The nervous system consists of billions of neurons, each
making thousands of contacts, termed synapses, with other
neurons. Unlike an electrical circuit in a computer chip,
however, the nervous system is not hard-wired based on
a predesigned template. Rather, synaptic contacts between
neurons are formed and modified during development of
the brain based on their ongoing utilization. Even after
contacts are made, the effectiveness of the information
transmitted through such synapses is modified during learning
and memory. Neuronal networks with modifiable synaptic
contacts enable us to be conscious thinkers, to learn
from experience, have complex emotions, and be creative
in the arts and sciences. One of the central tenets of
molecular and cellular neurobiology is that even complex
functions such as learning and memory are composed of
elementary units subject to experimental discovery.
The collective efforts of many neuroscientists in the
past three decades have successfully reduced certain forms
of learning and memory to a fundamental biochemical switch
that regulates the efficacy of synaptic transmission at
individual synapses. Work in my laboratory has focused
on the identification of a critical regulatory molecule,
termed CaM kinase 11, which may be intimately involved
in this memory switch.
Nerve cells respond to sensory inputs originating in
the environment by "firing" an electrical pulse that travels
to the tips of the nerve cell to elicit release of chemical
transmitters onto receptive neurons at synapses. It is
intriguing that receptive neurons respond to a relatively
brief increase in input firing frequency with a long-lasting
change in efficiency of synaptic transmission, an elementary
form of memory. A transmitter molecule called glutamate
is released onto the neuron. A recognition protein on
the receiving neuron (termed NMDA receptor) detects glutamate
and responds to high frequency glutamate release by allowing
calcium ions to flow into the neuron. Calcium serves as
an intracellular signal for the presence of glutamate
outside and triggers a switch in the response of the neuron
to subsequent stimulation.
Many years ago, I found the link between calcium entry
and the ultimate change in synaptic strength, a decoder
of calcium called CaM kinase 11. It is a protein catalyst
that is activated by elevated calcium, leading to several
consequences. First, CaM kinase 11 is very cleverly designed
to allow high frequency stimulation to produce a prolonged
"on" state. Calcium transiently activates the kinase by
displacing an inhibitory gate that normally suppresses
its catalytic activity. A segment of the NMDA receptor
recognizes the activated enzyme and recruits it to the
synapse by wedging itself in the "hinge" of this gate.
This keeps the gate open and the kinase active even after
calcium levels return to baseline, a short-term potentiation.
Furthermore, the active kinase chemically modifies its
inhibitory gate with a phosphate group that disables the
gate and keeps it open until the phosphate is removed
by another catalyst. In fact, Lisman and Zhabotinsky at
Brandeis have suggested conditions under which the autocatalytic
addition of phosphate exceeds its removal, producing a
memory switch. Other investigators have shown that the
"on" state of the kinase is necessary and sufficient to
produce some of the alterations at synapses that are responsible
for the increase in synaptic efficacy that is seen in
this form of learning and memory. These studies demonstrate
features of CaM kinase 11 that enable it to maintain an
"on" state that supports a synaptic switch. It explains
why mice with mutations that block the autocatalytic function
of CaM kinase 11 are deficient in learning and memory.
