letters of unlikely co-transmitters in other neuronal types could be explained similarly by postsynaptic uptake. The assumption that neurotransmitter uptake is entirely presynaptic has become widely accepted as dogma, but it was Harold Kimelberg based on evidence that pre-dated modern molecular techniques and Division of Neurosurgery, Albany Medical it needs re-examination. College,Albany, NY 12208, USA.
receptors are now beginning to be described. The molecular biology of the transporters from the different cell types could in the future help to resolve these intriguing questions.
Jonathan P. Bennett Margaret B. Lowrie
References 1 Uhl, G. R. (1992) TrendsNeurosci. 15, 265-268 2 Iversen, L. L. and Kelly, J. S. (1975) Biochem. Pharmacol. 24, 933-938 3 Kimelberg, H. K. and Norenberg, M. (1989) Sci. Am. 260, 66-76
Dept of Anatomy and Cell Biology, St Mary's Hospital Medical School, Imperial College, Norfolk Place,London, UK W12 1PG.
References
George Uhl's timely review of the molecular biology of neurotransmitter transporters I introduces the interesting idea that expression of the transporter for a particular neurotransmitter may be a more useful marker of neuronal type than some of the synthetic enzymes currently used. However this approach depends on the assumption that neurotransmitter uptake occurs solely at the presynaptic membrane. We have recently obtained evidence that under some circumstances neurotransmitter uptake can also be postsynaptic 2. In situ hybridization indicates that rat spinal motor neurons express mRNA for the GABA transporter identified by Guastella et al. 3 These neurons are not usually thought to have any GABAergic action, and they do not express mRNA for glutamic acid decarboxylase, the synthetic enzyme for GABA. We can only conclude that a requirement for fast removal of GABA from the synaptic cleft necessitates an uptake system on both membranes. There is no information as to whether other neurotransmitter transporters can similarly have a postsynaptic location. In the case of the GABA transporter, its presence on motor neurons allowed us to explain some paradoxical reports of immunochemical staining of GABA in these cells4'5: it is possible that some reports TINS, Vol. 15, No. 12, 1992
1 Uhl, G. R. (1992) TrendsNeurosci. 15, 265-268 2 Snow, H., Lowde, M. B. and Bennett, J. P. Neurosci. Lett. (in press) 3 Guastella, J. et al. (1990) Science 249, 1303-1306 4 Manolov, S, and Davidoff, M. (1989) Rev. NeuroL 145, 55-59 5 Philippe, E., Gaulin, F., Delagrave, C. and Geffard, M. (1990) Neurosci. Left. 116, 12-16
Reply The limitations of inferences derived from studies of neurotransmitter transporter expression for identifying specific neuronal and glial populations (mentioned in Ref. 1) are underscored by the letters of Bonanno and Raiteri, Kimelberg, and Bennett and Lowrie. As noted in the review, most data reported to date reflect the cellular distributions of the Na*-dependent membrane transporters for monoamines. These mRNAs are expressed in the same, apparently neuronal, cell populations expressing genes encoding transmitter-synthesizing enzymes and proton-dependent monoaminergic vesicular transporters; these expression patterns are thus quite consistent with classical notions for 'monoaminergic' neuronal genes (e.g. Ref. 2). Other possibilities certainly exist. Work comparing positive results for transporter expression with negative data for expression of transmitter-synthesizing enzymes or transmitter accumulation must
to the editor
consider false-positive results possible in this family of closelyrelated transporter mRNAs with often overlapping substrate specificities, and false negative results from, for example, the low sensitivity of techniques used to detect the accumulation of 'neurotransmission-related' vesicular pools of amino acids amidst large ubiquitous metabolic stores of the same substances. Nevertheless, expression of Na +-dependent plasma membrane transporters and proton-dependent vesicular transporters without expression of a specific synthetic enzyme would be anticipated of neurons utilizing many of these ubiquitous amino acids, such as glutamate and glycine, as transmitters. Expression of only the membranebound transporter without a vesicular transporter might conceivably render the expressing neuron, or glial cell, capable of modulating neurotransmission but not storing or re-releasing the transported substrate. The reported expression of glycine transporter-like mRNA in brain regions free from reported glycineimmunoreactive neurons 3, and the apparent glial localization of a glutamate transporter mRNA (Kanner, B., pets. commun.) may each provide examples of this potentially novel form of modulation of neuronal communication. Glycine transport, for example, could thus modulate activities at sites where glycine can act as a co-agonist on NMDA glutamate receptors, as well as at glycine receptors themselves. Finally, examples of neurotransmitters without known transporters, the neuropeptides, clearly suggest the possibility that neurotransmission can be mediated by neurons that do not reaccumulate each released transmitter. In specific circumstances, documented for several catecholamine transporters (e.g. Ref. 2), transporter expression could serve as relatively specific markers for specified neurons of a specific neurotransmitter phenotype. In other circumstances, however, transporter expression could reflect the various neurobiological roles suggested by its expression by neurons or glia lacking other 483
receptors are now beginning to be described. The molecular biology of the transporters from the different cell types could in the future help to resolve these intriguing questions.
