| dc.description.abstract |
<p>Obsessive-compulsive disorder (OCD) is a devastating illness that afflicts around
2% of the world's population with recurrent distressing thoughts (obsessions) and
repetitive ritualistic behaviors (compulsions). While dysfunction at excitatory glutaminergic
excitatory synapses leading to hyperactivity of the orbitofrontal cortex and head
of the caudate - brain regions involved in reinforcement learning - are implicated
in the pathology of OCD, clinical studies involving patients are unable to dissect
the molecular mechanisms underlying this cortico-striatal circuitry defect. Since
OCD is highly heritable, recent studies using mutant mouse models have shed light
on the cellular pathology mediating OCD symptoms. These studies point toward a crucial
role for deltaFosB, a persistent transcription factor that accumulates with chronic
neuronal activity and is involved in various diseases of the striatum. Furthermore,
elevated deltaFosB levels results in the transcriptional upregulation of Grin2b, which
codes GluN2B, an N-methyl-D-aspartate glutamate receptor (NMDAR) subunit required
for the formation and maintenance of silent synapses. Taken together, the current
evidence indicates that deltaFosB-mediated expression of aberrant silent synapses
in caudate medium spiny neurons (MSNs), in particular D1 dopamine-receptor expressing
MSNs (D1 MSNs), mediates the defective cortico-striatal synaptic transmission that
underlies compulsive behavior in OCD.</p>
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