Biology subjects

Maskos, U.

Publications and source records attributed to Maskos, U..

4 recordsLinked to original sources

bioRxiv2018

Mammalian vesicular glutamate transporter VGLUT1 reduces synaptic vesicle superpool size and spontaneous release frequency.

Glutamate secretion at excitatory synapses is tightly regulated to allow for the precise tuning of synaptic strength. Vesicular Glutamate Transporters (VGLUT) accumulate glutamate into synaptic vesicles (SV) and thereby regulate quantal size. Further, the number of release sites and the release probability of SVs maybe regulated by the organization of active zone proteins and SV clusters. In the present work, we uncover a mechanism mediating an increased SV clustering through a tripartite interaction of VGLUT1, endophilinA1 and intersectin1. This strengthening of SV clusters results in a combined reduction of axonal SV super-pool size and miniature excitatory events frequency. Our findings support a model in which clustered vesicles are held together through multiple weak interactions between SH3 domains and proline rich sequences of synaptic proteins. In mammals, VGLUT1 gained a poly-proline sequence that recruits endophilinA1 and turns the transporter into a dual regulator of quantal release parameters at excitatory synapses.

neuroscience↗

bioRxiv2018

Nicotinic modulation of hierarchal inhibitory control over prefrontal cortex resting state dynamics: modeling of genetic modification and schizophrenia-related pathology

Nicotinic acetylcholine receptors (nAChRs) strongly modulate the cholinergic drive to a hierarchy of inhibitory neurons in the superficial layers of the PFC, critical to cognitive processes. Genetic deletion of various types of nAChRs, located on specific interneurons, impacts the properties of ultra-slow transitions between high and low activity states (H-states and L-states, respectively), recorded in mice during quiet wakefulness. In addition, recent data indicate that a genetic mutation of the 5 nAChR subunit located on vasoactive intestinal polypeptide (VIP) inhibitory neurons, the rs16969968 single nucleotide polymorphism (5 SNP), appears to be responsible for \"hypofrontality\" observed in schizophrenia. Chronic nicotine application to 5 SNP mice restores neural activity to control levels. Using firing rate models of hierarchically organized neural populations, we showed that the change of activity patterns recorded in the genetically modified mice can be explained by a change of activity state stability, differentially modulated by cholinergic inputs to parvalbumin (PV), somatostatin (SOM) or VIP inhibitory populations. A change in amplitude, but not duration of H-states fully account for the lowered pyramidal (PYR) firing rates recorded in 5 SNP mice. We demonstrate that desensitization and upregulation of {beta}2 nAChRs located on SOM interneurons, but not activation of 5 nAChRs located on VIP interneurons, by chronic nicotine application could account for activity normalization recorded in 5 SNP mice. The model implies that subsequent nicotine withdrawal should lead to PYR activity depression more severe than the original hypofrontality caused by SNP mutation.

systems biology↗

bioRxiv2018

Somatic nicotinic acetylcholine receptors control the activity of dopamine neurons and reward-related behaviors.

Dopamine (DA) neurons of the ventral tegmental area (VTA) integrate cholinergic inputs to regulate key functions such as motivation and goal-directed behaviors. Yet the temporal dynamic range and mechanism of action of acetylcholine (ACh) on the modulation of VTA circuits and reward-related behaviors are not known. Here we used a chemical-genetic approach for rapid and precise optical manipulation of nicotinic neurotransmission in VTA neurons in vivo. We provide direct evidence that the ACh tone fine-tunes the firing properties of VTA DA neurons through somatic {beta}2-containing ({beta}2*) nicotinic ACh receptors (nAChRs). Furthermore, locally photo-antagonizing these receptors in the VTA was sufficient to reversibly switch nicotine reinforcement on and off. By enabling control of nicotinic transmission in targeted brain circuits, this technology will help unravel the various physiological functions of nAChRs and may assist in the design of novel therapies relevant to neuropsychiatric disorders.

neuroscience↗

bioRxiv2018

Acetylcholine-dependent phasic dopamine activity signals exploratory locomotion and choices

Dopamine neurons from the Ventral Tegmental Area (VTA) switch from tonic to phasic burst firing in response to reward-predictive cues and actions. Bursting is influenced by nicotinic acetylcholine receptors (nAChRs), which are not implicated in reinforcement learning, but rather in exploration and uncertainty-seeking. The leading model assigns these functions to tonic dopamine firing. To investigate this paradox, we recorded the activity of VTA dopamine neurons during a spatial decision-making task. When reward was certain, mice adopted a stereotyped behavior, and dopamine neurons signaled reward. When confronted with uncertain rewards or a novel environment, mice exhibited exploration. Modulation of phasic, but not tonic, dopamine activity predicted uncertainty-seeking and locomotor exploration. Deletion of nAChRs disrupted the influence of uncertainty and novelty on dopamine firing and behavior, sparing reward signaling and learning. Hence, nAChR modulation of dopamine neurons can influence cognitive functions on a short timescale, through the modulation of phasic, synchronous bursting.

neuroscience↗