Synapse regression in depression: the role of 5-HT receptors in modulating NMDA receptor function and synaptic...

Depression is accompanied by an increase in activity in the amygdala and a decrease in the rostral anterior cingulate cortex (rACC), with the former attributed to a failure of the latter to exert its normal inhibitory influence. This failure is likely due to regression of synaptic connections between the rACC and the amygdala, a process reversed in part by selective serotonin reuptake inhibitors (SSRIs). The present work presents a hypothesis as to how SSRIs might bring about this process and hence normalization of activity, at least in patients that are responsive to SSRIs. Serotonin receptors of the excitatory 5-HT(2A)R class increase N-methyl-D-aspartate receptor (NMDAR) efficacy, while those of the inhibitory 5-HT(1A)R class decrease NMDAR efficacy. A decrease of 5-HT transporter (5-HTT) efficacy, either during human development through functional polymorphisms, or in animals through 5-HTT transgenic knockouts, is accompanied by a decrease in 5-HT(1A)R and hence an increase in excitability and NMDAR efficacy which drives an increase in synaptic spines in the amygdala. As the limbic region of the brain normally possesses high levels of 5-HT(1A)R the effect of loss of these is to increase excitation in this region, as is observed. Changes in the level of extracellular 5-HT in adult animals also modulates the density of synaptic spines, with these increasing with an increase in 5-HT, possibly as a consequence of increases in 5-HT(2A)R activity over that of 5-HT(1A)R. Increasing extracellular levels of 5-HT with SSRIs would then lead to an increase in excitability and in synaptic spines for afferents in the dorsal rostral anterior cingulate cortex but not in the ventral regions such as the amygdala that have few 5-HT(2A)R. This allows dorsal regions to once more exert their inhibitory influence over ventral regions. In this way, SSRIs may exert their effect in normalizing dorsal hypometabolism and ventral hypermetabolism in those suffering from depression.