Testing HCN1 channel dysregulation in the prefrontal cortex using a novel piezoelectric silk neuromodulator

Abstract

Mental illnesses are prevalent in society, yet patients are widely undiagnosed and mistreated. Within this branch of diseases, schizophrenia is an underrecognized disorder that affects approximately 1% of adult patients that portray behavioral and cognitive impairments. Although no comprehensive characterization of schizophrenia exists, there is a general consensus that patients have electrical dysfunction in the prefrontal cortex. The goal of the first phase of this project was to analyze whether hyperpolarization-activated cyclic nucleotide-gated (HCN) channel expression was increased in a calcium/calmodulin-dependent protein kinase (CAMK2) knockout (KO) mouse model of schizophrenia. Fluorescence analysis of four CAMK2 KO and one wild-type mouse validated that HCN channels were upregulated in the prefrontal cortex of KO mice compared to wild-type, which was demonstrated by high localization in dendrites. Notably, there was a statistical difference between the control and schizophrenic infralimbic regions but not between the control and schizophrenic prelimbic regions, suggesting that electrical dysfunction is localized in the infralimbic prefrontal cortex and future treatments should focus there. In the second phase, we investigated the resynchronization of neuronal firing as a treatment strategy for abnormal electrical firing, which has proven to be effective in other neurological disorders. We designed a novel piezoelectric silk-based implant and optimized electrical output through the addition of conductive materials zinc oxide (ZnO) and aluminum nitride (AlN). Via ultrasound exposure, we determined that the 2 M ZnO-silk composite generated the highest electrical output. With further research and compatibility studies, this implant could rectify electrical misfiring in the infralimbic prefrontal cortex.