Altered function of cortical glutamate afferent and efferent projections is thought to contribute to the pathophysiology of schizophrenia. In particular, attention has focused on possible alterations in glutamate N-methyl-D-aspartate (NMDA) receptors in the prefrontal cortex (PFC). Individual NMDA receptors are comprised of a common NR1 subunit (necessary for functional NMDA receptors) together with a combination of NR2A-D subunits. Recent postmortem studies have found evidence of decreased NR1 transcript in the PFC of schizophrenic subjects. A goal of our research is to examine whether regionally restricted loss of NR1 function in the PFC contributes to cognitive and neurochemical deficits associated with the illness. The present studies will be performed in a mouse model in which loxP sites flank a functionally requisite exon of the NR1 subunit (fNR1 mice). Gene deletions will be performed by local administration of adeno-associated-virus Cre recombinase. Our previous studies indicate that impaired function of the NR1 subunit in the medial PFC and CA3 hippocampus of fNR1 mice differentially disrupts sustained attention and working memory, respectively.
Aim 1 of the present proposal is to further explore the effects of localized disruptions of the NR1 subunit in the PFC and CA3 hippocampus on cognitive function in adult fNR1 mice. Cognitive function will be examined using delayed spatial win-shift, non-delayed random foraging, and visual sustained attention tasks.
Aim 2 will assess whether NR1 dysfunction in the PFC results in secondary disruptions in the neurochemical activity of mesoprefrontal dopamine (DA) neurons. Dysfunction of mesoprefrontal DA neurons has long been thought to contribute to cognitive deficits in schizophrenia. Furthermore, considerable experimental evidence supports the existence of a glutamate-DA interaction in the PFC and, in turn, our hypothesis that chronic NR1 dysfunction will impair the functional capacity of mesocortical DA neurons. The effects of localized PFC NR1 dysfunction on regulation of local extracellular DA will be examined using in vivo microdialysis. Preliminary data from our lab supports the feasibility of performing microdialysis in fNR1 mice. The overall goal of the proposed research is to examine the behavioral and neurochemical effects of dysfunction of glutamate N-methyl-D-aspartate (NMDA) receptors in the prefrontal cortex (PFC) in an effort to further understand the neurobiological basis of cognitive deficits associated with schizophrenia. Consistent with the objective of the AREA grant mechanism, all preliminary and future experiments described in this proposal have involved and will continue to involve undergraduate students in our newly established behavioral neuroscience major at Western Washington University.
Schizophrenia is a debilitating disease affecting ~1% of the population. Cognitive deficits associated with the disease are the most disruptive and unfortunately, the least responsive to currently available treatments. The proposed research endeavors to further our understanding of the neurobiological basis of these deficits in the hopes of ultimately, contributing to ongoing efforts to develop novel treatments for the cognitive impairment.
| Finlay, Janet M; Dunham, Ginger A; Isherwood, Analiesse M et al. (2015) Effects of prefrontal cortex and hippocampal NMDA NR1-subunit deletion on complex cognitive and social behaviors. Brain Res 1600:70-83 |
