Retrosplenial Cortical Reorganization During Late Adolescence Introduces Instability of Episodic Memory Circuits

Impairments of episodic memory, the capacity to remember and re-live details from one's past, are common across mental illnesses, but are particularly severe in those with late adolescent onset, such as schizophrenia and major depression. Using mice, we demonstrate that during late adolescence, the retrosplenial cortex (RSP), an established hub of episodic memory and default mode networks, undergoes extensive reorganization, interfering with memory functions and potentially increasing vulnerability to these illnesses. Specifically, we demonstrated that the levels of perineuronal nets (PNN), key PNN constituents, and parvalbumin-positive (PVALB) interneurons established during early adolescence (p30), significantly declined by late adolescence(p60-75). Using context fear conditioning (CFC), we found that these structural, molecular, and cellular changes facilitated the formation of long-lasting and context-specific memories, but at the expense of memories acquired during early adolescence. Interestingly, early adolescent memories spontaneously recovered by middle adulthood but lost context specificity. The observed neurobiological and behavioral changes were attenuated by stabilizing PNN, and exacerbated by disrupting PNN, suggesting that PVALB neuron loss and memory expression deficits were secondary to PNN degradation. These findings showed that despite its superior performance during early adolescence relative to early life, the RSP memory circuit does not show full cortical maturity until late adolescence. In susceptible individuals, the observed dynamics of the extracellular matrix and PVALB neurons could interact with genetic factors, increasing risk for the development of late adolescent psychopathologies.