Excitatory GABA_B Receptors

Gamma-Amino Butyric acid(GABA)is the major inhibitory neurotransmitter of mammalian central nervous system.It inhibits neuron activity through two classes of receptors,ionotropic GABAA and metabotropic GABA_B receptors.GABA_B receptors are widely distributed throughout the whole nervous system.They are commonly considered to mediate only inhibitory response in both pre-synaptic site and post-synaptic site.They reduce neurotransmitter release and inhibit neuronal excitability through G?i/o-?? protein.Generally,the ?i/o subunit inhibits the activity of adenylyl cyclase,thus reduce the cytoplasmic cAMP level,following with the founctional down regulation of protein kinase A,exchange proteins activated by cAMP and cyclic nucleotide-gated ion channels,etc.The ?? subunits inhibit voltage-dependent calcium channel decreasing the calcium entry into cytoplasmid or open the G protein-coupled inwardly-rectifying potassium channel resulting in the hyperpolization of membrane potential.In this study,we investigated the physiological and behavioral function of pre-synaptic GABA_B receptors in the neural pathway from the medial habenula(MHb)to the interpeduncular nucleus(IPN).We found that both GABA and the selective agonist baclofen dratistically potentiate the co-release of glutamate,acetylcholine and neurokinin B.These GABA_B receptors mediate excitation by amplifying presynaptic calcium entry through R-type calcium channels.Inactivating these GABA_B receptors enhances fear memory expression,whereas activating these receptors reduces conditioned fear of animals.In conclusion,GABA_B receptors can also mediate excitatory response,which challenges and expands the traditional concept of neurotransmitter based neural circuit.These excitatory GABA_B receptors regulate the expression and extinction of fear memory,providing a new target for treating phobias and post-traumatic stress disorder.