Cell-type specific actions of Nogo-A in controlling spatial memory formation by modulating neuronal excitability
Year: 2025
Type: dissertation
Abstract: Experiences lead to lasting structural and functional changes in neurons, forming the basis for learning and memory. These persistent modifications are known as memory engrams. A critical step in engram formation is the allocation of neurons during learning, a process shown to depend on their relative excitability. Consequently, mechanisms that regulate excitation and inhibition can directly influence memory encoding. Nogo-A is widely known for inhibiting structural plasticity but has more recently been identified as a negative regulator of synaptic plasticity, stabilizing both excitatory and inhibitory synaptic transmission in a cell-type-specific manner. Notably, global deletion of Nogo-A in male mice enhances spatial learning. This study aimed to bridge the gap between the known cell-type-specific effects of Nogo-A in vitro and the behavioral improvements observed in constitutive knockouts (KO). A 3-day Morris water maze task followed by c-Fos immunohistochemistry was used to assess spatial learning and engram activation. Male constitutive Nogo-A KO mice successfully acquired the task, while their wildtype (WT) littermates and both female genotypes did not. Furthermore, mice with excitatory or PV+ inhibitory interneuron-specific deletion of Nogo-A showed no improvements in learning the task in comparison to their control groups, regardless of sex. Consistent with these behavioral findings, only male constitutive KO mice showed elevated c-Fos expression in CA1, CA3, and DG, suggesting enhanced recruitment of hippocampal neurons during memory formation. These findings suggest that combined Nogo-A deletion across multiple neuronal populations is required to improve spatial learning and that male mice may benefit more strongly from this effect. Patch-clamp recordings in CA3 pyramidal neurons of excitatory Nogo-A KO mice revealed a shift in the excitatory/inhibitory balance toward excitation, without changes to inhibitory input. Despite this excitatory bias, learning and c-Fos activation remained unchanged in cell-type-specific KO mice, implying that the synaptic changes were insufficient to drive improved memory formation under current conditions. Developmental compensations may also have masked potential effects. To overcome this limitation, a virus-based strategy for the acute, region-specific deletion of Nogo-A was developed for future studies.
Author: Flechtner, Jan
Language: English
Topic: Memory and Neural Mechanisms
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7082974013
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