P.1.004 - Morphological substrates of abnormal activity patterns in a mouse model of mental illness

Abstract

During the last years, a wealth of investigations has been dedicated to psychiatric diseases with developmental time course. However, the mechanisms leading to the devastating symptoms and specific adapted treatments are still poorly understood. The investigation of mouse models mimicking the etiology of disorders can expand the understanding of the ontogeny by determining the cellular substrates of mental illness [1]. To better comprehend the role and underlying molecular mechanisms of morphological deficits during early development of cortical dysfunctions, we investigated mice mimicking the genetic (Disrupted-In-Schizophrenia 1) and environmental (maternal immune activation) background of mental illness (dual-hit GE mice). We previously showed that they have an impaired maturation of prefrontal-hippocampal function [2]. To determine the cellular substrates of dysfunction we investigated the morphological and synaptic deficits of pyramidal neurons in the prefrontal cortex (PFC) of neonatal mice. For this, GE mice were in utero electroporated with pAAV-CAG-tDimer2 either at E12.5 or at E15.5 to target pyramidal neurons in layer V/VI and II/III of the PFC, respectively. We analyzed the complexity of dendritic arborizations by using the Sholl analysis method and spine density of tDimer2-expressing pyramidal neurons in layer II/III and V/VI. Furthermore, we quantified the layer- and age-specific density of pyramidal neurons and interneurons by immunohistochemistry with custom-written processing algorithms in ImageJ. Following a stream of recent investigations implying the involvement of microglial cells in synaptic pruning we investigated the maturation of the microglial population in GE mice using image processing algorithms in MATLAB. Data were tested for significant differences using t-test or two-way ANOVA. The GE mice showed major layer specific morphological deficits in the PFC including abnormal migration and an increase of interneuronal density in layer II/III at neonatal age (control: 322.2 ± 11.73 cells/mm2, GE mice: 407.1 ± 20.17 cells/mm2; p=0.0012). This layer II/III specific disruption was confirmed by a reduction of dendritic arborization complexity (20-130 μm p 0.05) and spine density (mino GE mice: 4.709 ± 0.1493 spines/10 μm; control vs. mino GE mice p=0.3945) of pyramidal neurons in layer II/III. These data reveal that the functional deficits of local circuits in the PFC of GE mice at neonatal age result from abnormal anatomy of pyramidal neurons and microglia maturation.