Investigators will use two-photon molecular imaging in a mouse model of depression to develop direct evidence of cellular changes that cause depression and whether pharmaceutical agents can reverse these changes.
Three types of anti-depressants are marketed for use in people with depression. All three prolong activity of the neurotransmitters serotonin and norepinephrine. Both tricyclic antidepressants and SSRI’s (selective serotonin reuptake inhibitors) prevent neurons sending the transmitters from taking back any excess that is released into the area around the synapse (the junction between two communicating brain cells). The transmitters therefore remain active at the synapse longer. Monomaine oxidase inhibitors act by blocking an enzyme that ordinarily destroys unused transmitter. These three drug types, however, have limited effectiveness; only 30 percent of depressed patients achieve remission, and it takes several weeks before these drugs can ameliorate depressive symptoms. Now recent evidence suggests that synapses that are hyperactive, and transmit glutamate, may be the key target, but their location and molecular changes remain largely unknown,
The investigators’ data indicate that the synapses are located in particular brain regions. They hypothesize that depression-inducing stimuli can cause sustained hyperactivity of these “glutamatergic” synapses in these brain regions, and that suppressing this hyperactivity is critical for effective anti-depressant treatment. Using two-photon imaging and molecular biology techniques, they will compare the brain cells, glutamate receptors, and other aspects of the synapse in a mouse model of depression compared to healthy mice. They then will relate identified biological changes in the mouse depression model to their depressive behaviors. Thereafter, they will determine whether synaptic hyperactivity in general, or specifically related to the neurotransmitter glutamate, is the causal factor. To test this, they will see whether ketamine, an agent that acts on glutamate receptors (but can have major side effects) produces acute and long-lasting effects both on the behavior and synapses in the depressed mouse model. Then they will find out whether an SSRI, which does not target glutamate, also can normalize the hyperactive synapses and affect depressive behaviors in the mice. If so, the findings would suggest that hyperactive synapses are the causal factor in depression.