Probing the deepest levels of brain chemistry to uncover clues to memory loss

By Juan Miguel Pedraza
“It’s a poor sort of memory that only works backwards,” remarks the Queen in Lewis Carroll’s Through the Looking Glass.  Even worse is memory that fails to work in any direction, a failure scientists are just now beginning to unravel from the tangled web of neural connections that makes up who each of us is, what we remember, and what we forget.

Perhaps scarier still are diseases such as epilepsy that seem to have a mind of their own, striking unpredictably, sometimes fatally, nearly always sadly, through no fault of the victim.  All too often, the cause is unknown.

Though researchers over the past two decades have unlocked many of the secrets of the brain — defining many neural pathways and brain circuits involved in memory, learning, and behavior — there remain numerous “mysteries” that continue to baffle science.  “We’re still a ways off from getting a clear handle on all of these brain functions.  There’s plenty of work to be done,” said Doze.

Epilepsy-controlling, or anti-seizure, drugs interfere with memory and learning (the two go hand in hand; it’s tough to learn what you can’t remember).  The human nervous system includes the central nervous system — the brain and the spinal cord — and the peripheral nervous system.  Epileptic and other seizures involve both systems.

At its core, the Doze-Porter collaborative research involves the close-up study of the noradrenergic system.  They are looking at the mechanics of the neurotransmitters involved in epileptic seizures, the drugs that control those seizures, and the collateral mechanisms in those drug interactions that can, with current therapies, cause learning and memory loss.

Doze said the adrenergic system — one of the essential neurochemical systems in the brain — synthesizes and controls the release of the neurotransmitter norepinephrine (also known as noradrenalin).

Norepinephrine works in both the central and peripheral nervous systems.  It’s responsible for many critical functions, but in this context, its key functions in the central nervous system include sleep, emotions, learning, and memory.  Norepinephrine also has been shown to possess potent antiepileptic properties, Doze says.

 In technical terms, the team is working on more clearly understanding and defining the adrenergic modulation of seizures and neurodegeneration.  They are attempting to uncover why the brain, essentially, does things that eventually will destroy itself and how the interventions they are working on will alleviate those reactions while enhancing learning and memory.  A key challenge, the team says, is that it is tough to pinpoint and exactly describe which cells do what in the brain.  There are so many with so many functions that it’s still the central problem of neuroscience to get it all neatly sorted out.

“However, we believe that there’s a specific set of neurons which we’ve found in rats that’s related to the processes we’re studying,” Doze said.  “One such heterogeneous area, the CA1 region of the rat hippocampus, possesses a number of different cells thought to play key roles in disorders such as epilepsy and Alzheimer’s disease.” Characterizing the molecular constitution of these cells is a critical step in the discovery of new receptor targets, which could be utilized pharmacologically.  Completion of the specific aims for this project could result in the elucidation of a novel strategy for the treatment of epileptic seizures.
Porter, a pharmacologist, is focusing on the molecular mechanisms of drug action and verification of potential therapeutic targets.  His goal is to combine the latest cell and biomolecular techniques with classic pharmacological methods to characterize the properties of neuroreceptors, such as those involved in epilepsy, using mammalian cell and tissue models of human diseases.

“The information we get from these studies will be used to develop molecular models that can identify chemical agents that could be used to treat chronic pain, epilepsy, stroke, and neurodegeneration,” Porter explains.
The science is abstruse and very technical; the desired outcome certainly is not.

“We understand that what we’re working on has profound implications for health care,” said Doze.

Among the more promising, and medically exciting, developments in this research is the possibility of adult neurogenesis, once thought absolutely impossible.  Earlier theorists suggested that humans were allotted a certain number of brain cells; if you lost any, tough luck — the body would not regenerate nerve cells.  But, Doze and Porter suggest, that theory now lacks much vigor.