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bioRxiv · 10.1101/2024.04.12.589167

Linking Altered Neuronal and Synaptic Properties to Nicotinic Receptor Alpha5 Subunit Gene Dysfunction: A Translational Investigation in Rat mPFC and Human Cortical Layer 6

Yang, D.·Qi, G.·Delev, D.·Maskos, U.·Feldmeyer, D.
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Abstract

BackgroundGenetic variation in the 5 nicotinic acetylcholine receptor (nAChR) subunit of mice results in behavioral deficits linked to the prefrontal cortex (PFC). A Single Nucleotide Polymorphisms (SNP) in CHRNA5 imparts a partial loss of function to the 5 subunit-containing (5*) nAChRs and have been demonstrated to be associated with psychiatric disorders in humans, including schizophrenia, nicotine dependence, cocaine and alcohol addiction. MethodsWe performed single cell-electrophysiology combined with morphological reconstructions on layer 6 (L6) excitatory neurons in the medial PFC (mPFC) of wild type (WT) rats (n = 25), rats carrying the human coding polymorphism rs16969968 in Chrna5 (n = 11) and 5 knockout (KO) rats (n = 28). Neuronal and synaptic properties were compared among three rat genotypes. Galantamine was applied to identified L6 neuron populations to specifically boost the nicotinic responses mediated by 5*nAChRs in the rat mPFC and human neocortex (n = 6 patients). ResultsCompared with neurons in WT rats, L6 regular spiking (RS) neurons in the 5KO group exhibited altered electrophysiological properties, while those in 5SNP rats remained unchanged. L6 RS neurons in mPFC of 5SNP and 5KO rats differed from WT rats in dendritic morphology, spine density and spontaneous synaptic activity. Galantamine acted as a positive allosteric modulator of 5*nAChRs in RS but not burst spiking (BS) neurons in both rat and human cortical L6. ConclusionOur findings suggest that dysfunction in the 5 subunit gene leads to aberrant neuronal and synaptic properties, shedding light on the underlying mechanisms of cognitive deficits observed in human populations carrying 5SNPs. They highlight a potential pharmacological target for restoring the relevant behavioral output.

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Yang, D., Qi, G., Delev, D., Maskos, U., Feldmeyer, D.. 2024-04-12. Linking Altered Neuronal and Synaptic Properties to Nicotinic Receptor Alpha5 Subunit Gene Dysfunction: A Translational Investigation in Rat mPFC and Human Cortical Layer 6. https://doi.org/10.1101/2024.04.12.589167

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