity is modulated during the acquisition and performance of these automated behaviors. The dorsal striatum and cortical inputs to this structure have emerged as key players in the wider basal ganglia circuitry encoding behavioral automaticity, and changes in the activity of different neuronal cell-types in these brain regions have been shown to co-occur with the formation of automatic behaviors. We highlight how disordered functioning of these neural circuits can result in neuropsychiatric disorders, such as obsessive-compulsive disorder (OCD) and drug addiction. Finally, we discuss how the next phase of research in the field may benefit from integration of approaches for access to cells based on their genetic makeup, activity, connectivity and precise anatomical location.

Rapid Assembly of Presynaptic Materials behind the Growth Cone in Dopaminergic Neurons Is Mediated by Precise Regulation of Axonal Transport.

The proper assembly of neural circuits depends on the process of synaptogenesis, or the formation of synapses between partner neurons. Using the dopaminergic PDE neurons in C. elegans, we developed an in vivo system to study the earliest steps of the formation of en passant presynaptic specializations behind an extending growth cone. We find that presynaptic materials coalesce into puncta in as little as a few minutes and that both synaptic vesicle (SV) and active zone (AZ) proteins arrive nearly simultaneously at the nascent sites of synapse formation. We show that precise regulation of UNC-104/Kinesin-3 determines the distribution of SV proteins along the axon. The localization of AZ proteins to en passant puncta, however, is largely independent of the major axonal kinesins: UNC-104/Kinesin-3 and UNC-116/Kinesin-1. Moreover, AZ proteins play a crucial role in recruiting and tethering SV precursors (SVPs).

Autoinhibition of a Neuronal Kinesin UNC-104/KIF1A Regulates the Size and Density of Synapses.

Kinesin motor proteins transport intracellular cargoes throughout cells by hydrolyzing ATP and moving along microtubule tracks. Intramolecular autoinhibitory interactions have been shown for several kinesins in vitro; however, the physiological significance of autoinhibition remains poorly understood. Here, we identified four mutations in the stalk region and motor domain of the synaptic vesicle (SV) kinesin UNC-104/KIF1A that specifically disrupt autoinhibition. These mutations augment both microtubule and cargo vesicle binding in vitro. In vivo, these mutations cause excessive activation of UNC-104, leading to decreased synaptic density, smaller synapses, and ectopic localization of SVs in the dendrite. We also show that the SV-bound small GTPase ARL-8 activates UNC-104 by unlocking the autoinhibition. These results demonstrate that the autoinhibitory mechanism is used to regulate the distribution of transport cargoes and is important for synaptogenesis in vivo.