Long-term potentiation (LTP) is a basic mechanism of synaptic plasticity that conforms to the principles of Hebbian learning (i.e., "neurons that fire together wire together"), and it is the leading candidate substrate of learning and memory. A variety of theoretical perspectives and observations suggest that the mechanisms of experience-mediated synaptic plasticity are compromised in schizophrenia: NMDA-hypofunction model of schizophrenia predicts dysfunction of NMDA-dependent LTP, and neuroinflammation is associated with deficits in both LTP and schizophrenia. Further, inflammation may be a primary mediator of the well-established decline in LTP function associated with normal aging. Moreover, LTP-related deficiencies in experience- mediated synaptic strengthening may contribute to functional dysconnectivity between brain regions in schizophrenia. Recently, two paradigms for assessing LTP-like synaptic plasticity in vivo in humans have been developed, allowing theories of impaired plasticity in schizophrenia to be tested. Ultimately, these paradigms may provide novel translational measures of synaptic plasticity for development of plasticity-enhancing interventions, including drugs. We ask whether the plasticity measures derived in the two paradigms are 1) correlated with each other, 2) associated with inflammation, and 3) reliable over time in schizophrenia patients. Accordingly, we address three specific aims, with the overarching aim to further validate human LTP-like neuroplasticity paradigms with respect to their sensitivity to schizophrenia and inflammation.
Aim 1) Schizophrenia (SZ) patients and healthy control (HC) subjects sampled across the adult age range (18-55) will undergo, in separate sessions two tests of LTP. We predict the neuroplastic changes produced by each paradigm will be correlated.
Aim 2) To examine whether inflammation plays a role in LTP-like plasticity in schizophrenia across the age range, blood will be drawn to assay the inflammatory cytokines. We predict higher inflammatory cytokine levels will be associated with reduced LTP-like potentiation in both paradigms. We further predict that the effects of schizophrenia and age on LTP-like plasticity will be partially mediated by inflammation.
Aim 3) In order to assess whether both measures of plasticity are reliable over time, SZ and HC will be retested with both paradigms 2 weeks after their initial assessment. We also have an exploratory aim to relate LTP-like plasticity to cognitive impairments assessed using the MATRICS cognitive test battery.

Public Health Relevance

Long-term potentiation is a basic neural mechanism responsible for learning and memory. Recent data suggest it is abnormal in schizophrenia. We ask whether the abnormalities are robust to methods, related to neuroinflammation, worsen with age, and underpin cognitive deficits.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH102727-01
Application #
8624579
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Meinecke, Douglas L
Project Start
2014-01-01
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$229,950
Indirect Cost
$79,950
Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121