Developmental Disruption of Erbb4 in Pet1+ Neurons Impairs Serotonergic Sub-System Connectivity and Memory Formation

Abstract

The serotonergic system of mammals innervates virtually all the central nervous system and regulates a broad spectrum of behavioral and physiological functions. In mammals, serotonergic neurons located in the rostral raphe nuclei encompass diverse sub-systems characterized by specific circuitry and functional features. Substantial evidence suggest that functional diversity of serotonergic circuits has a molecular and connectivity basis. However, the landscape of intrinsic developmental mechanisms guiding the formation of serotonergic sub-systems is unclear. Here, we employed developmental disruption of gene expression specific to serotonergic subsets to probe the contribution of the tyrosine kinase receptor ErbB4 to serotonergic circuit formation and function. Through an in vivo loss-of-function approach, we found that ErbB4 expression occurring in a subset of serotonergic neurons, is necessary for axonal arborization of defined long-range projections to the forebrain but is dispensable for the innervation of other targets of the serotonergic system. We also found that Erbb4-deletion does not change the global excitability or the number of neurons with serotonin content in the dorsal raphe nuclei. In addition, ErbB4-deficiency in serotonergic neurons leads to specific behavioral deficits in memory processing that involve aversive or social components. Altogether, our work unveils a developmental mechanism intrinsically acting through ErbB4 in subsets of serotonergic neurons to orchestrate a precise long-range circuit and ultimately involved in the formation of emotional and social memories.

Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models

“…Testing apparatuses were cleaned with a solution of 70% ethanol in water after each trial to avoid olfactory cues. Behavioral tasks were recorded and analyzed as previously described 102 . Open field.…”

“…The arena was delimited for analysis into two different regions: center (square area of 30 × 30 cm equidistant from the walls) and the remaining borders. The time spent, velocity, distance as well as transitions between the zones was calculated as described in 102 . Elevated plus maze.…”

“…Mice were gently placed in the center of the maze and their behavior was recorded for 5 minutes. Time spent and the number of entries in each arm was quantified post hoc 102 . Dark-light box.…”

“…Mice were placed facing the dark box and their behavior was recorded for 5 min. Mice were video-tracked and ratio of time in dark box over time in light box was calculated post hoc 102 .…”

5-HT-dependent synaptic plasticity of the prefrontal cortex in postnatal development

“…In rodents, part of PFC development occurs during the first three postnatal weeks, when layer 5 neurons exhibit high intrinsic excitability and enhanced rates of synaptogenesis [3][4][5][6] . Studies carried out in this phase identified that excitatory activity leads to the building of new synaptic connections and reorganization of cortical circuits, with critical consequences in adult behavioral phenotype [7][8][9][10][11][12] . According to these findings, prefrontal neurons undergo a temporal window of higher synaptic modifications in early life.…”