The nervous system is incredibly fast. A dog runs across the street in front of you, and your foot instinctively jumps to the brake pedal. All of this occurs in a fraction of second, often before you even have time to fully process the scene in front of you (was it a dog? or a raccoon?).

The brain is fast because electrical signals in the brain travel fast (over 200 miles and hour, in some cases). And it isn’t just reflexive actions, like slamming your brakes, or lunging to catch a falling glass. We can make complex decisions in the blink of an eye, especially with a little practice and training:

And yet, our decisions and actions, which exist only for a brief instants of time, are captured as memories that can endure for decades.

Electrical signals provide speed, but the brain relies on biochemical reactions as a substrate for slower, more permanent processes like learning and memory. While a discrete electrical impulse typically lasts a few milliseconds, a newly synthesized protein can last for minutes, hours, days, or even years before being degraded. A fundamental question is how these two fundamental languages of the brain — electricity and biochemistry — communicate to each other, despite their widely varying time scales.

Dr. Richard Tsien has been studying this question for many years, and certainly ranks among the very top contributors to this field. His principal insight was that calcium ions participate in both electrical and biochemical signaling, allowing brain cells transmit information from rapid (electrical) signals to slow (chemical) processes that store memories and re-calibrate the system.

Back in 1985, Tsien was the first to characterize the various types of voltage-gated calcium channels [1]. These are proteins that form holes/pores in in the cell’s membrane, and open rapidly in response to an electrical potential. When these channels open, calcium ions (Ca2+) flow into the cell from the extracellular space. These ions carry electrical charge, but also interact with a stupefying number of biochemical pathways that regulate gene expression, protein synthesis and degradation, molecular trafficking, the release of hormones and neurotransmitters, and much more.

Dr. Tsien has tirelessly and meticulously chased down many of these calcium-activated pathways over the years. Far too many to enumerate in this brief summary. But the back-and-forth interplay between electrical and biochemical signaling emerges as a common theme of his work. For example, Tara Thiagarajan, Dr. Tsien, and others [2,3] discovered that chronically blocking electrical activity induces a biochemical response from neurons, causing them to increase the strength of their excitatory connections to other neurons. Calcium plays a pivotal role in this response, as outlined in the flow chart below:

flowchart

In this case, calcium works a bit like the thermometer in a thermostat: a drop in calcium signals that activity levels have dropped too low, and turns on the “heat” (excitatory connections between neurons) to compensate. In other work, Tsien and colleagues have studied the calcium-activated pathways that reconfigure synaptic connections to store long-term memories [4], and tune gene expression [5].

Given the privileged position of calcium between the electrical and chemical languages of the brain, it is not surprising that many neuropsychiatric disorders are associated with dysfunction in calcium signaling. For example, progressive memory loss in Alzheimer’s disease is associated with a slow creep in internal calcium levels [6]. Prescribing memantine (Namenda), one of the two approved classes of drugs for Alzheimer’s, can sometimes slow the rate of memory loss by partially blocking calcium ion flow into neurons. While most of Dr. Tsien’s work is focused on unraveling basic biological mechanisms, his lab has also published papers on the role of calcium dysregulation in schitzophrenia, Timothy syndrome, ataxia, and Down Syndrome.

If you are interested in diving into the details of this work, come see Sam Scudder discuss a recent paper from the Tsien lab (6pm, Monday journal club), which examines how calcium signals in distal dendrites regulate gene expression from afar:

Ma et al. γCaMKII Shuttles Ca2+/CaM to the Nucleus to Trigger CREB Phosphorylation and Gene Expression (2014). Cell 159(2): 281-294.

And be sure to stop by CNCB to see Dr. Tsien’s talk on April 7th at 4pm, in the CNCB auditorium.


Alex Williams is a first-year student in the Neurosciences PhD program at UCSD. He applies computational and theoretical techniques to study the molecular mechanisms of neural plasticity and stability. He tweets @ItsNeuronal. Also, Running. Lifting. Burritos.

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