In this project, we will determine which neuronal populations expressing nAChRs in the prefrontal cortex represent the most promising target for symptomatic therapy in patients with autism spectrum disorder (ASD).
nAChRs have been associated with various neuropsychiatric disorders, including schizophrenia and autism spectrum disorder (ASD). Schizophrenia and ASD patients show markedly increased and decreased probability, respectively, of heavy smoking and nicotine addiction compared to the general population. Studies in ASD patients have indicated that alterations in the CHRNA7 gene, coding for the alpha7 nicotinic subunit, are linked to intellectual disability, attention deficit and ASD. In addition, nicotinic expression is markedly changed, mostly decreased, in different brain regions of ASD patients. Because of the suspected role of nicotinic signaling in ASD, several clinical trials have been launched to test the effect of nicotine and other nicotinic ligands in ASD patients. In preclinical studies, mouse models of autism showed a reversal of social deficit and repetitive behavior after the administration of nicotine and other nicotinic ligands. However, mechanisms underlying these effects have not yet been identified.
The prefrontal cortex (PFC) is one of the brain regions that play an important role in ASD pathophysiology. In the PFC, nAChRs are widely but specifically expressed by various neuronal populations and the expression pattern also changes based on the different cortical layers and nicotinic subunits. In certain layers of the PFC, the same nAChR subtypes are expressed by excitatory pyramidal neurons as well as by inhibitory interneurons, these two often having antagonistic effects on local circuits. We hypothesize that specific activation of nAChRs expressed by PFC interneurons could lead to the strengthening of inhibitory input in the PFC and therefore would be more efficient (and also safer) compared to general nicotinic activation. The goal of this project is to identify a PFC neuronal population whose activity can be modulated through nAChRs, leading to a reversal of typical ASD behavioral symptoms such as deficit of social behavior, cognitive flexibility impairment and aggression.
To achieve this goal, we are using mouse models of ASD crossed with other genetic mouse models which allows us to decrease or increase the expression of nAChRs in selected neuronal populations. We then evaluate the effect that nAChR modulation in specific neuronal types has on ASD-like behavior, neuronal activity in the PFC and synaptic plasticity.
