Structure-Activity Studies on Bis-Sulfonamide SHIP1 Activators.

The SH2-containing inositol polyphosphate 5-phosphatase 1 (SHIP1) enzyme opposes the activity of PI3K and therefore is of interest in the treatment of inflammatory disorders. Recent results also indicate that SHIP1 promotes phagolysosomal degradation of lipids by microglia, suggesting that the enzyme may be a target for the treatment of Alzheimer's disease. Therefore, small molecules that increase SHIP1 activity may have benefits in these areas. Recently we discovered a bis-sulfonamide that increases the enzymatic activity of SHIP1. A series of similar SHIP1 activators have been synthesized and evaluated to determine structure-activity relationships and improve in vivo stability. Some new analogs have now been found with improved potency. In addition, both the thiophene and the thiomorpholine in the parent structure can be replaced by groups without a low valent sulfur atom, which provides a way to access activators that are less prone to oxidative degradation.

Late-stage Attentional Bias towards Food Cues Varies According to Weight Status.

The Current food environment has become increasingly obesogenic, with rates of obesity and related conditions continually rising. Advertisements for energy-dense foods are abundant and promote unhealthy eating behaviors by capitalizing on one's attentional bias towards food cues, a cognitive process resulting from the sensitization of highly reinforcing food. A heightened awareness towards food cues may promote overconsumption of energy-dense foods. The current study employed novel eye-tracking methodology to capture sustained, or late-stage, attentional bias towards food cues. Late-stage attentional bias is the aspect of attentional bias under conscious control and likely more prone to modification compared to initial/ early-stage attentional bias, which reflects automatic processes. The present study hypothesized late-stage attentional bias towards food cues is greater among individuals classified as overweight/obese than those classified as normal weight. Thirty (30) participants classified as overweight/obese (BMI ≥25) and 47 classified as normal weight (BMI <25) were assessed for late-stage attentional bias towards food cues, conceptualized as the percentage of time fixated on food cues when both food and neutral images were presented during a food-specific visual probe procedure task. Percentage of time fixated on food cues was 51.25 ± 1.27 (mean + SE) among individuals classified as overweight to obese while those classified as normal weight had a percent fixation of 47.26 ± 0.87 (P=0.03). In conclusion, individuals classified as overweight to obese have greater late-stage attentional bias towards food cues. This establishes an important factor influencing energy intake that may be modified in future clinical trials.

The Role of Dietary Protein in Body Weight Regulation among Active-Duty Military Personnel during Energy Deficit: A Systematic Review.

Active-duty military personnel are subjected to sustained periods of energy deficit during combat and training, leaving them susceptible to detrimental reductions in body weight. The importance of adequate dietary protein intake during periods of intense physical training is well established, where previous research has primarily focused on muscle protein synthesis, muscle recovery, and physical performance. Research on how protein intake may influence body weight regulation in this population is lacking; therefore, the objective of this review was to evaluate the role of dietary protein in body weight regulation among active-duty military during an energy deficit. A literature search based on fixed inclusion and exclusion criteria was performed. English language peer-reviewed journal articles from inception to 3 June 2023 were selected for extraction and quality assessment. Eight studies were identified with outcomes described narratively. The study duration ranged from eight days to six months. Protein was directly provided to participants in all studies except for one. Three studies supplied additional protein via supplementation. The Downs and Black Checklist was used to assess study quality. Five studies were classified as good, two as fair, and one as excellent. All studies reported mean weight loss following energy deficit: the most severe was 4.0 kg. Protein dose during energy deficit varied from 0.5 g/kg/day to 2.4 g/kg/day. Six studies reported mean reductions in fat mass, with the largest being 4.5 kg. Four studies reported mean reductions in fat-free mass, while two studies reported an increase. Results support the recommendation that greater than 0.8 g/kg/day is necessary to mitigate the impact of energy deficit on a decline in lean body mass, while intakes up to 1.6 g/kg/day may be preferred. However, exact recommendations cannot be inferred as the severity and duration of energy deficit varied across studies. Longer and larger investigations are needed to elucidate protein's role during energy deficit in active-duty military.

Isolation of Neuronal Synaptic Membranes by Sucrose Gradient Centrifugation.

