Project description
Exploring the role of serotonin in synaptic plasticity in the prefrontal cortex
Serotonin or 5-hydroxytryptamine (5-HT) is an important neurotransmitter in the brain and periphery. The prefrontal cortex is essential for top-down control of higher-order executive processes such as learning, working memory and cognitive flexibility and it expresses five types of 5-HT receptor subtypes. Evidence supports a link between dysfunctional serotonergic modulation and working memory deficits, yet the cellular mechanisms are not known. The EU-funded PIANISM project is investigating the role of 5-HT in working memory formation. The team is manipulating cells in brain slices and measuring effects on characteristic synaptic activity thought to underly memory formation in the prefrontal cortex. Insight could be important for therapeutic targets to treat working memory deficits common in some neurodegenerative diseases and schizophrenia.
Objective
The prefrontal cortex (PFC) is essential for higher cognitive tasks such as learning, decision making and, in particular, working memory (WM). To fulfill these tasks, PFC neurons express several serotonin (5HT) receptor subtypes that are modulated by a high density of serotonergic axons projected from the raphe nuclei. Alterations of the neuronal mechanisms within PFC lead to an impaired top-down regulation, causing cognitive dysfunctions in mental disorders such as schizophrenia. A key cellular mechanism related to WM formation and maintenance in the PFC is sustained action potential firing of neurons that outlasts the initial excitatory drive. Persistent firing is likely enabled by synaptic networks and intracellular ionic mechanisms, including voltage sensitive sodium and calcium inward currents or G-Protein-coupled receptor mediated TRPC/ CAN currents. Moreover, experimental data supports a link between dysfunctional serotonergic modulation in the PFC and WM deficits, but yet, the underlying mechanisms are poorly understood. Here, I plan to gain a mechanistic understanding of the serotonergic modulation of WM at the cellular level including the link between 5HT receptor activity and prefrontal cellular circuits dependent WM formation and the role of 5HT in WM-related persistent firing. I will perform patch-clamp electrophysiology and optical voltage imaging (genetically encoded voltage indicators) of prefrontal pyramidal and GABAergic cells (PV-, SST-, VIP-subtypes) in acute slices from naïve and WM deficient mice (chronic ketamine model of schizophrenia), and examine how the activity of these cell types are modulated by optogenetically and pharmacologically controlled 5HT signalling. These experiments aim to understand the serotonergic transmission and intrinsic properties within the PFC involved in WM formation, maintenance and deficiency. Better understanding of these mechanisms will help to develop new and specific therapeutic targets for WM deficiencies.
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Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
NW1 1AT London
United Kingdom