Nicholas Spitzer, Ph.D.

Institute for Brain and Mind
University of California, San Diego
(October 4, 2010)

Activity-Dependent Transmitter Specification: Novel Plasticity

Dr. Nicholas Spitzer's research examines the fundamental questioof how the brain cells, or neurons, "decide" which neurotransmitters to release. It is well known that different neurotransmitters, the small molecules that neurons use to communicate, are capable of eliciting different responses. Dr. Spitzer's lab has shown that there is a complex set of genetic programs that neurons use to select which type of neurotransmitter to use and therefore how they communicate with other neurons in a given circuit. These are the basic building blocks of neural signaling that eventually give rise to behavior. Dr. Spitzer shows how these principles are revealed in the intriguing phenomenon of camouflage coloration in amphibian larvae.

Brain cells within neural circuits signal each other largely through the release of neurotransmitters and the activation of their receptors at synapses. Ever since Otto Loewi and Henry Dale discovered the chemical synapse, it has been thought that these transmitters are fixed characteristics of neuronal identity. The specification of neurotransmitters and receptors is a fundamental developmental process, critical for the establishment of functional connections at synapses. With a vast number of neurons, specifying the appropriate neurotransmitter for each one is a challenging task. Moreover, since neurons can receive thousands of different synaptic inputs, matching presynaptic neurotransmitters with appropriate postsynaptic neurotransmitter receptors is a daunting undertaking. The problem is even further complicated by the existence of the large number of neurotransmitters and neurotransmitter receptors.

Genetic programs are essential for the differentiation of different neuronal phenotypes and have been shown to establish default transmitter phenotypes. However, perturbations of calcium-dependent electrical activity in the embryonic spinal cord increase or decrease the number of neurons expressing the neurotransmitters glutamate, GABA, acetylcholine and glycine by as much as 50 percent. Additionally, it has been found that altering light exposure, which changes the sensory input to the circuit controlling adaptation of skin pigmentation to background, changes the number of neurons expressing dopamine in the brain of amphibian larvae in a circuit-specific and activity-dependent manner. Neurons newly expressing dopamine then regulate changes in camouflage coloration in response to illumination. Thus, physiological activity alters the numbers of behaviorally relevant amine-transmitter-expressing neurons in the brain at postembryonic stages of development. The results may be pertinent to changes in cognitive states that are regulated by biogenic amines.

The Spitzer lab has identified several molecular mechanisms that link endogenous calcium spike activity with intrinsic genetic pathways to specify neurotransmitter choice in the embryonic amphibian nervous system. In the brain of these modelorganisms, activity modulates specification of serotonergic neurons by regulating expression of the Lmx1b transcription factor. Activity acts downstream of Nkx2.2, but upstream of Lmx1b, leading to regulation of the serotonergic phenotype. Changes in the number of serotonergic neurons change larval swimming behavior. These results link activity-dependent regulation of a transcription factor to transmitter specification and altered behavior. In the spinal cord, early activity modulates transcription of the GABAergic/glutamatergic selector gene tlx3. Calcium signals through phosphorylation of the cJun transcription factor, which in turn binds to a cAMP response element (CRE) site in the tlx3 promoter. Binding with this CRE site modulates transcription, thus regulating the neurotransmitter phenotype. This mechanism provides a basis for early activity to regulate genetic pathways at critical decision points, switching the phenotype of developing neurons.