Severe Neurologic Impairment in Mice with Targeted Disruption of the Electrogenic Sodium Bicarbonate Cotransporter NBCe2 (Slc4a5 Gene)

Liyo Kao,Lisa M Kurtz,Xuesi Shao,Marios C Papadopoulos,Li Liu,Dean Bok,Steven Nusinowitz,Bryan Chen,Salvatore L Stella,Mark Andre,Josh Weinreb,Serena S Luong,Natik Piri,Jacky M.K Kwong,Debra Newman,Ira Kurtz

doi:10.1074/jbc.m111.249961

Abstract

The choroid plexus lining the four ventricles in the brain is where the majority of cerebrospinal fluid (CSF) is produced. The secretory function of the choroid plexus is mediated by specific transport systems that allow the directional flux of nutrients and ions into the CSF and the removal of toxins. Normal CSF dynamics and chemistry ensure that the environment for neural function is optimal. Here, we report that targeted disruption of the Slc4a5 gene encoding the electrogenic sodium bicarbonate cotransporter NBCe2 results in significant remodeling of choroid plexus epithelial cells, including abnormal mitochondrial distribution, cytoskeletal protein expression, and ion transporter polarity. These changes are accompanied by very significant abnormalities in intracerebral ventricle volume, intracranial pressure, and CSF electrolyte levels. The Slc4a5(-/-) mice are significantly more resistant to induction of seizure behavior than wild-type controls. In the retina of Slc4a5(-/-) mice, loss of photoreceptors, ganglion cells, and retinal detachment results in visual impairment assessed by abnormal electroretinogram waveforms. Our findings are the first demonstration of the fundamental importance of NBCe2 in the biology of the nervous system.

Highlights

Modulating the production and chemistry of CSF is utilized clinically in the treatment of intracranial hypertension, mountain sickness, and seizure disorders (8 –10) and would be of potential value in conditions such as Alzheimer disease [11, 12], normal pressure hydrocephalus [13], and aging [14], where the CSF turnover is abnormal leading to a buildup of harmful metabolites [6]
Fluid secretion is dependent on the active transepithelial transport of Naϩ mediated by an apical Naϩ-Kϩ-ATPase pump, carbonic anhydrase activity, basolateral sodium bicarbonate influx mediated by the SLC4 transporter NCBE, and water transfer across the apical membrane via aquaporin 1
Additional ion transporters are expressed in CPE cells, including NBCn1, AE2, NHE1, Clir channels, NBCe2, VRAC, and NKCC1, which are thought to play a role in CSF production [15]

Summary

Severe Neurologic Impairment in Mice with Targeted

Disruption of the Electrogenic Sodium Bicarbonate Cotransporter NBCe2 (Slc4a5 Gene)*. We report that targeted disruption of the Slc4a5 gene encoding the electrogenic sodium bicarbonate cotransporter NBCe2 results in significant remodeling of choroid plexus epithelial cells, including abnormal mitochondrial distribution, cytoskeletal protein expression, and ion transporter polarity. These changes are accompanied by very significant abnormalities in intracerebral ventricle volume, intracranial pressure, and CSF electrolyte levels. Neurons and glia express various ion transporters that have evolved to ensure their normal function The importance of these channels and transporters is highlighted by the abnormalities that result from human disease mutations and targeted gene disruption in animals, including sensorineural defects, decreased intelligence, seizures, paralysis, pain perception deficits, and ataxia [1, 4, 5]. The mice developed a severe retinopathy demonstrating, for the first time, the biologic importance of NBCe2 in visual sensori-neural transduction in the mammalian retina

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION