Adolescence represents a transitional period during which the brain undergoes substantial structural remodeling and new cognitive functions emerge. The cellular and synaptic mechanisms underlying the appearance of these functions, however, remain poorly understood. This work focused on the CA2 (Cornu Ammonis 2) area of the hippocampus, a region now recognized as essential for the formation of social memory. The cellular composition of the CA2 area displays a notable feature: the density of several interneuron subclasses, including parvalbumin-expressing interneurons (PV+), is higher there than in other hippocampal regions. This area also proves vulnerable in several psychiatric disorders.
The authors investigated, in mice, a particular form of long-term depression of inhibitory transmission (iLTD) originating from PV+ interneurons onto CA2 pyramidal neurons. Using patch-clamp electrophysiological recordings on hippocampal slices, complemented by immunohistochemical analyses at different developmental stages (from P17 to P50) and by in vivo stereotaxic manipulations, the team characterized the emergence and determinants of this plasticity. Behavioral assessment relied notably on a five-trial social memory test, measuring the animals' ability to recognize a previously encountered conspecific.
The results show that this iLTD is absent in young mice and emerges only at the end of adolescence. Two maturational components proved necessary for its establishment: on the one hand, the perineuronal net (PNN), an extracellular matrix structure surrounding certain interneurons, and on the other hand, signaling through the ErbB4 receptor, dependent on neuregulin-1 (NRG1). The GABA release controlled by the PNN and ErbB4 reaches maturity only at the end of adolescence. In parallel, social recognition memory exhibits the same age dependence as iLTD. Convergently, targeted degradation of the PNN in the CA2 area, achieved by injection of chondroitinase ABC, as well as the blockade of iLTD, impair the formation of this social memory. As the induction of iLTD is mediated by the delta opioid receptor, its inactivation in CA2 was also tested.
This work reveals an unusual developmental rule for the plasticity of PV+ interneuron transmission in the CA2 area and indicates that this plasticity contributes to the emergence of a higher cognitive function, the formation of social memory, at the end of adolescence. By linking the late maturation of the perineuronal net and ErbB4 signaling to the appearance of inhibitory plasticity and social behavior, this study sheds light on the synaptic bases of a cognitive transition characteristic of this period of life.