Sucrose gradient centrifugation is a very useful technique for isolating specific membrane types based on their size and density. This is especially useful for detecting fatty acids and lipid molecules that are targeted to specialized membranes. Without fractionation, these types of molecules could be below the levels of detection after being diluted out by the more abundant lipid molecules with a more ubiquitous distribution throughout the various cell membranes. Isolation of specific membrane types where these lipids are concentrated allows for their detection and analysis. We describe herein our synaptic membrane isolation protocol that produces excellent yield and clear resolution of five major membrane fractions from a starting neural tissue homogenate: P1 (nuclear), P2 (cytoskeletal), P3 (neurosynaptosomal), PSD (post-synaptic densities), and SV (synaptic vesicle).

A Bietti Crystalline Dystrophy Mouse Model Shows Increased Sensitivity to Light-Induced Injury.

Bietti crystalline corneo-retinal dystrophy (BCD) is an autosomal recessive inherited retinal dystrophy characterized by multiple shimmering yellow-white deposits in the posterior pole of the retina in association with atrophy of the retinal pigment epithelium (RPE), pigment clumps, and choroidal atrophy and sclerosis. Blindness and severe visual damage are common in late-stage BCD patients. We generated a Cyp4v3 knockout mouse model to investigate the pathogenesis of BCD. This model exhibits decreased RPE numbers and signs of inflammation response in the retina. Rod photoreceptors were vulnerable to light-induced injury, showing increased deposits through fundoscopy, a decrease in thickness and a loss of cells in the ONL, and the degeneration of rod photoreceptors. These results suggest that an inflammatory response might be an integral part of the pathophysiology of BCD, suggesting that it might be reasonable for BCD patients to avoid strong light, and the results provide a useful model for evaluating the effects of therapeutic approaches.

Exercise increases attentional bias towards food cues in individuals classified as overweight to obese.

BACKGROUND: The obesity epidemic continues to be a major public health concern. Although exercise is the most common weight loss recommendation, weight loss outcomes from an exercise program are often suboptimal. The human body compensates for a large percentage of the energy expended through exercise to maintain energy homeostasis and body weight. Increases in energy intake appear to be the most impactful compensatory behavior. Research on the mechanisms driving this behavior has not been fully elucidated. PURPOSE: To determine if exercise influences the attentional processing towards food cues (attentional bias) and inhibitory control for food cues among individuals classified as overweight to obese who do not exercise. METHODS: Thirty adults classified as overweight to obese participated in a counterbalanced, crossover trial featuring two assessment visits on separate days separated by at least one week. Attentional bias and inhibitory control towards food cues was assessed prior to and after a bout of exercise where participants expended 500 kcal (one assessment visit) and before and after a 60 min bout of watching television (second assessment visit). Attentional bias was conceptualized as the percentage of time fixated on food cues when both food and neutral (non-food) cues were presented during a food-specific dot-probe task. Inhibitory control, specifically motor impulsivity, was assessed as percentage of inhibitory failures during a food-specific Go/NoGo task. RESULTS: A significant condition by time effect was observed for attentional bias towards food cues, independent of hunger, whereas attentional bias towards food cues was increased pre-post exercise but not after watching TV. Inhibitory control was not affected by exercise or related to attentional bias for food cues. CONCLUSIONS: An acute bout of exercise increased attentional bias for food cues, pointing to a mechanism that may contribute to the weight loss resistance observed with exercise. Future trials are needed to evaluate attentional bias towards food cues over a longitudinal exercise intervention.

W246G Mutant ELOVL4 Impairs Synaptic Plasticity in Parallel and Climbing Fibers and Causes Motor Defects in a Rat Model of SCA34.

Spinocerebellar ataxia (SCA) is a neurodegenerative disorder characterized by ataxia and cerebellar atrophy. A number of different mutations gives rise to different types of SCA with characteristic ages of onset, symptomatology, and rates of progression. SCA type 34 (SCA34) is caused by mutations in ELOVL4 (ELOngation of Very Long-chain fatty acids 4), a fatty acid elongase essential for biosynthesis of Very Long Chain Saturated and Polyunsaturated Fatty Acids (VLC-SFA and VLC-PUFA, resp., ≥28 carbons), which have important functions in the brain, skin, retina, Meibomian glands, testes, and sperm. We generated a rat model of SCA34 by knock-in of the SCA34-causing 736T>G (p.W246G) ELOVL4 mutation. Rats carrying the mutation developed impaired motor deficits by 2 months of age. To understand the mechanism of these motor deficits, we performed electrophysiological studies using cerebellar slices from rats homozygous for W246G mutant ELOVL4 and found marked reduction of long-term potentiation at parallel fiber synapses and long-term depression at climbing fiber synapses onto Purkinje cells. Neuroanatomical analysis of the cerebellum showed normal cytoarchitectural organization with no evidence of degeneration out to 6 months of age. These results point to ELOVL4 as essential for motor function and cerebellar synaptic plasticity. The results further suggest that ataxia in SCA34 patients may arise from a primary impairment of synaptic plasticity and cerebellar network desynchronization before onset of neurodegeneration and progression of the disease at a later age.

