P.1.010 - Brain-derived neurotrophic factor enhances glutamic acid decarboxylase and perineuronal net maturation in mouse primary cortical cultures

Abstract

Schizophrenia is a debilitating mental illness which affects approximately 1% of the global population, and is characterised by positive (e.g. hallucinations) and negative (e.g. anhedonia) symptoms, combined with cognitive deficits. Evidence suggests diminished cortical inhibitory drive as a major contributing factor in schizophrenia pathophysiology. Reductions in glutamic acid decarboxylase (GAD65/67) and deficits in the extracellular matrix structures, perineuronal nets (PNNs), which enwrap parvalbumin-containing interneurons have been observed in patients [1,2]. Members of the c-Jun N-Terminal kinase (JNK) family of mitogen-activated protein kinases (MAPKs) and their upstream kinase MKK7 have been implicated in neocortical development. Interestingly, MAP2K7 (encoding MKK7) has been implicated as a candidate risk gene for schizophrenia [3]. However, the impact of disrupted MAP2K7-JNK signalling on GABAergic interneuron development remains elusive. Reduced levels of brain-derived neurotrophic factor (BDNF) have also been found in patients [4]. Previous research highlights BDNF as a promoter of GABAergic maturation in hippocampal neurons [5]. Consequently, altered BDNF activity could result in abnormal cortical circuitry development and contribute to the cortical neuronal dysfunction underlying schizophrenia. Here we study the effects of BDNF on the development of primary cortical GABAergic interneurons and surrounding PNNs along with the possible involvement of JNK signalling. Mouse primary cortical neuronal cultures were treated at 7 days in vitro with either vehicle, BDNF (50 ng/ml), JNK inhibitor (SP600125, 5 μM) or BDNF+JNK inhibitor. Subsequently, immunofluorescent-cytochemistry (ICC) was performed. PNN development was assessed using Wisteria floribunda agglutinin (WFA) lectin which labels interneuron PNNs. Cultures were double-labelled with GAD65/67. Normalised intensity data (in relative optical density) were expressed as a percentage of vehicle and analysed via three-way ANOVA with Tukey post-hoc multiple comparisons with results considered significant if p Analysis of WFA staining intensity revealed significant main effects of BDNF (F1, 982 = 45.46, p Our data demonstrate that BDNF increased GAD65/67 levels and PNN density in developing cortical interneurons. Our data suggest this enhancing effect of BDNF on GAD65/67 and PNN maturation is dependent on JNK signalling. Given evidence of reduced BDNF levels in schizophrenia patients, we speculate that impairments in MAP2K7-JNK signalling may be linked with functional BDNF deficits in schizophrenia and that BDNF disruption could be involved in disorder aetiology and pathophysiology.