Pennsylvania: Fathers who use cocaine at the time of conceiving a
child may be putting their sons at risk of learning disabilities and
memory loss. The findings of the animal study were published online in Molecular Psychiatry by a team of researchers from the Perelman School of Medicine
at the University of Pennsylvania. The researchers say the findings
reveal that drug abuse by fathers—separate from the well-established
effects of cocaine use in mothers— may negatively impact cognitive
development in their male offspring.
The study,
which was led by Mathieu Wimmer, PhD, a post-doctoral researcher in the
laboratory of R. Christopher Pierce, PhD, a professor of Neuroscience
in Psychiatry in the Perelman School of Medicine at the University of
Pennsylvania, found evidence that the sons of fathers that ingested
cocaine prior to conception struggle to make new memories. Their
findings demonstrated that the sons -- but not the daughters -- of male
rats that consumed cocaine for an extended period of time could not
remember the location of items in their surroundings and had impaired
synaptic plasticity in hippocampus, a brain region critical for learning
and spatial navigation in humans and rodents.
“These results suggest that the sons of male cocaine addicts may be
at risk for learning deficits,” said senior author, R. Christopher
Pierce, PhD, a professor of Neuroscience in Psychiatry in the Perelman
School of Medicine at the University of Pennsylvania.
Pierce and his colleagues propose that epigenetic mechanisms are at
the root of the problem. Epigenetics refers to heritable traits that are
not caused by changes in the DNA sequence, as is the case with genetic
inheritance. DNA is tightly wound around proteins called histones, like
thread around a spool, and chemical changes to histones influence the
expression of genes, which is an epigenetic process. Their research
showed that cocaine use in dads caused epigenetic changes in the brain
of their sons, thereby changing the expression of genes important for
memory formation. D-serine, a molecule essential for memory, was
depleted in male rats whose father took cocaine and replenishing the
levels of D-serine in the sons’ hippocampus improved learning in these
animals.
In collaboration with Benjamin Garcia, PhD, presidential professor of Biochemistry and Biophysics in the Epigenetics Institute at the Perelman School of Medicine,
the authors showed that cocaine abuse in dads broadly altered the
chemical marks on histones in the brain of their sons, even though the
offspring were never exposed to cocaine. Chemical modifications on the
histones were changed to favor active transcription of genes in the
hippocampus of male rats with a paternal history of cocaine taking,
allowing more production of the enzyme D-amino acid oxidase, which
degrades D-serine. The authors propose that increased expression of the
enzyme, driven by changes in the epigenetic landscape, cause the memory
problems in the sons of addicted rats.
“There is substantial interest in the development of D-serine and
related compounds, which are well tolerated by humans, as drug
therapies,” Pierce said. “The ability of D-serine to reverse the adverse
effects of paternal cocaine taking on learning adds potential clinical
relevance to our research.”
Penn Medicine co-authors of the article include Lisa Briand, Bruno
Fant, Leonardo Guercio, Adrian Arreola, Heath Schmidt, Simone Sidoli and
Yumiao Han.
This research was supported with grants by the National Institutes of
Health and the National Institute on Drug Abuse (T32 DA28874, R01
DA33641, K02 DA18678, K01 DA30445, K01 DA039308, R00 DA033372, R21
MH102679, R21 GM110174, DOD W81XWH-13-1-0426).