Disputation: Nancy Saana Banono

Doctoral candidate Nancy Saana Banono at the Department of Pharmacy, Faculty of Mathematics and Natural Sciences, is  defending the thesis "Functional analysis of psychiatric risk genes in zebrafish (Danio rerio): a focus on the L-type voltage-gated calcium channel subtypes Cav 1.2 and Cav 1.3" for the degree of Philosophiae Doctor.

Portrait of Nancy Sanaa Banono

Trial lecture - time and place

07.10.2021, 10.15, Auditorium 2, Pharmacy building

Cognitive dysfunctions in psychotic disorders

Conferral summary

I hennes doktorgradsavhandling har Nancy og kollegaene hennes forsøkt å forstå rollen til to kalsiumkanalgener (CACNA1C og CACNA1D) i utviklingen av nevropsykiatriske sykdommer. For å oppnå målet deres har de brukt sebrafisklarver som bærer mutasjoner i disse genene. De oppdaget at når funksjonene til CACNA1C og CACNA1D er genetisk forstyrret oppstår endringer i uttrykk av gener som er viktige for nervecellenes overlevelse og funksjon og hjernen går inn i en tilstand av økt eksitasjon, noe som kan bidra til forekomsten av atferdsmessige defekter observert i deres mutante dyr.

Main research findings

CACNA1C and CACNA1D are voltage-gated calcium channel genes that have been repeatedly associated with psychiatric disorders by various genomic studies. These genes are involved in gene expression regulation, neurotransmitter release and integration of dendritic information in the brain, but the mechanisms through which they cause disease are poorly understood.

The goal of this thesis was to characterise the effects of mutations in CACNA1C and CACNA1D on early brain function using three zebrafish mutant lines (one cacna1d and two cacna1c mutants) that were characterised through an arsenal of molecular, behavioural, neurophysiological and pharmacological methods.

Larval zebrafish with global cacna1da haploinsufficiency showed a hyperlocomotor phenotype that could be improved or reversed using the antipsychotics haloperidol and risperidone and the mood stabiliser, valproate. Furthermore, larvae with global loss-of-function (LOF) of cacna1c was associated with observable dysmorphologies, changes in downstream molecular targets, compensatory overexpression of cacna1d, and deficits in sensorimotor gating. In addition, spectral analysis of local field potential recordings and neurotransmitter analysis revealed gross neural excitability in the cacna1c LOF mutants.

Together, we have shown that mutations that alter the function of cacna1da and cacna1c lead to a wide-range of phenotypes reminiscent of relevant functional domains observed in psychiatric disorders.

Published Sep. 23, 2021 9:24 AM - Last modified Sep. 27, 2021 11:48 AM