Emergence of inhibitory plasticities in hippocampal area CA2 underlying normal and pathological develpment of social memory during adolescence – PlasticAdo

Adolescence is a transition period characterized by considerable brain remodeling leading to behavioral and cognitive changes including social cognition. This developmental period is also characterized by a high sensitivity to environmental factors that can facilitate the emergence of psychiatric diseases. Despite the fact that adolescence is now considered as a critical period during development, very little is known about the cellular and molecular mechanisms underlying changes in cognitive function.
There is growing evidence that area CA2, an understudied region of the hippocampus, plays an important role in hippocampal activity and in cognitive function. Area CA2 is critical for social memory formation and is a site of generation of sharp-wave ripple, a synchronous activity believed to be a substrate for memory consolidation.
Parvalbumin interneurons (PV+ INs) in CA2 express a unique long-term depression mediated by delta-opioid receptors (DOR-iLTD). We have evidence that area CA2 undergoes major developmental changes at the end of adolescence, both in normal and pathological conditions. Indeed, we found a decrease in PV+ IN density and plasticity in a mouse model of schizophrenia that occurs only at the end of adolescence. Recently, we also found that DOR-iLTD is emerging at the end of adolescence and plays an active role in social memory formation.
However, several evidence suggest that DOR-iLTD is not sufficient to underlie social memory. We made the surprising discovery that DOR-iLTD, by allowing CA2 PNs to fire action potentials, creates a permissive background for the induction of a 2nd inhibitory LTD mediated by endocannabinoids (eCBs). Furthermore, we found that the “social” peptide vasopressin as well as an enriched environment are also permissive for the induction of eCB-iLTD.
Our overall hypothesis is that the PV+ INs network in area CA2 undergoes a series of changes during adolescence that underlie emergence of inhibitory plasticity and social memory, and this process is disrupted during psychiatric disease. Furthermore, we have results demonstrating that inhibitory plasticity can be strongly influenced by environmental factors. We propose to use a combination of slice physiology, chemogenetics and behavioral experiments to better elucidate this developmental process in both healthy and diseased brains.
In Aim 1, we will identify the conditions required for the induction of eCB-mediated plasticity and investigate its role in social memory. We will first determine the condition required for the induction of eCB-iLTD and its precise mechanisms. We will then determine whether eCB-iLTD is induced by social interaction and whether it is involved in social memory formation.
In Aim 2, we will examine the alterations that occur in CA2 interneuron plasticity during adolescence in a mouse model of schizophrenia. We have shown that DOR-iLTD is impaired and PNs are less excitable in a mouse model of the 22q11.2 deletion syndrome (DS), the highest known genetic factor for developing schizophrenia. Thus, we hypothesize that eCB-iLTD will be impaired. We will first confirm this hypothesis and then try to rescue it. Our preliminary data indicate that depolarization of PNs with fluoxetine (through blockade of K+ TRECK channels) might be an efficient strategy to restore eCB-iLTD in 22q11.2 mice. We will determine whether fluoxetine can also restore social memory in these mice.
It is known that environmental factors can be very influential during adolescence. Thus, in Aim 3, we will determine how environmental conditions alter inhibitory plasticity and social memory in normal and pathological conditions. We found that DOR-iLTD is already induced in mice that have spent 3 weeks in an enriched environment (EE). We have data indicating that EE is permissive for the induction of eCB-iLTD. We will determine whether EE can also rescue the deficits in inhibitory plasticity and in social memory in 22q11.2DS mice.