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Neuronal Glucose Transporter Isoform 3 Deficient Mice Demonstrate

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Neuronal Glucose Transporter Isoform 3 Deficient Mice Demonstrate Molecular Psychiatry (2010) 15, 286–299 & 2010 Nature Publishing Group All rights reserved 1359-4184/10 $32.00 www.nature.com/mp ORIGINAL ARTICLE Neuronal glucose transporter isoform 3 deficient mice demonstrate features of autism spectrum disorders Y Zhao1,2,6, C Fung1,2,6, D Shin2,3, B-C Shin1,2, S Thamotharan1,2, R Sankar2,3,4, D Ehninger5, A Silva5 and SU Devaskar1,2 1Divisions of Neonatology and Developmental Biology, Neonatal Research Center, David Geffen School of Medicine UCLA, Los Angeles, CA, USA; 2Department of Pediatrics, David Geffen School of Medicine UCLA, Los Angeles, CA, USA; 3Division of Neurology, Department of Pediatrics, David Geffen School of Medicine UCLA, Los Angeles, CA, USA; 4Department of Neurology, David Geffen School of Medicine UCLA, Los Angeles, CA, USA and 5Department of Neurobiology, David Geffen School of Medicine UCLA, Los Angeles, CA, USA Neuronal glucose transporter (GLUT) isoform 3 deficiency in null heterozygous mice led to abnormal spatial learning and working memory but normal acquisition and retrieval during contextual conditioning, abnormal cognitive flexibility with intact gross motor ability, electroencephalographic seizures, perturbed social behavior with reduced vocalization and stereotypies at low frequency. This phenotypic expression is unique as it combines the neurobehavioral with the epileptiform characteristics of autism spectrum disorders. This clinical presentation occurred despite metabolic adaptations consisting of an increase in microvascular/glial GLUT1, neuronal GLUT8 and monocarboxylate transporter isoform 2 concentrations, with minimal to no change in brain glucose uptake but an increase in lactate uptake. Neuron-specific glucose deficiency has a negative impact on neurodevelopment interfering with functional competence. This is the first description of GLUT3 deficiency that forms a possible novel genetic mechanism for pervasive developmental disorders, such as the neuropsychiatric autism spectrum disorders, requiring further investigation in humans. Molecular Psychiatry (2010) 15, 286–299; doi:10.1038/mp.2009.51; published online 9 June 2009 Keywords: brain metabolism; seizures; cognition; monocarboxylate transporters; development Introduction chromosome 16 that are responsible for only 1% of the clinical disorder.1 Mounting evidence has sup- Autism spectrum disorders (ASDs) constitute a ported environmental factors such as perinatal events chronic debilitating neuropsychiatric condition diag- and nutrition to have an etiological function in nosed in childhood and with long-term conse- ASD.2,3 Positron emission tomography of human quences. At present there are no specific treatments brain has revealed decreased brain glucose uptake in targeted at complete reversal of symptoms toward ASD.4–6 Abnormal neuronal energy metabolism due to achieving functional competence. ASDs are part of aberrant fuel supply, particularly glucose, during pervasive developmental disorders that present with development may form the common denominator abnormal social interactions, aberrant verbal and for these disorders. nonverbal communication skills, learning disabilities, Glucose forms the essential substrate that fuels mild mental retardation, stereotypic behaviors with a neuronal oxidative metabolism. This substrate is subset of individuals developing electroencephalo- transported across the blood–brain barrier and into graphic (EEG) seizure activity. These disorders neurons and glia by a family of structurally related are diagnosed in infancy/childhood and seen in membrane-spanning glycoproteins, termed the facil- adolescence and adults.1 While a genetic basis for itative glucose transporters.7 Of the multiple isoforms this disorder has been put forth, the underlying cloned to date, GLUT1 is the predominant isoform definitive cause has remained elusive. More recently expressed in the blood–brain barrier and glial cells,8 proposed gene(s) for autism have been located on and GLUT3 is the neuronal isoform.9 Although other isoforms are expressed to a lesser extent in neurons, Correspondence: Dr SU Devaskar, Department of Pediatrics, David such as GLUT8 and GLUT4,10,11 GLUT3 is the Geffen School of Medicine UCLA, 10833, Le Conte Avenue, predominant neuronal isoform that fuels ATP genera- MDCC-B2-375, Los Angeles, CA 90095-1752, USA. tion and thereby the energy metabolism.12 We there- E-mail: [email protected] 6These authors contributed equally to this work. fore hypothesized that GLUT3 deficiency will alter Received 9 October 2008; revised 30 April 2009; accepted 6 May brain metabolism and perturb neurobehavior through 2009; published online 9 June 2009 development, resulting in a