A “molecular volume knob” that regulates electrical signals in the brain
helps with learning and memory, according to a Dartmouth study.
The molecular system controls the width of electrical signals that flow
across synapses between neurons.
The finding of the control mechanism, and the identification of the molecule
that regulates it, could help researchers in their search for ways to manage
neurological disorders, including Alzheimer’s disease, Parkinson’s disease
and epilepsy.
The research, published in Proceedings of the National Academy of Sciences,
describes the first study of how the shapes of electrical signals contribute
to the functioning of synapses.
“The synapses in our brain are highly dynamic and speak in a range of
whispers and shouts,” said Michael Hoppa, an assistant professor of
biological sciences at Dartmouth and the research lead. “This finding puts
us on a straighter path toward being able to cure stubborn neurological
disorders.”
Synapses are tiny contact points that allow neurons in the brain to
communicate at different frequencies. The brain converts electrical inputs
from the neurons into chemical neurotransmitters that travel across these
synaptic spaces.
The amount of neurotransmitter released changes the numbers and patterns of
neurons activated within circuits of the brain. That reshaping of synaptic
connection strength is how learning happens and how memories are formed.
Two functions support these processes of memory and learning. One, known as
facilitation, is a series of increasingly rapid spikes that amplifies the
signals that change a synapse’s shape. The other, depression, reduces the
signals. Together, these two forms of plasticity keep the brain in balance
and prevent neurological disorders such as seizures.
“As we age, its critical to be able to maintain strengthened synapses. We
need a good balance of plasticity in our brain, but also stabilization of
synaptic connections,” said Hoppa.
The research focused on the hippocampus, the center of the brain that is
responsible for learning and memory.
In the study, the research team found that the electric spikes are delivered
as analog signals whose shape impacts the magnitude of chemical
neurotransmitter released across the synapses. This mechanism functions
similar to a light dimmer with variable settings. Previous research
considered the spikes to be delivered as a digital signal, more akin to a
light switch that operates only in the “on” and “off” positions.
“The finding that these electric spikes are analog unlocks our understanding
of how the brain works to form memory and learning,” said In Ha Cho, a
postdoctoral fellow at Dartmouth and first author of the study. “The use of
analog signals provides an easier pathway to modulate the strength of brain
circuits.”
Beyond discovering that the electrical signals which flow across synapses in
the brain’s hippocampus are analog, the Dartmouth research also identified
the molecule that regulates the electrical signals.
The molecule—known as Kvβ1—was previously shown to regulate potassium
currents, but was not known to have any role in the synapse controlling the
shape of electrical signals. These findings help explain why loss of Kvβ1
molecules had previously been shown to negatively impact learning, memory
and sleep in mice and fruit flies.
The research also reveals the processes that allow the brain to have high
computational power at low energy. A single, analog electrical impulse can
carry multi-bit information, allowing greater control with low frequency
signals.
“This helps our understanding of how our brain is able to work at
supercomputer levels with much lower rates of electrical impulses and the
energy equivalent of a refrigerator light bulb. The more we learn about
these levels of control, it helps us learn how our brains are so efficient,”
said Hoppa.
Nobel laureate Eric Kandel conducted work on the connection between learning
and the change in shapes of electrical signals in marine sea slugs in 1970.
The process was not thought to occur in the more complex synapses found in
the mammalian brain at the time.
For decades, researchers have searched for molecular regulators of synaptic
plasticity by focusing on the molecular machinery of chemical release. Until
now, measurements of the electrical pulses had been difficult to observe due
to the small size of the nerve terminals.
The research finding was enabled by technology developed at Dartmouth to
measure voltage and neurotransmitter release by using light to measure
electrical signals in synaptic connections between neurons in the brain.
In future work, the team will seek to determine how the discovery relates to
changes in brain metabolism that occur during aging and cause common
neurological disorders.
According to the research team, the molecular system exists in an area of
the brain that is easily targeted by pharmaceuticals and could lend itself
to the development of drug therapies.
Reference:
In Ha Cho, Lauren C. Panzera, Morven Chin, Scott A. Alpizar, Genaro E.
Olveda, Robert A. Hill, Michael B. Hoppa. The potassium channel subunit Kvβ1
serves as a major control point for synaptic facilitation. Proceedings of
the National Academy of Sciences, 2020; 202000790 DOI:
10.1073/pnas.2000790117