Browsing by Subject "Receptors, Dopamine"
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Item Behavioral, Neurochemical, and Histological Characterization of Mice Deficient for Parkin, DJ-1, and Antioxidant Proteins(2011-08-26T17:35:01Z) Seamans, Katherine Webster; Goldberg, Matthew S.Parkinson’s disease is a progressive neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra. The cause of Parkinson’s disease remains uncertain, however, evidence implicates mitochondrial dysfunction and oxidative stress with selective vulnerability of dopaminergic neurons. Although most cases of Parkinson’s disease are sporadic, 5-10% of cases are caused by mutations in a single gene. Loss-of-function mutations in parkin and DJ-1 were the first to be linked to recessively inherited parkinsonism. Surprisingly, mice bearing similar loss-of-function mutations in parkin and DJ-1 do not show age-dependent loss of nigral dopaminergic neurons or depletion of dopamine in the striatum. Although the normal cellular functions of Parkin and DJ-1 remain unclear, we hypothesized that Parkin and DJ-1 protect cells from oxidative stress and that loss-of-function mutations in these genes cause neurodegeneration in Parkinson’s disease by rendering cells more sensitive to mitochondrial dysfunction and oxidative stress. We crossed mice deficient for Parkin and DJ-1 with mice deficient for the major mitochondrial antioxidant protein Mn-superoxide dismutase or Cu/Zn-superoxide dismutase. Previous studies have shown that mice with reduced levels of Cu/Zn-superoxide dismutase or Mn-superoxide dismutase are more sensitive to dopaminergic neurotoxins whereas mice with increased levels of superoxide dismutase are more resistant to dopaminergic neurotoxins. We predicted that reducing levels of antioxidant proteins in parkin-/-DJ-1-/- mice would result in age-dependent nigral cell loss, striatal dopamine depletion or behavioral abnormalities. Characterization of these mice for behavioral abnormalities, neurotransmitter defects and neuropathology, revealed significant behavioral abnormalities in the mutant mice even in the absence of significant changes to dopamine levels in the striatum, dopamine receptor density, or dopaminergic neuron numbers. Aged parkin-/-DJ-1-/- and Mn-superoxide dismutase triple deficient mice have a surprising enhanced rotorod performance without the presence of an anxiety phenotype or hyperactivity. Cu/Zn-superoxide dismutase and Mn-superoxide dismutase triple deficient mice have elevated levels of dopamine in the striatum, however none of the mice present with nigral cell loss. Levels of D1-like and D2-like dopamine receptors in the striatum were unchanged. It is evident from our studies that on a parkin/DJ-1 null background, additional loss of major antioxidant proteins does not lead to a progressive loss of dopaminergic neurons in mice.Item Dopamine D1/5 Receptor Modulation of Excitatory Neurotransmission and Synaptic Plasticity(2009-06-18) Leverich, Leah Schaal; Greene, Robert W.Dopamine D1/5 receptor (D1/5R) activation modulates glutamate-dependent neuroplasticity thought to underlie learning and memory. Disturbances in dopamine-glutamate signaling have been implicated in neuropsychiatric disorders such as schizophrenia and addiction. Despite its importance, a mechanism responsible for D1/5R modulation of glutamate-dependent neuroplasticity remains unknown. Here we present evidence using field potential recordings from hippocampal slices showing that D1/5R activation establishes a prolonged temporal window for the induction of NMDA receptor-dependent synaptic plasticity. We found that D1/5R activation increases synaptic responses and long-term potentiation (LTP) expression through a pathway involving NR2B-NMDARs, PKA, PKC, PKM zeta, and src-family tyrosine kinases. D1/5R activation produced sustained increases in the surface expression of NR2B and GluR1 subunits in hippocampal slices, and this increase required the activity of NR2B-NMDARs. Consistent with our field potential recordings, D1/5R activation during memory consolidation facilitates extinction learning to conditioned fear, providing functional relevance for a prolonged window of synaptic potentiation ediated by D1/5Rs at the level of behavioral output.