Hippocampal Cc2d1a/Freud-1 Knockdown Alters Serotonin and Dopamine Systems and Depressive-Like Behavior in ASC (Antidepressants Sensitive Catalepsy) Male Mice.

Brain monoamine systems regulate a wide spectrum of behaviors. Serotonin (5-HT) is traditionally linked to depression, whereas dopamine (DA) is associated with anhedonia and impaired motivation. The genes for the 5-HT1A receptor (Htr1a) and DRD2 receptor (Drd2) share a common transcription factor, Freud-1, encoded by Cc2d1a. We investigated the effect of hippocampal Cc2d1a/Freud-1 knockdown (via adeno-associated viral construct in vivo) in genetically predisposed to depressive-like behavior ASC (Antidepressants Sensitive Catalepsy) male mice on behavior and on the brain 5-HT and DA systems. Cc2d1a/Freud-1 knockdown, confirmed at both the mRNA and protein levels, led to led to disinhibition of Htr1a and Drd2 expression, reduced immobility time, and decreased the percentage of cataleptic mice in the catalepsy test. It attenuated depressive-like behavior in the forced swim test, improved social interaction in the resident-intruder test, and enhanced spatial memory in the Morris water maze, without affecting anhedonia or anxiety. In experimental animals, 5-HT1A receptor functional activity, assessed by 8-OH-DPAT-induced hypothermia, was increased, whereas 5-HT2A receptor activity, assessed by 25CN-NBOH-induced head-twitches, was decreased. Cc2d1a/Freud-1 knockdown also elevated hippocampal catechol-O-methyltransferase mRNA levels and monoamine oxidase A protein levels, as well as midbrain tryptophan hydroxylase-2 activity. The ratios of DA and 5-HT to their metabolites remained unchanged. Our findings indicate that Cc2d1a/Freud-1 is involved in emotional and social behaviors, likely through modulation of serotonergic signaling and 5-HT receptor function. This study highlights hippocampal Cc2d1a as a potential transcriptional regulator of monoaminergic systems in depression-related phenotypes.