Tandem elimination-oxidation of tertiary benzylic alcohols with an oxoammonium salt.

Tertiary benzylic alcohols react with oxoammonium salts, undergoing a tandem elimination/allylic oxidation to provide an allylic ether product in a single step. This mode of reactivity provides a rapid entry into allylic ethers from certain benzylic tertiary alcohols. The allylic ether may be cleaved under reductive conditions to reveal the allylic alcohol.

Loss of Class III Phosphoinositide 3-Kinase Vps34 Results in Cone Degeneration.

The major pathway for the production of the low-abundance membrane lipid phosphatidylinositol 3-phosphate (PI(3)P) synthesis is catalyzed by class III phosphoinositide 3-kinase (PI3K) Vps34. The absence of Vps34 was previously found to disrupt autophagy and other membrane-trafficking pathways in some sensory neurons, but the roles of phosphatidylinositol 3-phosphate and Vps34 in cone photoreceptor cells have not previously been explored. We found that the deletion of Vps34 in neighboring rods in mouse retina did not disrupt cone function up to 8 weeks after birth, despite diminished rod function. Immunoblotting and lipid analysis of cones isolated from the cone-dominant retinas of the neural retina leucine zipper gene knockout mice revealed that both PI(3)P and Vps34 protein are present in mouse cones. To determine whether Vps34 and PI(3)P are important for cone function, we conditionally deleted Vps34 in cone photoreceptor cells of the mouse retina. Overall retinal morphology and rod function appeared to be unaffected. However, the loss of Vps34 in cones resulted in the loss of structure and function. There was a substantial reduction throughout the retina in the number of cones staining for M-opsin, S-opsin, cone arrestin, and peanut agglutinin, revealing degeneration of cones. These studies indicate that class III PI3K, and presumably PI(3)P, play essential roles in cone photoreceptor cell function and survival.

The Elovl4 Spinocerebellar Ataxia-34 Mutation 736T>G (p.W246G) Impairs Retinal Function in the Absence of Photoreceptor Degeneration.

Elongation of very long chain fatty acids-4 (ELOVL4) is essential for synthesis of very long chain polyunsaturated and saturated fatty acids (VLC-PUFA and VLC-SFA, respectively) of chain length greater than 26 carbons. Mutations in the ELOVL4 gene cause several distinct neurodegenerative diseases including Stargardt-like macular dystrophy (STGD3), spinocerebellar ataxia 34 (SCA34), and a neuro-ichthyotic syndrome with severe seizures and spasticity, as well as erythrokeratitis variabilis (EKV), a skin disorder. However, the relationship between ELOVL4 mutations, its VLC-PUFA and VLC-SFA products, and specific neurological symptoms remains unclear. We generated a knock-in rat line (SCA34-KI) that expresses the 736T>G (p.W246G) form of ELOVL4 that causes human SCA34. Lipids were analyzed by gas chromatography and mass spectrometry. Retinal function was assessed using electroretinography. Retinal integrity was assessed by histology, optical coherence tomography, and immunolabeling. Analysis of retina and skin lipids showed that the W246G mutation selectively impaired synthesis of VLC-SFA, but not VLC-PUFA. Homozygous SCA34-KI rats showed reduced ERG a- and b-wave amplitudes by 90 days of age, particularly for scotopic responses. Anatomical analyses revealed no indication of neurodegeneration in heterozygote or homozygote SCA34-KI rats out to 6-7 months of age. These studies reveal a previously unrecognized role for VLC-SFA in regulating retinal function, particularly transmission from photoreceptors to the inner retina, in the absence of neurodegeneration. Furthermore, these findings suggest that the tissue specificity and symptoms associated with disease-causing ELOVL4 mutations likely arise from selective differences in the ability of the mutant ELOVL4 enzymes to support synthesis of VLC-PUFA and/or VLC-SFA.

Total synthesis of (+)-pilosinine via a stereodivergent conjugate addition strategy.