phenotype that may glut3 and autism spectrum disorder Y Zhao et al 287 resemble clinical ASD. To test this hypothesis, method18 in which a mixture of L-[14C(U)]-lactate we created a glut3 null mouse and observed embryo- and [3H]-water (0.1 mCi each) was injected through the nic lethality in homozygotes13 whereas the left ventricle with collection of whole brains 15–20 s heterozygotes had no malformations and survived later. The ratio of 14Cto3H in brain tissue relative to into adulthood. We examined these glut3 the ratio of 14Cto3H in the injectate determined the heterozygous null (glut3 þ /À) mice through develop- amount of lactate lost to brain tissue on a single ment for neurobehavioral changes and observed passage through brain microcirculation. features relevant to ASD. Immunohistochemical studies Paraformaldehyde prefixed vibratome floating coro- Materials and methods nal brain sections were subjected to immunofluores- Glut3 null mouse lines cence staining using the rabbit anti-mouse GLUT3, The mouse glut3 (Slc2a3) knockout targeting con- guinea pig anti-GLUT1 (from Dr Takata, Japan) or struct was created by isolating and characterizing the mouse anti-tubulin (1:500 dilution each) IgGs as entire glut3 gene in a P1 clone (Genome Systems, St primary antibodies with the fluorescent tag being Louis, MO, USA) and using the pKO Scrambler NTK FITC for GLUT1 and Texas Red for GLUT3 or tubulin. 1903 vector (Stratagene, La Jolla, CA, USA) to delete a Slides with sections were examined under a Nikon E- 3.5 kb fragment consisting of exons 7, 8, 9 and the 600 fluorescence microscope (Nikon, Melville, NY, coding region of 10.13 Glut3 (Slc2a3) knockout mouse USA) equipped with a cooled charged-coupled device lines were generated and backcrossed to achieve a camera as previously described.11,13 Neuronal nitric homogeneous C57/BL6 strain background, genotyped oxide synthase enzyme immunoreactivity was as- as described previously by us,13 housed in 12-h light sessed by the primary rabbit anti-nNOS antibody and 12-h dark cycle and maintained in approved (1:100 dilution) (BD Biosciences, San Jose, CA, USA), mouse housing areas. All mouse studies were biotinylated-peroxidase-DAB reaction and viewed approved by Animal Research Committee of the under the light microscope and cells counted by the University of California, Los Angeles in accordance NIH image analysis system.10,13 with guidelines set by the National Institutes of Health (NIH). Neuroligin-3 mRNA studies Total RNA was isolated from snap frozen dissected Glucose transporter protein studies hippocampi (RNeasy lipid tissue mini kit; Qiagen, Whole brains at different postnatal stages (PN1, 7, 14, Valencia, CA, USA).19,20 Real-time PCR primers used 21 and 60 days) were subjected to western blot amplified a 75 bp isoform-specific DNA fragment analysis as described previously.10,11 The primary (forward, 50-ggagctggcagcattacagtt-30; reverse, 50-aggc antibodies consisted of rabbit anti-mouse GLUT1 IgG gaagtgtgtcatgtg-30) of the mouse neuroligin-3 (NLGN3) (1:2000 dilution),14 anti-mouse GLUT3 IgG (1:2000 sequence (GenBank no. NM_172932). TaqMan probe dilution),15 rabbit anti-mouse GLUT8 IgG, rabbit anti- was the intervening sequence (50-ccactcaccatgaatgt rat MCT1 (1:200 dilution) and anti-rat MCT2 antibody gaggccg-30), which was synthesized and labeled with (1:400 dilution) (the latter three antibodies were fluorescent dyes, 6-carboxyfluorescein on the 50 end obtained from Alpha Diagnostic International, San and N,N,N,N-tetramethyl-6-carboxyrhodamine on the Antonio, TX, USA). The internal control was detected 30 end (Applied Biosystems, Foster City, CA, USA). using a monoclonal anti-human vinculin antibody Quantitative real-time PCR was performed in tripli- (1:4000 dilution) (Sigma Chemical Co., St Louis, MO, cate with glyceraldehyde-3-phosphate dehydrogenase USA). The protein bands were quantified by densito- serving as the internal control on the StepOnePlus metry and the arbitrary units expressed as a ratio to Real-Time PCR system (Applied Biosystems). The vinculin. The developmental expression of each amplification conditions consisted of initial 12-min protein was presented as a percent of PN60 wild-type activation at 95 1C followed by 40 cycles of denatura- (WT) value normalized to 100%. tion at 95 1C for 30 s, annealing at 58 1C for 30 s and extension at 72 1C for 30 s. Relative quantification of Brain 2-deoxyglucose uptake the PCR amplification products was performed using 14 Cerebral C-2-deoxyglucose uptake in the PN60 WT the comparative critical threshold (CT) method as and glut3 þ /À brains was measured using a modified previously described.19,20 Sokoloff’s method following the intraperitoneal ad- ministration of 0.5 mCi gÀ1 of 2-deoxy-D-[14C]-glucose Continuous video-EEG monitoring tracer. The specific activity of glucose in circulation Following isoflurane
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