Cognitive deficits resulting from selective vulnerability of septal inhibitory neurons: mitochondrial dysfunction as a driver?

Introduction

Septal GABAergic projection neurons are considered “pacemaker” cells as they enable the temporal organization of neuronal spike firing in hippocampal and entorhinal networks that support spatial- and object-coding. Accordingly, medial septum inactivation is associated with cognitive impairments, but the specific role of the septal-entorhinal GABAergic projections therein has remained unexplored.

Importance of the Study

This is a pressing question, as we have evidence that septal GABAergic projections exhibit enhanced vulnerability. In mouse models with neurodegeneration, we found that septal GABAergic axons exhibit signs of degeneration when target cells in the entorhinal cortices are not yet impaired. Furthermore, we have evidence for mitochondrial pathology in the degenerating axons.

Research Questions

These results prompt the following questions:

1. How does malfunction of septal GABAergic projections translate into dysfunction of downstream networks involved in episodic memory and spatial navigation?
2. What are the mechanisms that render septal GABAergic projections prone to vulnerability?

Methodology

Employing in vivo electrophysiology combined with optogenetics, behavioral studies, 2-photon imaging of axons and mitochondria in live mice, and spatial transcriptomics, we will tackle the following issues:

• (A) Assess how impaired septal GABAergic projections affect spatial- and object-coding in the medial and lateral entorhinal cortex (MEC and LEC).
• (B) Assess the functional consequence thereof on spatial and associative memory in the LEC.
• (C) Gauge putative cellular mechanisms, with a focus on mitochondria, that render septal long-range GABAergic projections vulnerable.
• (D) Identify genes/gene networks whose expression is involved in the degeneration of septal GABAergic neuron axons.

Expected Outcomes

With these studies, we will elucidate how septal neurons contribute to cognition, reveal common mechanisms for axonal degeneration, and ideally identify novel biomarkers and therapeutic targets for “mitochondropathies.”