l-Glutamate as a Central Neurotransmitter: Looking Back

The high concentration in brain of unbound l-glutamic acid (in its anionic form, l-glutamate) fuelled considerable speculation as to its role in central nervous function more than 50 years ago. Claims in the 1940s that it could improve cognitive acuity in patients with mental impairment were particularly intriguing, though later refuted. In the early 1950s Hayashi [(1954) Keio J. Med. 3, 183–192] found that l-glutamate could cause convulsions and proposed that it might be a central synaptic transmitter. Soon thereafter, Curtis and colleagues [Curtis, Phillis and Watkins (1959) Nature (London) 183, 611] showed that l-glutamate depolarized and excited central neurons, as expected for an excitatory transmitter; however, various aspects of the action of l-glutamate seemed to argue strongly against a transmitter function. This negative view prevailed for some 20 years, before compelling evidence for such a role was adduced. Over the last two decades, extensive research has revealed a host of glutamate receptor subtypes, subserving several different functions in excitatory synaptic transmission. This paper gives a very brief and personal overview of the development of the field over the last 50 years from a mainly pharmacological standpoint.