QnAs with Nicholas C. Spitzer

The developing human brain is known for its remarkable plasticity, whereas the adult brain has been considered relatively unchanging. However, learning and memory continue throughout adult life, as do changes in synapse strength and synapse number. Adding to these facets of adult brain plasticity is the phenomenon of neurotransmitter switching, discovered by National Academy of Sciences member Nicholas C. Spitzer, of the University of California, San Diego, and colleagues. According to Spitzer, neurotransmitter switching refers to the down-regulation of one neurotransmitter and up-regulation of another within the same neurons. Such switching usually converts the neurons from excitatory to inhibitory or vice versa, with the receptors of connecting neurons undergoing corresponding changes. Neurotransmitter switching typically occurs in response to sustained stimulation and can cause changes in behavior. For example, nocturnal rats experience neurotransmitter switching from dopamine to somatostatin when exposed to long-day photoperiods for a week, which causes anxious and depressed behavior. In his Inaugural Article, Spitzer and his colleagues explore the mechanism of neurotransmitter switching, which may have relevance to human mental illness (1). Spitzer recently spoke with PNAS about his findings.

Nicholas C. Spitzer. Image courtesy of Nicholas C. Spitzer.

PNAS: How did you first encounter the phenomenon of neurotransmitter switching?

Spitzer: We got our first clues to transmitter switching in 1993, while studying differentiation of spinal cord neurons in culture. Forty percent of these neurons expressed GABA, an inhibitory neurotransmitter, when calcium ions were present in the culture medium; only 10% of neurons expressed GABA when calcium ions were absent or when RNA synthesis was blocked. We think that the presence of calcium signaling stimulated elevated GABA expression, while the absence of calcium signaling allowed only a basal level of expression. Transmitter switching is homeostatic in the sense that increased activity leads to appearance of inhibitory transmitters, as if to suppress the activity, and leads to disappearance of excitatory transmitters that would generate activity. Seeing plasticity in transmitter identity was a bit of a shock, frankly. The word on the street was that transmitters are fixed and unchanging.

PNAS: What is the mechanism of neurotransmitter switching that you found in your Inaugural Article (1)?

Spitzer: We had shown that embryonic transmitter switching over a couple of hours depended on changes in activity that involved calcium influx and release of brain-derived neurotrophic factor, leading to changes in gene transcription. Changes in activity were our first choice for the adult nervous system as well, but the fact that a week of altered photoperiod was required raised the possibility that it was changes in metabolism or in the levels of hormones, as alternatives.

So often in science it’s the availability of tools that allow one to do interesting experiments and make new observations. In this case, the availability of a TH-Cre transgenic rat line from Karl Deisseroth at Stanford was an enabling tool for us in allowing first author Da Meng to suppress activity in these tyrosine-hydroxylase–expressing dopaminergic neurons. Is it the activity of the neurons that are switching the transmitter, or could it be the activity of neighboring neurons? Da’s experiments showed that it is the activity of the neurons themselves. One would describe it as a cell-autonomous switch that depends upon the activity of the neurons that are doing the switching, not on the activity of their neighbors and friends.

PNAS: What evidence is there for neurotransmitter switching in humans?

Spitzer: Tim Aumann in Melbourne, Australia set up a collaboration I was delighted to be involved in that compared the brains of people who died in the winter to those of people who had died in the summer for reasons very likely unrelated to changes in activity in their brains. We obtained brains from a brain bank in Glasgow, Scotland, which is located at 55.8° north latitude, with long summer days and short winter days. People who had died in the summer had more neurons with markers of dopamine expression in the midbrain, compared with people who had died in the winter. This evidence motivates further studies of humans and the use of positron emission tomography to detect changes in receptor expression as a marker of changes in transmitter expression. One could track changes dynamically and noninvasively in single individuals.

PNAS: How do your results add to the body of knowledge about neurotransmitter switching?

Spitzer: Long-term exposure to a stimulus can change transmitter identity in neurons in the adult brain by the sustained change in activity of these neurons.

Transmitter switching is activity-dependent in the adult, as well as in the developing brain. Mental illness is frequently characterized as a chemical imbalance in the brain. This fuels our thinking that stressors of any kind that alter the electrical activity in the brain in a sustained manner could contribute to mental illness by changing the balance of neurotransmitters. We’re exploring this hypothesis to determine the extent to which it is a reality.

The switching neurons Da Meng found coexpress another transmitter, glutamate. Neurotransmitter switching typically involves only 20–30% of a population of neurons expressing a particular transmitter in a particular region of the brain. This invites the thinking that transmitter coexpression might be a biomarker for a priori identification of switching neurons before they are found to switch. That would be helpful in understanding the extent of transmitter switching throughout the brain.

PNAS: What do these results tell us about how the brain reshapes itself in response to our experiences?

Spitzer: The brain is constantly changing, not only during development, but in the adult as well. Neurotransmitter switching brings another dimension of flexibility to the adult brain. We have a variety of experiences with different intensities and different durations. The information about those experiences appears to be registered by different forms of plasticity. A short-term, brief stimulus might be registered by a change in synaptic strength. A longer stimulus could be noted by changes in synapse number. If a stimulus is persistent over a sustained period, then transmitter switching may be induced.