In recent work, asymmetric conjugate addition reactions to chiral 4-phenyl-N-enoyl-1,3-oxazolidinones have been shown to give different stereochemical outcomes depending on the conditions employed. Through the application of stereodivergent reaction conditions, the total synthesis of (+)-pilosinine and the formal synthesis of (-)-pilosinine has been completed from a single enantiomer of the 1,3-oxazolidi-none auxiliary.

Novel Cellular Functions of Very Long Chain-Fatty Acids: Insight From ELOVL4 Mutations.

Elongation of Very Long chain fatty acids-4 (ELOVL4) protein is a member of the ELOVL family of fatty acid elongases that is collectively responsible for catalyzing formation of long chain fatty acids. ELOVL4 is the only family member that catalyzes production of Very Long Chain Saturated Fatty Acids (VLC-SFA) and Very Long Chain Polyunsaturated Fatty Acids (VLC-PUFA) with chain lengths ≥28 carbons. ELOVL4 and its VLC-SFA and VLC-PUFA products are emerging as important regulators of synaptic signaling and neuronal survival in the central nervous system (CNS). Distinct sets of mutations in ELOVL4 cause three different neurological diseases in humans. Heterozygous inheritance of one set of autosomal dominant ELOVL4 mutations that leads to truncation of the ELOVL4 protein causes Stargardt-like macular dystrophy (STGD3), an aggressive juvenile-onset retinal degeneration. Heterozygous inheritance of a different set of autosomal dominant ELOVL4 mutations that leads to a full-length protein with single amino acid substitutions causes spinocerebellar ataxia 34 (SCA34), a late-onset neurodegenerative disease characterized by gait ataxia and cerebellar atrophy. Homozygous inheritance of a different set of ELOVL4 mutations causes a more severe disease with infantile onset characterized by seizures, spasticity, intellectual disability, ichthyosis, and premature death. ELOVL4 is expressed widely in the CNS and is found primarily in neurons. ELOVL4 is expressed in cell-specific patterns within different regions of the CNS that are likely to be related to disease symptoms. In the retina, ELOVL4 is expressed exclusively in photoreceptors and produces VLC-PUFA that are incorporated into phosphatidylcholine and enriched in the light sensitive membrane disks of the photoreceptor outer segments. VLC-PUFA are enzymatically converted into "elovanoid" compounds that appear to provide paracrine signals that promote photoreceptor and neuronal survival. In the brain, the main ELOVL4 products are VLC-SFA that are incorporated into sphingolipids and enriched in synaptic vesicles, where they regulate kinetics of presynaptic neurotransmitter release. Understanding the function of ELOVL4 and its VLC-SFA and VLC-PUFA products will advance our understanding of basic mechanisms in neural signaling and has potential for developing novel therapies for seizure and neurodegenerative diseases.

Decreased very long chain polyunsaturated fatty acids in sperm correlates with sperm quantity and quality.

PURPOSE: To determine if levels of very long chain polyunsaturated fatty acids (VLC-PUFA; ≥ 28 carbons;4-6 double bonds) in human sperm correlate with sperm quantity and quality as determined by a complete semen analysis. METHODS: Ejaculates from 70 men underwent a complete semen analysis, which included volume, count, motility, progression, agglutination, viscosity, morphology, and pH. For lipid analysis, sperm were pelleted to remove the semen. Lipids were extracted from the cell pellet and methyl esters of total lipids analyzed by gas chromatography. The sphingolipids were enriched and sphingomyelin (SM) species measured using tandem mass spectrometry. Pair-wise Pearson correlation and linear regression analysis compared percent VLC-PUFA-SM and percent docosahexaenoic acid (DHA) to results from the semen analysis. RESULTS: VLC-PUFA-SM species having 28-34 carbon fatty acids were detected in sperm samples, with 28 and 30 carbon VLC-PUFA as most the abundant. The sum of all VLC-PUFA-SM species comprised 0 to 6.1% of the overall SM pool (mean 2.1%). Pair-wise Pearson analyses showed that lower levels of VLC-PUFA-SM positively correlated with lower total motile count (0.68) and lower total count (0.67). Total VLC-PUFA-SM and mole % DHA (22:6n3) were not strongly correlated (- 0.24). Linear regression analysis confirmed these findings. CONCLUSION: This study revealed a positive correlation between the levels of VLC-PUFA with sperm count and total motile count and suggests that both sperm quality and quantity may depend on the presence of VLC-PUFA. The lack of correlation between VLC-PUFA and DHA suggests that low VLC-PUFA levels do not result from inadequate PUFA precursors.

ELOVL4: Very long-chain fatty acids serve an eclectic role in mammalian health and function.

