Activation of the CA2-ventral CA1 pathway reverses social discrimination dysfunction in Shank3B knockout mice.

Mutation or deletion of the SHANK3 gene, which encodes a synaptic scaffolding protein, is linked to autism spectrum disorder and Phelan-McDermid syndrome, conditions associated with social memory impairments. Shank3B knockout mice also exhibit social memory deficits. The CA2 region of the hippocampus integrates numerous inputs and sends a major output to the ventral CA1 (vCA1). Despite finding few differences in excitatory afferents to the CA2 in Shank3B knockout mice, we found that activation of CA2 neurons as well as the CA2-vCA1 pathway restored social recognition function to wildtype levels. vCA1 neuronal oscillations have been linked to social memory, but we observed no differences in these measures between wildtype and Shank3B knockout mice. However, activation of the CA2 enhanced vCA1 theta power in Shank3B knockout mice, concurrent with behavioral improvements. These findings suggest that stimulating adult circuitry in a mouse model with neurodevelopmental impairments can invoke latent social memory function.

The estrous cycle modulates early-life adversity effects on mouse avoidance behavior through progesterone signaling.

Early-life adversity (ELA) increases the likelihood of neuropsychiatric diagnoses, which are more prevalent in women than men. Since changes in reproductive hormone levels can also increase the probability of anxiety disorders in women, we examined the effects of ELA on adult female mice across the estrous cycle. We found that during diestrus, when progesterone levels are relatively high, ELA mice exhibit increased avoidance behavior and increased theta oscillation power in the ventral hippocampus (vHIP). We also found that diestrus ELA mice had higher levels of progesterone and lower levels of allopregnanolone, a neurosteroid metabolite of progesterone, in the vHIP compared with control-reared mice. Progesterone receptor antagonism normalized avoidance behavior in ELA mice, while treatment with a negative allosteric modulator of allopregnanolone promoted avoidance behavior in control mice. These results suggest that altered vHIP progesterone and allopregnanolone signaling during diestrus increases avoidance behavior in ELA mice.

Inhibition of adult neurogenesis reduces avoidance behavior in male, but not female, mice subjected to early life adversity.

Early life adversity (ELA) increases the risk of developing neuropsychiatric illnesses such as anxiety disorders. However, the mechanisms connecting these negative early life experiences to illness later in life remain unclear. In rodents, plasticity mechanisms, specifically adult neurogenesis in the ventral hippocampus, have been shown to be altered by ELA and important for buffering against detrimental stress-induced outcomes. The current study sought to explore whether adult neurogenesis contributes to ELA-induced changes in avoidance behavior. Using the GFAP-TK transgenic model, which allows for the inhibition of adult neurogenesis, and CD1 littermate controls, we subjected mice to an ELA paradigm of maternal separation and early weaning (MSEW) or control rearing. We found that mice with intact adult neurogenesis showed no behavioral changes in response to MSEW. After reducing adult neurogenesis, however, male mice previously subjected to MSEW had an unexpected decrease in avoidance behavior. This finding was not observed in female mice, suggesting that a sex difference exists in the role of adult-born neurons in buffering against ELA-induced changes in behavior. Taken together with the existing literature on ELA and avoidance behavior, this work suggests that strain differences exist in susceptibility to ELA and that adult-born neurons may play a role in regulating adaptive behavior.