Nicotine ameliorates schizophrenia cognitive deficits in mice [PreClinical]

1. A gene alteration in the nicotinic acetylcholine receptor (nAChR) α5 subunit, previously found to be associated with schizophrenia, was recapitulated in mice and led to increased neuron firing in the prefrontal cortex and reduced pyramidal cell activity.

2. Following the administration of nicotine, neuronal firing was normalized in mice deficient in the α5 subunit.

Evidence Rating Level: 2 (Good)

Study Rundown: Schizophrenia is a complicated mental illness that is not fully understood mechanistically. A recent genome-wide association study found a single nucleotide polymorphism (SNP) associated with schizophrenia in the nAChR α5 subunit gene. The researchers in this study developed mouse models with alterations in this gene to mechanistically characterize this mutation and to determine its role in schizophrenia.

First, mice expressing the α5 SNP were behaviorally and cognitively tested. These mice showed impaired social ability as well a decrease in prepulse inhibition (PPI), two characteristics seen in patients with schizophrenia. A knockout mouse model was then produced that lacked the α5 subunit. These mice showed decreased activity of neurons in layer II/III of the prefrontal cortex (PFC) and reduced pyramidal cell activity, recapitulating the hypofrontality that is a defining feature of schizophrenia. Neuronal activity was restored when this subunit was re-expressed in these mice. Finally, α5SNP mice were treated with nicotine due to prior evidence that it can improve schizophrenia symptoms. Mice treated with nicotine showed a restoration of neuronal firing, demonstrating the potential clinical efficacy of this drug. Overall, this study clarified specific neuronal changes that occur in schizophrenia and provided evidence for using nicotine administration as a therapeutic strategy for schizophrenic patients.

Click to read the study in Nature Medicine

Relevant Reading: Going up in smoke? A review of nAChRs-based treatment strategies for improving cognition in schizophrenia

In-Depth [animal study]: First, a mouse line was generated to express the human α5 SNP associated with schizophrenia. A three-chamber social test demonstrated impaired social ability in these mice, specifically a lack of preference to interact with another mouse compared to an inanimate object as well as a decrease in exploration (p<0.001). The PPI of these mice was then tested. The α5SNP mice had a decreased PPI over a range of decibel levels.

Next, the α5 subunit was knocked out in a mouse model to elucidate the role of this gene in neuronal firing. The neurons in these mice showed decreased firing of neurons in layer II/III of the PFC (p<0.001), paralleling the hypofrontality commonly seen in schizophrenia patients. When this subunit was re-expressed in these PFC layers, pyramidal neuron activity was completely restored (p<0.001). Conversely, when an α5-Cas9 lentiviral vector was used to knockdown α5, there was an increase in interneuron activity and reduced pyramidal cell activity. Researchers concluded that in layers II/III of the PFC, the α5 subunit serves to inhibit interneurons, leading to the activation of pyramidal cell activity.

Finally, due to the potential benefit of nicotine administration in schizophrenia, nicotine treatment was tested in α5SNP mice. A mini-pump was subcutaneously implanted that secreted 2.4 mg nicotine per kg body weight per day to mimic the nicotine concentration seen in smokers. These mice were treated for 1 to 2 weeks, and an increase in pyramidal neuron activity was observed (p<0.001).

Image: PD

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