Diagnostic Breakthrough in Autism and Mental Retardation Reported
The May 4, 2000 on-line issue of USA Today Health announced the findings of an intriguing study: "New Test May Find Autism in Newborns." The article reported that a study of stored blood samples taken from 249 infants in the 1980's had revealed the presence of unusually high levels of four proteins in children who were later diagnosed with autism or mental retardation. The proteins identified were: vasoactive intestinal peptide (V.I.P.), calcitonin-related gene peptide (C.G.R.P.), brain-derived neurotrophic factor (B.D.N.F.), and neurotrophin-4 (NT4). The article and the authors of the original study (to be published later) caution that the results are preliminary, have not been duplicated, and it is not clear exactly what the results may indicate.
For another (more complete) article see the New York Times May 4, 2000 on-line issue: "4 Brain Chemicals in Babies May Foretell Autism and Retardation." Note: the NYT requires a free registration to view the article on-line. For a synopsis of the study from the National Alliance for Autism Research (NAAR) click here.
Medline Abstracts Concerning the Four Proteins
1. Vasoactive Intestinal Peptide (V.I.P.): My comments: The study demonstrated that learning may be impaired by inhibiting the binding of VIP.
Title: Learning impairment following intracerebral administration of the HIV envelope protein gp120 or a VIP antagonist.
Author: Glowa JR; Panlilio LV; Brenneman DE; Gozes I; Fridkin M; Hill JM
Source: Brain Res, 1992 Jan, 570:1-2, 49-53
Abstract: The external envelope glycoprotein (gp120) of the human immunodeficiency virus (HIV) has been shown to be toxic to neurons in culture. To further investigate the neurological effects of gp120, the involvement of this protein with the acquisition of spatial discrimination was assessed. Both native and recombinant gp120 were administered into the cerebral ventricles of adult rats and performance was evaluated in the Morris swim maze. Gp120 treatment retarded acquisition after daily administration of 12 ng. The specificity of this impairment was demonstrated in that the performance of animals given the same amount of gp120 from recombinant baculovirus was not different from animals given saline. Vasoactive intestinal peptide (VIP) has been shown to block gp120-induced neurotoxicity in culture and a VIP receptor antagonist has displayed toxic properties to neurons in culture. We show here that this antagonist, which competitively inhibits VIP binding and blocks VIP-mediated functions in cell cultures from the CNS, also produced an impairment of performance. This retardation was attenuated by cotreatment with VIP, supporting the specificity of the observed impairment. Thus, gp120 and the VIP antagonist produced similar retardation of spatial discrimination, suggesting that both may impair memory for spatially related stimulus control.
2. Calcitonin-Related Gene Peptide (C.G.R.P.): My comments: The study demonstrated that Williams Syndrome (a disorder which typically includes symptoms of autism) may be associated with abnormal levels of CGRP.
Title: Williams syndrome. A middle-aged case of markedly delayed diagnosis.
Author: Matsumoto A; Nitta M; Niwa A; Hosoda H; Shirai T; Sakamoto T; Suzuki A
Source: Jpn Heart J, 1993 Sep, 34:5, 653-9
Abstract : A rare case of Williams syndrome diagnosed at the age of 41 is documented. The first subjective symptom was chest pain and the patient displayed many other features in addition to severe supravalvular aortic stenosis with a systolic gradient of 60 mmHg. The stenotic lesion had an area of 0.5 cm2, and was associated with dilated and tortuous coronary arteries. Extended aortoplasty was successfully performed and the postoperative course has been excellent without any cardiac symptoms. In spite of the severe cardiac lesions, this case had been largely asymptomatic and presented unusual features related to the diagnosis and management of this syndrome in an adult. The pattern of abnormalities found in this case suggested problems in relation to the calcitonin/calcitonin gene related peptide (CGRP) and the elastin gene occurring in embryonic organogenesis.
3. Brain-Derived Neurotrophic Factor (B.D.N.F.): My comments: Autism has been associated with abnormal serotonin levels and aggressiveness. Prader-Willi Syndrome (a disorder that may include symptoms of autism) has been associated with both aggressiveness and hyperphagia. It may be that the abnormal levels of BDNF are responsible for much of this.
Title: Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities.
