The role of GABA in synaptic transmission in the mammalian central nervous system is more firmly established than for any other neurotransmitter. With virtually every neuron studied, the synaptic action of GABA is mediated by bicuculline-sensitive GABAA receptors which selectively increase chloride conductance. However, it has been shown that GABA has a presynaptic inhibitory action on transmitter release that is insensiive to bicuculline and is selectively mimicked by baclofen. The receptors involved in this action are referred to as GABAB receptors, to distinguish them from the classic bicuculline-sensitive GABAA receptors. In hippocampal pyramidal cells an additional postsynaptic action of GABA and baclofen has been reported that is also insensitive to GABAA antagonists, and may be mediated by GABAB receptors on the postsynaptic neuron. This action of GABA and baclofen involves an increase in potassium conductance. Synaptic activation of pathways converging on hippocampal pyramidal cells results in a slow inhibitory postsynaptic potential which involves an increase in potassium conductance, and it has been suggested that GABAB receptors might be responsible for this synaptic potential. However, to establish convincingly that GABAB receptors are physiologically important in the central nervous system, a selective GABAB antagonist is required. Here we provide this missing evidence. Using the hippocampal slice preparation, we now report that the phosphonic acid derivative of baclofen, phaclofen, is a remarkably selective antagonist of both the postsynaptic action of baclofen and the bicuculline-resistant action of GABA, and that it selectively abolishes the slow inhibitory postsynaptic potential in pyramidal cells.

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Nucleus HVc of the songbird is a distinct forebrain region that is essential for song production and shows selective responses to complex auditory stimuli. Two neuronal populations within HVc give rise to its efferent projections. One projection, to the robust nucleus of the archistriatum (RA), serves as the primary motor pathway for song production, and can also carry auditory information to RA. The other projection of HVc begins a pathway through the anterior forebrain, (area X --> medial portion of the dorsolateral nucleus of the thalamus (DLM) --> lateral portion of the magnocellular nucleus of the anterior neostriatum (L-MAN) --> RA) that is crucial for song learning but, although active during singing, is not essential for adult song production. To test whether these different projection neuron classes have different functional properties, we recorded intracellularly from neurons in nucleus HVc in brain slices. We observed at least three classes of neuron based on intrinsic physiological and pharmacological properties as well as on synaptic inputs. We also examined the morphological properties of the cells by filling recorded neurons with neurobiotin. The different physiological cell types correspond to separate populations based on their soma size, dendritic extent, and axonal projection. Thus HVc neurons projecting to area X have large somata, show little spike-frequency adaptation, a hyperpolarizing response to the metabotropic glutamate receptor (mGluR) agonist (1S,3R)-trans-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), and exhibit a slow inhibitory postsynaptic potential (IPSP) following tetanic stimulation. Those HVc neurons projecting to motor nucleus RA have smaller somata, show strong accommodation, are not consistently hyperpolarized by ACPD, and exhibit no slow IPSP. A third, rarely recorded class of neurons fire in a sustained fashion at very high-frequency and may be interneurons. Thus the neuronal classes within HVc have different functional properties, which may be important for carrying specific information to their postsynaptic targets.

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