ELOngation of Very Long chain fatty acids-4 (ELOVL4) is an elongase responsible for the biosynthesis of very long chain (VLC, ≥C28) saturated (VLC-SFA) and polyunsaturated (VLC-PUFA) fatty acids in brain, retina, skin, Meibomian glands, and testes. Fascinatingly, different mutations in this gene have been reported to cause vastly different phenotypes in humans. Heterozygous inheritance of seven different mutations in the coding sequence and 5' untranslated region of ELOVL4 causes autosomal dominant Stargardt-like macular dystrophy (STGD3), while homozygous inheritance of three more mutant variants causes severe seizures with ichthyosis, hypertonia, and even death. Some recent studies have described heterozygous inheritance in yet another three mutant ELOVL4 variants, two that cause spinocerebellar ataxia-34 (SCA34) with erythrokeratodermia (EKV) and one that causes SCA34 without EKV. We identified the specific enzymatic reactions catalyzed by ELOVL4 and, using a variety of genetically engineered mouse models, have actively searched for the mechanisms by which ELOVL4 impacts neural function and health. In this review, we critically compare and contrast the various animal model and case studies involving ELOVL4 deficiency via either mutation or deletion, and the resulting consequences on neuronal health and function in both the retina and central nervous system.

Day 7 blastocyst euploidy supports routine implementation for cycles using preimplantation genetic testing.

OBJECTIVE: To determine if Day 7 blastocysts merit biopsy, vitrification and transfer consideration by contrasting their aneuploidy and implantation rates to Day 5 and 6 blastocysts. METHODS: A total of 1,925 blastocysts were biopsied from 402 PGT-A cycles over a 12 to 16 month interval. All embryos were cultured under tri-gas, humidified conditions (37ºC) for up to 7 days (168 hours post-insemination). Biopsied blastocysts were vitrified and trophectoderm samples analyzed using NextGen sequencing. Single euploid embryo transfers were performed (n=254) using either a Day 5 (n=145), Day 6 (n=92) or a Day 7 blastocyst (n=16) post-warming. Euploidy rates and pregnancy outcomes were subsequently assessed and differences determined by day of development and blastocyst quality grade. RESULTS: No differences were observed in implantation, pregnancy loss or ongoing pregnancy rates between Day 5 and Day 6 blastocysts. Development to Day 7 accounted for 6.6% of all blastocysts. Euploidy rates were higher in Day 5 blastocysts (53.5%; p<0.05) compared to Day 6 (40.4%) and Day 7 (35.9%). High implantation potential (56.3% to 79.3%) of vitrified-warmed euploid blastocyst occurred independent to the day of development. However, miscarriage/loss rates increased (22.2% vs. 2%; p<0.05) with Day 7 blastocysts, resulting in lower (p<0.05) live birth rates (43.8% vs. 67.4-77.2%). CONCLUSION: Culturing blastocysts to Day 7 has proven beneficial by achieving viable euploid embryos that would have otherwise been discarded. An extra Day of embryo growth allows select patients additional opportunities for in vitro development and possible healthy term live births.

Correction to: Retinal Degenerative Diseases.

The title of the chapter is "Melatonin as the Possible Link Between Age-Related Retinal Degeneration and the Disrupted Circadian Rhythm in Elderly" but degeneration was incorrectly published as regeneration. Now this has been corrected to degeneration.

Differential composition of DHA and very-long-chain PUFAs in rod and cone photoreceptors.

Long-chain PUFAs (LC-PUFAs; C20-C22; e.g., DHA and arachidonic acid) are highly enriched in vertebrate retina, where they are elongated to very-long-chain PUFAs (VLC-PUFAs; C 28) by the elongation of very-long-chain fatty acids-4 (ELOVL4) enzyme. These fatty acids play essential roles in modulating neuronal function and health. The relevance of different lipid requirements in rods and cones to disease processes, such as age-related macular degeneration, however, remains unclear. To better understand the role of LC-PUFAs and VLC-PUFAs in the retina, we investigated the lipid compositions of whole retinas or photoreceptor outer segment (OS) membranes in rodents with rod- or cone-dominant retinas. We analyzed fatty acid methyl esters and the molecular species of glycerophospholipids (phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine) by GC-MS/GC-flame ionization detection and ESI-MS/MS, respectively. We found that whole retinas and OS membranes in rod-dominant animals compared with cone-dominant animals had higher amounts of LC-PUFAs and VLC-PUFAs. Compared with those of rod-dominant animals, retinas and OS membranes from cone-dominant animals also had about 2-fold lower levels of di-DHA (22:6/22:6) molecular species of glycerophospholipids. Because PUFAs are necessary for optimal G protein-coupled receptor signaling in rods, these findings suggest that cones may not have the same lipid requirements as rods.

