Pathophysiology of an autosomal recessive neurodevelopmental disorder caused by SLC4A10 loss-of-function

最近，我们与遗传学家和临床医生团队一起，在一种特有的常染色体隐性遗传病患者中发现了SLC4A10基因的突变。患者表现为脑室裂隙和严重的智力残疾，并有自闭症行为。SLC4A10的编码是位于质膜上的离子转运体，它利用钠的梯度将碳酸氢盐输送到细胞内，从而缓冲细胞内的酸当量。我们的初步工作表明，结构性SLC4a10基因敲除小鼠也显示出行为异常和脑室塌陷，因此是一种有希望的疾病模型。除了脑脊液(CSF)产生受损的迹象外，我们还在基因敲除小鼠的急性脑片中观察到GABA能抑制受损。这与脉络丛上皮细胞以及兴奋性和抑制性神经元的胞体异常表达是一致的。后者也在其神经末梢表达SLC4a10。这种复杂的表达模式使结构性基因敲除小鼠中可能重叠的不同机制的阐明变得复杂起来。因此，我建议研究脉络丛和神经元间特异性条件性SLC4a10基因敲除小鼠的脑形态、行为和网络特性，以阐明该病的病理生理机制。需要回答以下问题：1.SLC4A10在脑脊液分泌和脑间质液体组成中起什么作用？2.Slc4a10基因敲除小鼠的脑脊液分泌受损是否影响脑发育？3.Slc4a10基因敲除小鼠的脑脊液产生受损是否有长期影响？4.SLC4a10对神经网络、癫痫倾向和认知起什么作用？5.GABA能传递的调节能否改善结构性Slc4a10基因敲除小鼠的网络特性甚至行为异常？从长远来看，我们希望这种方法不仅能提供对基本机制的洞察，还能为患者可能的治疗干预提供指征。

Together with a team of geneticists and clinicians, we were recently able to identify mutations in the SLC4A10 gene in patients with a characteristic autosomal recessive disease. Patients show slit cerebral ventricles and severe intellectual disability with autistic behavior. SLC4A10 codes for an ion transporter located in the plasma membrane, which uses the sodium gradient to transport bicarbonate into the cell and thus buffers intracellular acid equivalents. Our preliminary work shows that constitutive Slc4a10 knockout mice also show behavioral abnormalities and collapsed cerebral ventricles and therefore represent a promising model for the disease. In addition to indications of impaired production of the cerebrospinal fluid (CSF), we observed compromised GABAergic inhibition in acute brain slices of knockout mice. This is consistent with the exceptional expression in epithelial cells of the choroid plexus and in the somata of excitatory and inhibitory neurons. The latter also express Slc4a10 at their terminal nerve endings. The complex expression pattern complicates the elucidation of the putatively overlapping different mechanisms in constitutive knockout mice. Therefore, I propose to study brain morphology, behavior and network properties in choroid plexus and interneuron-specific conditional Slc4a10 knockout mice in order to elucidate the pathophysiology of the disease. The following questions should be answered: 1. What role does SLC4A10 play in CSF secretion and the composition of the interstitial fluid of the brain? 2. Does impaired CSF production in Slc4a10 knockout mice affect brain development? 3. Are there long-term effects of impaired CSF production in Slc4a10 knockout mice? 4. What role does Slc4a10 play for the neural network, seizure tendency, and cognition? 5. Can modulation of GABAergic transmission improve network properties or even behavioral abnormalities in constitutive Slc4a10 knockout mice? In the long term, we hope that this approach will not only provide insights into basic mechanisms but also indications for possible therapeutic interventions in patients.