Regulation of excitability
One of the most salient properties of the nervous system is its plasticity or capacity to change. An undesirable consequence of plasticity is the potential instability of the system. In spite of being highly plastic, neurons and neural networks maintain relatively stable properties. This can be seen at all levels of complexity, all the way from single neurons to the whole behaving animal. This is true for crabs as well as for humans. Neurons maintain an identity while simultaneously changing and adapting to external stimuli.
What are the mechanisms that allow the nervous system to retain its plasticity and be stable simultaneously? Plasticity has been studied mostly at the level of synapses, and is believed to underlie learning and memory. However, long-term plasticity also takes place at the level of the voltage-gated ionic currents that determine cellular excitability and the electric activity of both neurons and neural networks. This plasticity can in principle also underlie some forms of learning and memory, as well as the recovery from injury and different sorts of perturbation. Using both electrophysiological, pharmacological and computational tools, in my lab we study mechanisms of neuronal plasticity and homeostasis of the ionic currents that determine the excitability and electric activity of neurons and simple neural networks in the crustacean stomatogastric ganglion (STG).
Two mechanisms of long-term regulation of activity appear to be at work in STG neurons and neural networks. One appears to be activity-dependent, the other appears to be mediated by long-term effects of neuromodulatory input, also known to rapidly affect network activity in response to their release. We are currently characterizing these two mechanisms and their relative role in producing and maintaining a relatively constant (but modifiable) level of rhythmic activity. One surprise has been to find that neuromodulators, up to now thought to have only short term effects, also control coordination of the levels of expression (or of activation) of several ionic channels over long periods of time (hours). The cellular mechanisms and the functional implications of this phenomenon are unknown and is the current focus of most of the research in the lab. For this we use electrophysiology, computer modeling, molecular biology (e.g. RNA transfection and single cell PCR) and imaging tools.
These projects are currently funded by an NIH grant (2R01MH064711).
The role of gap junctions in the generation of neuronal activity is a topic of great interest. In my lab and in collaboration with Dr. Farzan Nadim we are studying the role of gap junctions in the generation of activity by neurons and neuronal networks of the STG. Using computational, electrophysiological and analytical techniques we look at how gap junctional currents interact with other ionic currents expressed by the connected neurons and how these interactions depend on current flow along the intricate branches of a neuronal dendritic tree to produce electrical activity.
We have discovered that dendrite diameter controls in a non-intuitive way the transmission of signals across gap junctions. Furthermore, gap-junction coupled neurons can form networks in which oscillatory activity emerges in the absence of chemical synapses or pacemaker neurons. We believe these properties may have important consequences for network function.
No trophic factors that can regulate
neuronal growth and survival in crustaceans have to date been discovered.
In the lab we are currently screening several neuropeptides known to have
short-term neurmodulatory effects for their possible involvement in trophic
regulation of dissociated adult neurons in cultured and in long term organotypical culture.
So far we have identified one peptide family with putative trophic function and
we are continuing with this screen. We plan to then study the
intracellular signaling pathways involved in these effects, as well as their
function in the adult and in development.
Important discoveries made in crustaceans
- Na-K ATPase was first characterized as having the properties of such an ATPase (dependence on external Na+ and internal K+, etc) by Skou (1957. Biochem. Biophys. Acta, 23: 394-401).
- Na-Ca exchange system was characterized in crab nerve (Baker & Blaustein, 1968, Biochem. Biophys. Acta, 150: 167-179) at the same time as in squid axon and cardiac muscle.
- Furshpan and Potter discovered of electric synapses in 1959 working with nerve fibers of the abdominal nerve cord of the crayfish (Furshpan & Potter, 1959, J. Physiol. (Lond), 145: 289-325)
- The pioneering studies showing direct inhibitory synaptic transmission were performed on the crustacean neuromuscular junction (Dudel & Kuffler, 1961, J. Physiol. (Lond), 155: 543-562, Takeuchi & Takeuchi, 1967, J. Physiol. (Lond), 191: 575-590), and the crayfish stretch receptor (Kuffler & Eyzaguirre, 1955, J. Gen Physiol, 130: 326-373).
- Identification of GABA as an inhibitory transmitter was
done first in the crustacean neuromuscular junction by Zack Hall, John
Hildebrand and Ed Kravitz in 1974 (Chemistry of Synaptic transmission, Chiron
Press, Newton, MA). See also
Otsuka, Iversen, Hall, Kravitz (1966) Release of gamma-aminobutyric
acid from inhibitory nerves of lobster. Proc Natl Acad Sci U S A. (1966)
Copyright: STG Lab 2012