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

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract Background Genetic variation in the α5 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 α5 subunit-containing (α5*) nAChRs and have been demonstrated to be associated with psychiatric disorders in humans, including schizophrenia, nicotine dependence, cocaine and alcohol addiction. Methods We 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 α5 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 α5*nAChRs in the rat mPFC and human neocortex (n = 6 patients). Results Compared with neurons in WT rats, L6 regular spiking (RS) neurons in the α5KO group exhibited altered electrophysiological properties, while those in α5SNP rats remained unchanged. L6 RS neurons in mPFC of α5SNP and α5KO rats differed from WT rats in dendritic morphology, spine density and spontaneous synaptic activity. Galantamine acted as a positive allosteric modulator of α5*nAChRs in RS but not burst spiking (BS) neurons in both rat and human cortical L6. Conclusion Our findings suggest that dysfunction in the α5 subunit gene leads to aberrant neuronal and synaptic properties, shedding light on the underlying mechanisms of cognitive deficits observed in human populations carrying α5SNPs. They highlight a potential pharmacological target for restoring the relevant behavioral output.

Authors 5

1. Danqing Yang corresponding

   Forschungszentrum Jülich

   Affiliation as printed

   Research Centre Juelich;

   Research Centre Juelich

2. Guanxiao Qi

   Forschungszentrum Jülich

   Affiliation as printed

   Research Centre Juelich;

   Research Centre Juelich

3. Daniel Delev Aachen

   RWTH Aachen University

   Affiliation as printed

   RWTH Aachen University;

   RWTH Aachen University

4. Uwe Maskos

   Institut Pasteur

   Affiliation as printed

   Institut Pasteur

5. Dirk Feldmeyer

   Forschungszentrum Jülich

   Affiliation as printed

   Research Centre Juelich;

   Research Centre Juelich