Jonathan P. Bennett Margaret B. Lowrie
References 1 Uhl, G. R. (1992) TrendsNeurosci. 15, 265-268 2 Iversen, L. L. and Kelly, J. S. (1975) Biochem. Pharmacol. 24, 933-938 3 Kimelberg, H. K. and Norenberg, M. (1989) Sci. Am. 260, 66-76
Dept of Anatomy and Cell Biology, St Mary's Hospital Medical School, Imperial College, Norfolk Place,London, UK W12 1PG.
References
George Uhl's timely review of the molecular biology of neurotransmitter transporters I introduces the interesting idea that expression of the transporter for a particular neurotransmitter may be a more useful marker of neuronal type than some of the synthetic enzymes currently used. However this approach depends on the assumption that neurotransmitter uptake occurs solely at the presynaptic membrane. We have recently obtained evidence that under some circumstances neurotransmitter uptake can also be postsynaptic 2. In situ hybridization indicates that rat spinal motor neurons express mRNA for the GABA transporter identified by Guastella et al. 3 These neurons are not usually thought to have any GABAergic action, and they do not express mRNA for glutamic acid decarboxylase, the synthetic enzyme for GABA. We can only conclude that a requirement for fast removal of GABA from the synaptic cleft necessitates an uptake system on both membranes. There is no information as to whether other neurotransmitter transporters can similarly have a postsynaptic location. In the case of the GABA transporter, its presence on motor neurons allowed us to explain some paradoxical reports of immunochemical staining of GABA in these cells4'5: it is possible that some reports TINS, Vol. 15, No. 12, 1992
1 Uhl, G. R. (1992) TrendsNeurosci. 15, 265-268 2 Snow, H., Lowde, M. B. and Bennett, J. P. Neurosci. Lett. (in press) 3 Guastella, J. et al. (1990) Science 249, 1303-1306 4 Manolov, S, and Davidoff, M. (1989) Rev. NeuroL 145, 55-59 5 Philippe, E., Gaulin, F., Delagrave, C. and Geffard, M. (1990) Neurosci. Left. 116, 12-16
Reply The limitations of inferences derived from studies of neurotransmitter transporter expression for identifying specific neuronal and glial populations (mentioned in Ref. 1) are underscored by the letters of Bonanno and Raiteri, Kimelberg, and Bennett and Lowrie. As noted in the review, most data reported to date reflect the cellular distributions of the Na*-dependent membrane transporters for monoamines. These mRNAs are expressed in the same, apparently neuronal, cell populations expressing genes encoding transmitter-synthesizing enzymes and proton-dependent monoaminergic vesicular transporters; these expression patterns are thus quite consistent with classical notions for 'monoaminergic' neuronal genes (e.g. Ref. 2). Other possibilities certainly exist. Work comparing positive results for transporter expression with negative data for expression of transmitter-synthesizing enzymes or transmitter accumulation must
to the editor
consider false-positive results possible in this family of closelyrelated transporter mRNAs with often overlapping substrate specificities, and false negative results from, for example, the low sensitivity of techniques used to detect the accumulation of 'neurotransmission-related' vesicular pools of amino acids amidst large ubiquitous metabolic stores of the same substances. Nevertheless, expression of Na +-dependent plasma membrane transporters and proton-dependent vesicular transporters without expression of a specific synthetic enzyme would be anticipated of neurons utilizing many of these ubiquitous amino acids, such as glutamate and glycine, as transmitters. Expression of only the membranebound transporter without a vesicular transporter might conceivably render the expressing neuron, or glial cell, capable of modulating neurotransmission but not storing or re-releasing the transported substrate. The reported expression of glycine transporter-like mRNA in brain regions free from reported glycineimmunoreactive neurons 3, and the apparent glial localization of a glutamate transporter mRNA (Kanner, B., pets. commun.) may each provide examples of this potentially novel form of modulation of neuronal communication. Glycine transport, for example, could thus modulate activities at sites where glycine can act as a co-agonist on NMDA glutamate receptors, as well as at glycine receptors themselves. Finally, examples of neurotransmitters without known transporters, the neuropeptides, clearly suggest the possibility that neurotransmission can be mediated by neurons that do not reaccumulate each released transmitter. In specific circumstances, documented for several catecholamine transporters (e.g. Ref. 2), transporter expression could serve as relatively specific markers for specified neurons of a specific neurotransmitter phenotype. In other circumstances, however, transporter expression could reflect the various neurobiological roles suggested by its expression by neurons or glia lacking other 483
