Hippocampal GABA-inhibitory circuitry regulates despair-like behavior in mice

Abstract Despair is a core symptom of depressive disorders. However, little is known about the neural circuits mediating despair and how they are modified by antidepressants. Here we show that the balance between excitatory and inhibitory neurotransmission (E/I balance) in the hippocampus affects behavioral despair in mice. Reduced interneuron density, knockdown of Gabrg2 or DREADD-mediated suppression of interneuron activity resulted in disinhibition of CA1 neurons and anti-despair-like behaviors in mice. Conversely, pharmacological and chemogenetic potentiation of GABAergic transmission in CA1 neurons rapidly induced despair-like behaviors. Disinhibition induced by the GABAAR antagonist pentylenetetrazol produced transient antidepressant effects without BDNF elevation in the hippocampus, while ketamine exhibited rapid and sustained antidepressant effects, but the latter was sensitive to the TrkB receptor blocker ANA-12. These results suggest that rapid disinhibition and BDNF-induced long-lasting synaptic modification leads to enhanced E/I balance, which may contribute to acute and sustained behavioral effects of rapid-acting antidepressants.