Same but different

GABA (γ-aminobutyric acid), the main inhibitory neurotransmitter in the vertebrate nervous system, has many modes of action. For one of its receptors GABA_B — a heterodimer consisting of GABA_B1 and GABA_B2 subunits — functional diversity is achieved by different synaptic localization and physiological action of its subunit isoforms GABA_B1a and GABA_B1b, according to two studies published in Neuron.

To uncover the role of different GABA_B1 versions in inhibitory neurotransmission, Bernhard Bettlers and colleagues used an ingenious approach to generate knockout mice in which GABA_B1a and GABA_B1b were inactivated one at a time. Electron microscopy studies showed that, in the hippocampus, GABA_B1a was predominantly localized at glutamatergic terminals, whereas GABA_B1b was mainly found at dendritic spines opposite to the glutamate release sites. This differential localization of GABA_B1 isoforms correlated with their functional differences: at hippocampal CA3-to-CA1 synapses, GABA_B1a assembled receptors that blocked presynaptic glutamate release, while GABA_B1b was involved in postsynaptic inhibition of neuronal firing. Intriguingly, the constitutive absence of GABA_B1a, but not GABA_B1b, resulted in impaired synaptic plasticity and hippocampus-dependent memory formation. This suggests that different GABA_B receptor compositions might mediate distinct neural functions.

In a companion paper, Perez-Garci and colleagues report similar results of distinct GABA_B1 receptor functions in pyramidal neurons residing in layer 5 (L5) of the neocortex. These L5 neurons are innervated by numerous inhibitory inputs, including those from interneurons in L1. The researchers first established that extracellular stimulation of L1 inhibited the dendritic Ca²⁺ spikes in L5 pyramidal neurons. Further, the short-lasting component of this inhibitory effect was mediated by GABA_A receptors, whereas the long-term counterpart was mediated by GABA_B receptors. Using the knockout mice generated by Bettler et al., the researchers found that L5 pyramidal neurons from GABA_B1a-deficient mice showed normal short- and long-lasting inhibitory components in response to L1 stimulation. By contrast, the absence of GABA_B1b completely abolished the long-term inhibitory response of L5 pyramidal neurons, but the GABA_A-mediated short-term inhibition was unaffected.

These two studies shed fresh light on the apparent contradiction between functional diversity and molecular simplicity of the GABA_B receptor system. It will be interesting to test whether other GABA receptors deploy similar strategies to generate distinct activity under different physiological conditions.