The Neurobiology of Slow Synaptic Transmission

A Mathematician Who Became a Neuroscientist for the Right Reasons

Paul Greengard was born in New York in 1925, the son of a vaudeville comedian. His mother, Pearl Meister Greengard, died giving birth to him. He never knew her. His sister Irene was raised alongside him in a household that soon acquired a stepmother; the siblings were brought up in the Christian tradition, though their family was Jewish. It is a childhood marked more by absence than incident — and Greengard, who rarely spoke about it, let one action speak for him: when he received the Nobel Prize money in 2000, he gave it entirely to Rockefeller University to fund an annual prize for outstanding women in biomedical research. He named it the Pearl Meister Greengard Prize. It honours the mother he never had.

His route into neuroscience was characteristically indirect. He graduated from Hamilton College in mathematics and physics in 1948, then chose not to pursue graduate work in physics — post-war physics, he observed, was dominated by nuclear weapons research, and he wanted no part of it. He enrolled instead at Johns Hopkins, where a lecture by the British physiologist Alan Hodgkin on the electrical properties of nerve cells redirected his life. He received his PhD in biophysics in 1953 and spent years moving through postdoctoral positions in London, Cambridge, and Amsterdam before landing at the Geigy pharmaceutical company as director of biochemical research, where he stayed for nearly a decade. He joined Rockefeller University in 1983, and it was there, over the following decades, that the work for which he won the Nobel Prize reached full maturity.

Two Kinds of Conversation: Fast and Slow Synaptic Transmission

The lecture opens with a distinction that organises everything that follows. Neurons communicate with each other across tiny gaps called synapses, and they do so in two fundamentally different ways — one rapid and direct, one slower and far more consequential.

Fast synaptic transmission works within a millisecond. A neurotransmitter such as glutamate (the brain's main excitatory signal) or GABA (the main inhibitory signal) docks onto a receptor that is itself an ion channel. The channel opens immediately. Ions flood in or out. The neuron fires or is silenced. The whole transaction is over in less time than it takes to blink.

Slow synaptic transmission is different in almost every respect. It is triggered by a different family of neurotransmitters — dopamine, serotonin, noradrenaline, and many neuropeptides. It operates over hundreds of milliseconds to minutes. And rather than directly opening a channel, it sets off a chain of biochemical events inside the neuron that can alter the cell's behaviour for seconds, minutes, or even longer. Greengard's life work was to map this chain — to trace what happens, molecule by molecule, from the moment dopamine docks at the cell surface to the moment the neuron changes.

The Cascade: How Dopamine Changes a Neuron from the Inside

Greengard's key insight came from an analogy with hormones. Earl Sutherland had shown in the 1950s and 60s — work that won him a Nobel Prize in 1971 — that hormones like adrenaline exert their effects on cells not by entering them, but by triggering the production of a small internal messenger molecule called cyclic AMP (cAMP). This messenger then activates enzymes inside the cell, which carry the signal forward. The hormone never enters; it sends a message that gets relayed and amplified inside.

Greengard asked whether neurotransmitters might work the same way. Dopamine, serotonin, noradrenaline — these chemicals dock at receptors on the cell's outer membrane. Could they too be triggering an internal messenger system? The answer, which his lab demonstrated through painstaking biochemistry across the 1960s and 70s, was yes. And the machinery involved was more elaborate and more powerful than anyone had imagined.

The cascade is a signal amplifier as much as a relay. One dopamine molecule triggering one receptor can activate many molecules of protein kinase A, each of which can phosphorylate many target proteins. A whisper at the cell surface becomes a shout inside the cell — and the effects are broad, coordinated, and slow to fade.

DARPP-32: The Rosetta Stone of Neuropharmacology

If the cascade described above were the whole story, it would already be significant. But the most important discovery in Greengard's lecture — the one he calls his Rosetta Stone — came from mapping the proteins that protein kinase A actually phosphorylates, and finding one that was, in his words, unlike anything else in the brain.

