Dendritogenesis of neocortical pyramidal cells and interneurons: regulation by AMPA and NMDA receptors.

所有皮质神经元都表达离子型谷氨酸受体。它们是突触传递和成体功能的基本决定因素，也是出生后早期分化的重要调节因素。通过过度表达策略，我们展示了特定的生物物理上不同的AMPA受体亚型对锥体神经元和多极中间神经元的树突生长和棘突形成的贡献。此外，我们还发现AMPA受体诱导的树突状细胞生长需要NMDA型受体和L型钙通道。我们现在专注于两个目标。首先，我们建议通过使用1.跨膜AMPA受体调节蛋白的过表达和2.Ampakines作为正变构调节剂来分析内源性AMPA受体功能增强的效果。关于新皮质神经元中各种TARP亚型的功能知之甚少，也没有在发育和形态分化的背景下对它们进行分析。其次，我们建议表征NMDA受体亚型在树突状细胞生长中的作用，特别是皮质中间神经元。关于NMDA受体在中间神经元中的作用的知识令人惊讶地有限。该项目将对I型和II型tarp在两个皮质神经元类别中的功能提供新的见解，并揭示NMDA受体的作用，特别是对神经元间分化的作用。

All cortical neurons express ionotropic glutamate receptors. They are essential determinants of synaptic transmission and adult function, and important regulators of early postnatal differentiation. With an overexpression strategy, we demonstrated a contribution of specific biophysically distinct AMPA receptor isoforms for dendritic growth and spine formation of pyramidal neurons and multipolar interneurons. Furthermore, we showed that the AMPA receptor-induced dendritic growth requires NMDA receptors and L-type calcium channels. We are now focussing on two aims. First, we propose to analyze the effects of an enhancement of endogenous AMPA receptor function by using 1. an overexpression of transmembrane AMPA receptor regulatory proteins, TARPs, and 2. Ampakines as positive allosteric modulators. Little is known on the function about the various TARP isoforms in neocortical neurons, and they have not been analysed in the context of development and morphological differentiation. Second, we propose to characterize the role of NMDA receptor isoforms for dendritic growth, in particular of cortical interneurons. Knowledge of the role of NMDA receptors in interneurons is surprisingly limited. The project will deliver novel insights into the function of type I and type II TARPS in the two cortical neuron classes, and unravel the role of NMDA receptors, in particular for interneuronal differentiation.