Author: Lyons WE; Mamounas LA; Ricaurte GA; Coppola V; Reid SW; Bora SH; Wihler C; Koliatsos VE; Tessarollo L
Source: Proc Natl Acad Sci U S A, 1999 Dec, 96:26, 15239-44
Abstract: Brain-derived neurotrophic factor (BDNF) has trophic effects on serotonergic (5-HT) neurons in the central nervous system. However, the role of endogenous BDNF in the development and function of these neurons has not been established in vivo because of the early postnatal lethality of BDNF null mice. In the present study, we use heterozygous BDNF(+/-) mice that have a normal life span and show that these animals develop enhanced intermale aggressiveness and hyperphagia accompanied by significant weight gain in early adulthood; these behavioral abnormalities are known to correlate with 5-HT dysfunction. Forebrain 5-HT levels and fiber density in BDNF(+/-) mice are normal at an early age but undergo premature age-associated decrements. However, young adult BDNF(+/-) mice show a blunted c-fos induction by the specific serotonin releaser-uptake inhibitor dexfenfluramine and alterations in the expression of several 5-HT receptors in the cortex, hippocampus, and hypothalamus. The heightened aggressiveness can be ameliorated by the selective serotonin reuptake inhibitor fluoxetine. Our results indicate that endogenous BDNF is critical for the normal development and function of central 5-HT neurons and for the elaboration of behaviors that depend on these nerve cells. Therefore, BDNF(+/-) mice may provide a useful model to study human psychiatric disorders attributed to dysfunction of serotonergic neurons.
----------------------- My comments: The hippocampus is one of the brain regions thought to be involved in the symptoms of autism, especially memory and learning impairment. According to the following study, it appears that lesions of the hippocampus also affect BDNF levels.
Title: Unilateral hippocampal lesions in newborn and adult rats: effects on spatial memory and BDNF gene expression.
Author: van Praag H; Qu PM; Elliott RC; Wu H; Dreyfus CF; Black IB
Source: Behav Brain Res, 1998 Apr, 92:1, 21-30
Abstract: Subcortical damage at birth often produces more severe deficits than similar lesions in an adult. In the present study, effects of unilateral electrolytic hippocampal ablations made on postnatal day 1 or in 3-month-old adult rats, were compared. Exploratory behavior and spatial navigation in the Morris water maze (MWM) were assessed 8 and 20 weeks after hippocampal damage. Rats with neonatal damage did not respond to novelty in the environment and did not learn to find the hidden platform in the MWM. Rats lesioned as adults did learn the water maze task, but slower than controls. We hypothesized that behavioral deficits observed in rats lesioned at birth, may be due, in part, to neurochemical dysfunction of the contralateral hippocampus. Specifically, cholinergic and GABAergic neurotransmission were assessed by measuring choline-acetyltransferase (ChAT) and GABAdecarboxylase (GAD) activity. In addition, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) mRNA levels were assayed in the remaining (contralateral) hippocampus. Of these molecules, only BDNF gene expression was significantly reduced (by 30%) at 8 and 20 weeks after neonatal and adult unilateral ablation. The similar reduction in BDNF mRNA in both treatment groups does not correspond with the lesion's differential effect on memory function. However, the more severe learning impairment after neonatal lesion may reflect increased dependence on trophins during development.
------------------------- My comments: The following study demonstrates that infusing the midbrain with BDNF has an anti-depressant effect on rats. The rats improved their performance and were less likely to "freeze" when under stress. Symptoms of autism has been treated with anti-depressants for years - could this be correcting a dysfunctioning BDNF system?
Title: Antidepressant-like effect of brain-derived neurotrophic factor (BDNF).
Author: Siuciak JA; Lewis DR; Wiegand SJ; Lindsay RM
Source: Pharmacol Biochem Behav, 1997 Jan, 56:1, 131-7
Abstract: Previous studies have shown that infusion of brain-derived neurotrophic factor (BDNF) into the midbrain, near the PAG and dorsal/median raphe nuclei, produced analgesia and increased activity in monoaminergic systems. Alterations in monoaminergic activity have also been implicated in the pathogenesis and treatment of depression. The present studies examined the ability of centrally administered BDNF to produce antidepressant-like activity in two animal models of depression, learned helplessness following exposure to inescapable shock and the forced swim test. In the learned helplessness paradigm, vehicle-infused rats pre-exposed to inescapable shock (veh/shock) showed severe impairments in escape behavior during subsequent conditioned avoidance trials, including a 47% decrease in the number of escapes and a 5 fold increase in escape latency, as compared to vehicle-infused rats which received no pre-shock treatment (veh/no shock). Midbrain BDNF infusion (12-24 micrograms/day) reversed these deficits, and in fact, BDNF-infused rats pre-exposed to inescapable shock (BDNF/shock) showed escape latencies similar to veh/no shock and BDNF/no shock rats. In the forced swim test, BDNF infusion decreased the immobility time by 70% as compared to vehicle-infused controls. Non-specific increases in activity could not account for these effects since general locomotor activity of BDNF- and vehicle-infused animals was not different. These findings demonstrate an antidepressant-like property of BDNF in two animal models of depression, which may be mediated by increased activity in monoaminergic systems.
4. Neurotrophin-4 (NT-4): My comments: The following study indicates that BDNF and NT-4 must be balanced correctly with granule neurons to aid the development and survival of Purkinje cells. Several studies have shown that Purkinje cells are unusual in persons with autism.
Title: Granule neuron regulation of Purkinje cell development: striking a balance between neurotrophin and glutamate signaling.
Author: Morrison ME; Mason CA
Source: J Neurosci, 1998 May, 18:10, 3563-73
Abstract: Granule neurons, presynaptic afferents of Purkinje cells, are potent regulators of Purkinje cell development. Purified Purkinje cells survive and differentiate poorly, whereas coculture with granule neurons enhances their survival and dendritic development. Here we investigate the role of neurotrophins in granule-Purkinje cell interactions. BDNF or NT-4 improves, but NT-3 or CNTF reduces, survival of isolated Purkinje cells. When granule neurons are present, however, BDNF or NT-4 treatment leads to Purkinje cell loss. This decrease is overcome by anti-BDNF or TrkB-IgG-blocking reagents or by CNQX, a non-NMDA glutamate receptor antagonist. Furthermore, BDNF increases the spine density on the surviving Purkinje cells. These results suggest that Purkinje cell survival and differentiation are context-dependent and require a balance between neurotrophin- and activity-dependent signaling.
------------------------- My comments: The following study suggests that neurotrophins (e.g., NT-4) may be related to developmental defects of the nervous system and may be related to insensitivity to pain (a fairly common symptom in autism).
Title: Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis.
Author: Indo Y; Tsuruta M; Hayashida Y; Karim MA; Ohta K; Kawano T; Mitsubuchi H; Tonoki H; Awaya Y; Matsuda I
Source: Nat Genet, 1996 Aug, 13:4, 485-8
Abstract: Congenital insensitivity to pain with anhidrosis (CIPA; MIM 256800) is an autosomal-recessive disorder characterized by recurrent episodes of unexplained fever, anhidrosis (absence of sweating) and absence of reaction to noxious stimuli, self-mutilating behaviour and mental retardation. The genetic basis for CIPA is unknown. Nerve growth factor (NGF) induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons. Mice lacking the gene for TrkA, a receptor tyrosine kinase for NGF, share dramatic phenotypic features of CIPA, including loss of responses to painful stimuli, although anhidrosis is not apparent in these animals. We therefore considered the human TRKA homologue as a candidate for the CIPA gene. The mRNA and genomic DNA encoding TRKA were analysed in three unrelated CIPA patients who had consanguineous parents. We detected a deletion-, splice- and missense-mutation in the tyrosine kinase domain in these three patients. Our findings strongly suggest that defects in TRKA cause CIPA and that the NGF-TRKA system has a crucial role in the development and function of the nociceptive reception as well as establishment of thermoregulation via sweating in humans. These results also implicate genes encoding other TRK and neurotrophin family members as candidates for developmental defect(s) of the nervous system.
Links
OMIM Entry - Vasoactive Intestinal Peptide (V.I.P.)
OMIM Entry - Calcitonin-Related Gene Peptide (C.G.R.P.)
OMIM Entry - Brain-Derived Neurotrophic Factor (B.D.N.F.)
OMIM Entry - Neurotrophin-4 (NT-4)