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December 2005
Children's Research Institute News Brief
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Bernard L. Maria, MD, MBA
Executive Director
Darby Children's Research Inst. |
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Inderjit Singh, PhD
Scientific Director
Darby Children's Research Inst. |
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The Neuroscience of Psychiatric Diseases and Addiction
In this issue of Kids Connection, the focus is on programs that address the needs of adolescents at a critical juncture in
development. Prevalent disorders such as depression, bipolar disorder, generalized stress disorder, drug addiction, obsessive
compulsive disorder and attention deficit hyperactivity disorder (ADHD) are all seen in adolescents. Genetic and environmental
factors each contribute to occurrence of these disorders. Of the environmental influences, life stress is clearly the most
important factor. This can range from stress during pregnancy such as infection or hypoxia, to stresses such as physical or
psychological child abuse and malnutrition.
Our research group in the Charles P. Darby Children's Research Institute (DCRI) is studying the interplay between genetics and
early adolescent environmental stress in the development of neuropsychiatric disorders and addiction.
In these studies, rodents are exposed to either enriched or impoverished environments throughout late childhood and adolescence
(beginning as soon as the animals are weaned at 21 days after birth, and continuing until sexual maturity at 60 days after birth).
In the enriched environment animals are housed in groups of eight to10 in a large environment where objects (toys) are traded in
and out everyday. These toys include tunnels, textured objects, assorted balls and chew toys. In addition, an investigator handles
the subjects for 20 min each day. By contrast, the impoverished rats live alone in a relatively small environment with no interesting
objects and are never handled by the investigator. Dr Roberto Melendez and a graduate student, Mary Lee Gregory, showed that animals
reared in the impoverished environment show a number of deficits in the development of their brains, ranging from molecular changes in
cell signaling to poor performance in memory tasks.
Dr. Peter Kalivas's group has focused on changes produced in the prefrontal cortex, a brain region implicated in a number of neuropsychiatric
disorders. They have found that signaling through glutamate receptors in this area is defective in the impoverished animals, and this confers
a reduced ability to perform memory tasks. They suspect that the problem may result, in part, from poor attention to the task, akin to ADHD.
Another graduate student, Jamie Peters, demonstrated that rats reared in an impoverished environment also show greater sensitivity to
psychostimulant drugs of abuse, such as cocaine. This is consistent with other recent findings from the laboratory by Dr Karen Szumlinski
(now an assistant professor at UC Santa Barbara) who used genetic mouse models of deficits in glutamate transmission in the prefrontal cortex.
In these studies a family of genes called the Homers, which encode proteins critical for glutamate receptor signaling, were deleted. These mice
showed deficits in cell signaling and behavior akin to the rats reared in an impoverished environment, including memory deficits and increased
addiction to cocaine. Interestingly, it was recently shown that a mutation in the Homer gene is associated with the development of schizophrenia,
a disease with typical onset in late adolescence. Finally, Dr Alejandra Pacchioni and collaborators at the University of Pennsylvania showed
that a mutant mouse deficient in a gene called Nac-1 is unresponsive to an acute injection of cocaine in both behavior and neurotransmission,
and Dr Haowei Shen and Dr Ryan LaLumiere have found that this may be related to a role they recently discovered for Nac-1 to transport protein
degrading machinery to the synaptic cleft in response to cellular activation. For an illustration of the role of Nac-1, see Figures 1 and 2
below. They demonstrate that the proteosome is trafficked to the spine by Nac-1. Given the ability of the Homer and Nac-1 genes to regulate
psychostimulant effects or learning and memory, it will next be determined if rearing environments can exacerbate or ameliorate these genetic
vulnerabilities.
Note the effects of synaptic activity on NAC1 and cullin-3 proteins.
Note the effects of PKC activation on the post-synaptic localization of NAC1.
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