Dr. Pardo leads a research program which seeks to 1) elucidate the functional architecture of the human brain with particular emphasis on how dysfunction within neural networks relates to psychiatric disorders; 2) to identify neural systems mediating cognitive operations (e.g., attention, memory); 3) to define the pathophysiology of mental illness.
His team identified the anterior cingulate cortex as a locus of attentional operations (PNAS 1990; 87:256) and the major site of cognitive aging in otherwise healthy individuals (Neuroimage 2007; 35(3):1231. They have also applied brain imaging for early diagnosis of the dementias (Alzheimers Dement 2010; 6(4): 326).
These studies point to a high degree of genetic heterogeneity especially in psychiatric nosology. To address this issue, a major effort underway is the discovery of Mendelian genes (rare, high penetrance, simple inheritance). An international collaboration was established 1) to recruit multiplex, first-cousin marriages with a defined phenotype (e.g., psychosis); 2) whole genome sequencing of pedigree members; and 3) filtering for variants of interest, VOI (e.g., homozygosity mapping, evolutionary conservation, predicted damaged protein; absence in normative databases). Currently, the prime VOI is USP53 p.C228R. Preliminary molecular studies show this protein localizes to the hippocampus and dentate granular regions and interacts with GRIA2 and GRIP2—components of the AMPA synapse. These findings support the glutamate hypothesis of schizophrenia and motivate additional molecular studies of the variant.
