ΔFosB Decreases Excitability of Dorsal Hippocampal CA1 Neurons

Abstract

Both the function of hippocampal neurons and hippocampus-dependent behaviors are dependent on changes in gene expression, but the specific mechanisms that regulate gene expression in hippocampus are not yet fully understood. The stable, activity-dependent transcription factor ΔFosB plays a role in various forms of hippocampal-dependent learning and in structural plasticity of synapses onto CA1 neurons. The authors examined the consequences of viral-mediated overexpression or inhibition of ΔFosB on the function of adult mouse hippocampal CA1 neurons using ex vivo slice whole-cell physiology. We found that overexpression of ΔFosB decreased excitability of CA1 pyramidal neurons, while inhibition increased excitability. Interestingly, these manipulations did not affect resting membrane potential or spike frequency adaptation, but ΔFosB overexpression reduced hyperpolarization-activated current. Both ΔFosB overexpression and inhibition decreased spontaneous excitatory postsynaptic currents, while only ΔFosB inhibition affected AMPA/NMDA ratio which was mediated by decreased NMDA receptor current, suggesting complex effects on synaptic inputs to CA1 that may be driven by homeostatic cell-autonomous or network-driven adaptations to the changes in CA1 cell excitability. Because ΔFosB is induced in hippocampus by drugs of abuse, stress, or antidepressant treatment, these results suggest that ΔFosB-driven changes in hippocampal cell excitability may be critical for learning and, in maladaptive states, are key drivers of aberrant hippocampal function in diseases such as addiction and depression.

Significance Statement Memory consolidation is a key component of adaptive learned behavior which can be disrupted in psychiatric conditions, and regulated gene expression in hippocampus is critical for learning and memory. ΔFosB is a highly stable, activity-dependent transcription factor that regulates hippocampus-dependent memory, yet its specific role in hippocampal neuronal function is unclear. The authors use whole-cell slice electrophysiology to uncover a novel role for ΔFosB in regulating neuronal excitability in the CA1 region of hippocampus. These findings suggest that ΔFosB-driven changes in gene expression drive intrinsic excitability of hippocampal CA1 pyramidal neurons, potentially regulating learning, antidepressant responses, and psychiatric diseases such as drug addiction and depression.