Profiling and rescue of disease-relevant electrophysiological and morphological phenotypes in neurons of transgenic mouse models of schizophrenia

Warnhoff, Michaela Inanna (2024): Profiling and rescue of disease-relevant electrophysiological and morphological phenotypes in neurons of transgenic mouse models of schizophrenia. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)

Abstract

Schizophrenia is a debilitating mental disorder caused by a combination of genetic and environmental factors. It is characterized by a triad of positive, negative, and cognitive symptoms: These can include delusions and hallucinations, social withdrawal and anhedonia, and broad attentional, executive, language, and memory impairments, respectively. The molecular and cellular correlates of these cognitive impairments and changes in neuronal circuit connectivity associated with them include altered neurotransmission in the prefrontal cortex, impaired synaptic plasticity, and aberrant neuronal morphology, contributing to functional and structural dysconnectivity between brain regions. However, they are still poorly understood. Treatment approaches mainly focus on alleviating positive symptoms. Cognitive symptoms, however, are largely resistant to current treatment and often persist or worsen throughout life. Thus, they constitute a major determinant of the extent of functional disability and long-term prognosis. To study cellular correlates of cognitive symptoms and novel treatment approaches and their specific mode of action, I used transgenic mouse models of schizophrenia focusing on the mPFC, a hub for higher cognitive functions. One of these models is the Neurod6 KO mouse. NEUROD6 is a transcription factor involved in neuronal differentiation and development of the nervous system predominantly expressed in excitatory neurons. It interacts with the well-known TCF4 risk gene for schizophrenia and is downregulated in DLPFC pyramidal neurons in schizophrenic patients. Neurod6 KO mice display increased behavioral impulsivity and hyperactivity. Here, I focused on electrophysiological correlates of these behavioral phenotypes, the pharmacological rescue of electrophysiological phenotypes paralleling the pharmacological rescue of behavioral phenotypes, and the mode of action of effective pharmacological compounds. Performing whole-cell patch-clamp recordings in acute brain slices in L5 output neurons in the PL of the mPFC, I found neuronal hyperexcitability and a disturbed use-dependent action potential generation. The latter was rescued by application of the tricyclic antidepressant protriptyline and DPO-1, a specific Kv1.5-blocker. This hints at a possible depolarization block in Neurod6 KO neurons which may contribute to the observed behavioral phenotypes. Additionally, I used another mouse model – the Taok2xEmx1-Cre conditional KO mouse. TAOK2 is a serine/threonine protein kinase involved in microtubule stability, and mutations on the TAOK2 gene carry susceptibility to schizophrenia and autism spectrum disorders. Moreover, TAOK2 downregulation has been shown to affect spine density and dendrite formation, structures important for neuron-neuron communication and circuit integration. Thus, I focused on the influence of cre-dependent KO of Taok2 on morphological characteristics and circuit integration of neurons. To this end, I performed whole-cell patch-clamp recordings and 2-Photon imaging in acute brain slices in L5 output neurons in the PL of the mPFC and primary neuronal cortical cultures from Taok2xEmx1-Cre KO mice. Interestingly, there was no effect of Cre-conditional KO of Taok2 on the complexity of dendritic arborization, spine density, or synaptic integration in acute slices. However, the complexity of dendritic arborization was reduced in primary neuronal cortical cultures. Compensatory mechanisms might be at play in the live organism, or other layers than those investigated might be affected. In summary, these findings may contribute to the understanding of cognitive symptoms in schizophrenia and novel approaches regarding their treatment.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: schizophrenia, cognitive impairment, impulsivity, medial prefrontal cortex, prelimbic cortex, NEUROD6, TAOK2, hyperexcitability, sustained action potential firing, depolarization block, protriptyline, DPO-1, Kv1.5, dendritic arborization, spine density, circuit integration, whole-cell patch-clamp recordings, 2-photon imaging
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Graduate School of Systemic Neurosciences (GSN)
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 20. Februar 2024
• 1. Bericht­erstatter:in: Scheuss, Volker