The GAD-given Right of Dentate Gyrus Granule Cells to Become GABAergic

JANUS, THE ANCIENT ROMAN GOD OF GATES AND DOORS HAD TWO FACES: one looked into the past, and the other, into the future. Do neurons possess a Janus face when it comes to neurotransmitters, or a given neuron is to be forever solely gamma-aminobutyric acid (GABA) ergic, glutamatergic, dopaminergic, peptidergic, or YOURPREFERREDTRANSMITTERergic? The answer is that the terminals of many neurons are homes to even more than two neurotransmitters. All this in spite of the "one neuron-one transmitter" usual misinterpretation of Sir Henry Hallett Dale's postulate, originally meant to indicate that a metabolic process taking place in the cell body can influence all processes of the same neuron. A large variety of neurons in the CNS, many of them GABAergic, produce and release chemicals that satisfy some of the criteria used to define neurotransmitters. The usual scenario for a dual-transmitter terminal is that the fast-acting transmitter such as GABA or glutamate is stored in regular synaptic vesicles, whereas a neuropeptide is stored in dense core vesicles (1). The vesicular zinc found in many glutamatergic terminals also may be considered to be a second neurotransmitter, based on its vesicular packaging with the aid of a specific vesicular transporter, and its postsynaptic actions through high-affinity binding sites and permeation through certain channels (2). Whenever a "fast" and a "slow" neurotransmitter are present in the same presynaptic terminal, it is customary to assume that their release can be differentially regulated (1). There is little convincing experimental support for this phenomenon in the mammalian CNS. The coexistence of two "fast" neurotransmitters in the same terminal is less frequent, but not unheard of. In neonatal sympathetic neurons cocultured with cardiac myocytes, norepinephrine and acetylcholine coexist and have opposite actions on the cardiac muscle cells (3). Very recently we learned that brain-derived neurotrophic factor acting at the low-affinity neurotrophin receptor p75(NTR), perhaps as part of a programmed developmental switch, can convert the phenotype of the sympathetic neuron from noradrenergic to cholinergic (4). Other examples of two fast neurotransmitters released from the same neuron include GABA and glycine in interneurons of the spinal cord (5) and glutamate and dopamine in ventral midbrain dopamine neurons (6). Of all CNS neurons, the granule cells of the dentate gyrus appear to be the champions of neurotransmitter colocalization: glutamate, enkephalin, dynorphin, zinc, and finally GABA (2)(7)(8)(9). With this many transmitters in a single neuron, there are probably different ways in which they can be released. Dynorphin and other opioid peptides can be released directly from the dendrites to inhibit excitatory transmission (8). A similar mechanism may take place for GABA, as described in cortical GABAergic neurons (10).