Exciting extinction

Credit: JEFF SMITH/Alamy Stock Photo

Just as it is essential for animals to rapidly form associations (fear memories) between threats and the cues that predict them, it is important to temper the expression of fear behaviour in response to the cue once the threat is removed. Luo and colleagues now reveal an unexpected role for GABA_B receptor (GABA_BR)-mediated presynaptic excitation in habenula neurons in fear memory extinction in mice.

GABA_BRs have been linked to the control of anxiety and fear and are expressed at high levels along the axons of cholinergic neurons projecting from the medial habenula (MHb) to the interpeduncular nucleus (IPN); however, little is known about the contribution of this pathway to fear-memory formation or extinction. Here, the authors used a transgenic strategy to selectively ablate MHb cholinergic neurons in mice that were then conditioned to associate an auditory tone with a footshock. Although the mice lacking MHb cholinergic neurons formed a fear memory (reliably freezing in response to the tone during conditioning), when compared with control mice they exhibited delayed extinction of the fear response in a subsequent phase in which the tone was presented repeatedly without a footshock. Conversely, optogenetic activation of MHb–IPN projections in wild-type mice boosted the rate of fear extinction.

To determine the contribution of the presynaptic GABA_BRs present on MHb neurons to fear extinction, the authors genetically inactivated Gabbr1, which encodes an essential GABA_BR subunit. This impaired fear extinction, as did the infusion of a GABA_BR antagonist into the IPN. Activation of GABA_BRs using the agonist baclofen increased the rate of fear extinction.

they were surprised to find that application of baclofen increased the amplitude of the excitatory postsynaptic currents and the number of action potentials evoked

Presynaptic GABA_BRs were thought to have predominantly inhibitory effects on synaptic transmission. However, when the authors recorded from IPN neurons in brain slices, they were surprised to find that application of baclofen increased the amplitude of the excitatory postsynaptic currents and the number of action potentials evoked in these neurons in response to stimulation of MHb-neuron terminals. Further experiments showed that baclofen-induced GABA_BR activation resulted in an increase in presynaptic Ca²⁺ influx, which might facilitate synaptic transmission. Blocking or genetically inactivating R-type Ca²⁺ channels abolished the effect of baclofen on presynaptic Ca²⁺, suggesting that these channels are involved in the potentiation of fear extinction triggered by GABA_BR activation.

These findings show that GABA_BR activation in MHb cholinergic neurons can facilitate fear extinction through a previously unknown capacity to potentiate synaptic transmission. Given that dysfunctional fear extinction is thought to contribute to human disorders such as phobias and post-traumatic stress disorder, these findings may point to new candidate targets for therapeutic intervention.