Pyruvate kinase M2 regulates photoreceptor structure, function, and viability.

Pyruvate kinase M2 (PKM2) is a glycolytic enzyme that is expressed in cancer cells. Its role in tumor metabolism is not definitively established, but investigators have suggested that regulation of PKM2 activity can cause accumulation of glycolytic intermediates and increase flux through the pentose phosphate pathway. Recent evidence suggests that PKM2 also may have non-metabolic functions, including as a transcriptional co-activator in gene regulation. We reported previously that PKM2 is abundant in photoreceptor cells in mouse retinas. In the present study, we conditionally deleted PKM2 (rod-cre PKM2-KO) in rod photoreceptors and found that the absence of PKM2 causes increased expression of PKM1 in rods. Analysis of metabolic flux from U-13C glucose shows that rod-cre PKM2-KO retinas accumulate glycolytic intermediates, consistent with an overall reduction in the amount of pyruvate kinase activity. Rod-cre PKM2-KO mice also have an increased NADPH availability could favor lipid synthesis, but we found no difference in phospholipid synthesis between rod-cre PKM2 KO and PKM2-positive controls. As rod-cre PKM2-KO mice aged, we observed a significant loss of rod function, reduced thickness of the photoreceptor outer segment layer, and reduced expression of photoreceptor proteins, including PDE6ß. The rod-cre PKM2-KO retinas showed greater TUNEL staining than wild-type retinas, indicating a slow retinal degeneration. In vitro analysis showed that PKM2 can regulate transcriptional activity from the PDE6ß promoter in vitro. Our findings indicate that both the metabolic and transcriptional regulatory functions of PKM2 may contribute to photoreceptor structure, function, and viability.

Homozygous Expression of Mutant ELOVL4 Leads to Seizures and Death in a Novel Animal Model of Very Long-Chain Fatty Acid Deficiency.

Lipids are essential components of the nervous system. However, the functions of very long-chain fatty acids (VLC-FA; ≥ 28 carbons) in the brain are unknown. The enzyme ELOngation of Very Long-chain fatty acids-4 (ELOVL4) catalyzes the rate-limiting step in the biosynthesis of VLC-FA (Agbaga et al., Proc Natl Acad Sci USA 105(35): 12843-12848, 2008; Logan et al., J Lipid Res 55(4): 698-708, 2014), which we identified in the brain as saturated fatty acids (VLC-SFA). Homozygous mutations in ELOVL4 cause severe neuropathology in humans (Ozaki et al., JAMA Neurol 72(7): 797-805, 2015; Mir et al., BMC Med Genet 15: 25, 2014; Cadieux-Dion et al., JAMA Neurol 71(4): 470-475, 2014; Bourassa et al., JAMA Neurol 72(8): 942-943, 2015; Aldahmesh et al., Am J Hum Genet 89(6): 745-750, 2011) and are post-natal lethal in mice (Cameron et al., Int J Biol Sci 3(2): 111-119, 2007; Li et al., Int J Biol Sci 3(2): 120-128, 2007; McMahon et al., Molecular Vision 13: 258-272, 2007; Vasireddy et al., Hum Mol Genet 16(5): 471-482, 2007) from dehydration due to loss of VLC-SFA that comprise the skin permeability barrier. Double transgenic mice with homozygous knock-in of the Stargardt-like macular dystrophy (STDG3; 797-801_AACTT) mutation of Elovl4 with skin-specific rescue of wild-type Elovl4 expression (S + Elovl4 mut/mut mice) develop seizures by P19 and die by P21. Electrophysiological analyses of hippocampal slices showed aberrant epileptogenic activity in S + Elovl4 mut/mut mice. FM1-43 dye release studies showed that synapses made by cultured hippocampal neurons from S + Elovl4 mut/mut mice exhibited accelerated synaptic release kinetics. Supplementation of VLC-SFA to cultured hippocampal neurons from mutant mice rescued defective synaptic release to wild-type rates. Together, these studies establish a critical, novel role for ELOVL4 and its VLC-SFA products in regulating synaptic release kinetics and epileptogenesis. Future studies aimed at understanding the molecular mechanisms by which VLC-SFA regulate synaptic function may provide new targets for improved seizure therapies.