The protein is called DARPP-32: Dopamine- and cAMP-Regulated Phosphoprotein, molecular weight 32 kilodaltons. It is found in enormous concentrations in the striatum — the brain region where dopamine signalling is richest, and where movement, reward, and motivation are orchestrated. When protein kinase A phosphorylates DARPP-32 at a specific site, the protein transforms into a potent inhibitor of another enzyme called protein phosphatase-1. And protein phosphatase-1 is itself a broad brake on the cascade — it dephosphorylates (switches off) many of the same proteins that kinase A switched on.

The pharmacological implications were immediate and vast. If DARPP-32 is the integration point for dopamine and related signalling, and if it turns out to mediate the effects of major drug classes on the brain, then understanding it means understanding, at the molecular level, why those drugs work. Greengard and his colleagues showed exactly this: cocaine, amphetamines, antipsychotics, antidepressants, and drugs of abuse all alter DARPP-32 phosphorylation in characteristic ways. The proteins that Carlsson had shown were depleted or overactive in brain disease, Greengard showed were regulated through this common molecular hub.

Not Just the Receiver: Regulating the Release of Signals Too

The cascade described so far operates in the receiving neuron — the one that dopamine is acting upon. But Greengard's lab also made major discoveries about the sending side: how neurotransmitter release from presynaptic terminals is itself regulated by phosphorylation.

The key proteins here are the synapsins — a family of proteins that coat the small vesicles (membrane-bound packets) in which neurotransmitters are stored inside the presynaptic terminal. Greengard and his collaborators showed that when synapsins are unphosphorylated, they tether neurotransmitter vesicles away from the release site, keeping them in reserve. When the neuron fires rapidly, calcium floods in and activates a kinase that phosphorylates the synapsins. They release their grip. More vesicles move to the release site. More neurotransmitter floods out.

Together, the presynaptic (synapsin) and postsynaptic (DARPP-32) arms of Greengard's work offered something genuinely new: a unified molecular account of how slow neurotransmission regulates both the sending and the receiving of signals — and how that regulation can be altered by drugs, disease, or experience.

What Happens Inside the Black Box

It is worth pausing on what Greengard's work actually accomplished. Before it, pharmacologists knew that dopamine caused effects — Carlsson had shown this in animals, Hornykiewicz had confirmed it in Parkinson's brains, and clinical psychiatry had built an entire field of antipsychotic drugs on the observation that blocking dopamine relieved psychosis. But the mechanism — the molecular machinery that translated the docking of dopamine at a receptor into a changed neuron — was a black box. The drugs worked, but nobody knew why at the level of molecules.

Greengard opened the box. He showed that slow synaptic transmission is mediated by a cascade of biochemical events — second messengers, protein kinases, phosphorylation — and that this cascade is the common mechanism through which not just dopamine but serotonin, noradrenaline, and numerous other neurotransmitters exert their lasting effects. He identified DARPP-32 as the convergence point of these cascades in the striatum, and showed that it mediates the actions of antipsychotics, cocaine, amphetamines, and antidepressants. He showed that synapsin phosphorylation controls neurotransmitter release and provides a molecular substrate for synaptic strengthening.

The practical implications are still unfolding. Because DARPP-32 and the phosphorylation cascade are so central to the action of existing drugs, understanding them in detail opens the possibility of designing new drugs that act with much greater specificity — targeting particular steps in the cascade rather than entire neurotransmitter systems at once. The side effects of current antipsychotics and antidepressants are largely the result of their bluntness: they affect dopamine or serotonin signalling throughout the brain, not just in the circuits where the problem lies. The molecular map that Greengard drew is a guide to a more precise pharmacology.

Greengard died in April 2019, at ninety-three, still active at Rockefeller. The Pearl Meister Greengard Prize continues to be awarded each year. His lecture, read alongside Carlsson's, forms one of the most coherent double acts in Nobel history: one man showing what dopamine does, the other showing exactly how it does it — the macroscopic story and its molecular explanation, delivered in the same room, in the same week, in Stockholm, in December 2000.