Cholinergic Activity in Autism: Abnormalities in the Cerebral Cortex and Basal Forebrain

Perry, Elaine K.; Lee, Mandy L.W.; Martin-Ruiz, Carmen; Court, Jennifer A.; Volsen, Stephen G.; Merrit, Jenny; Folly, Elizabeth A.; Iversen, Portia; Bauman, Margaret L.; Perry, Robert H.; Wenk, Gary L.

doi:10.1176/appi.ajp.158.7.1058

Cited by 345 publications

(222 citation statements)

References 45 publications

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“…Conversely, it is of potential importance for the design of nicotinic agents acting on psychiatric or neurologic diseases that hit nAChRs. Various cognitive dysfunctions such as those associated with Alzheimer's disease (45), schizophrenia (46), and autism (10) have been reported to differentially affect diverse subtypes of nicotinic receptors. The phenotypes observed with the ␤2 Ϫ/Ϫ mice are characterized by alterations of behavioral flexibility and adaptive behaviors coupled with unimpaired memory and anxiety.…”

Section: Discussionmentioning

confidence: 99%

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Executive and social behaviors under nicotinic receptor regulation

Granon

Fauré

Changeux

2003

Proc. Natl. Acad. Sci. U.S.A.

154

164

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Nicotine enhances several cognitive and psychomotor behaviors, and nicotinic antagonists cause impairments in tasks requiring cognitive effort. To explore the contribution of nicotinic receptors to complex cognitive functions, we developed an automated method to investigate sequential locomotor behavior in the mouse and an analysis of social behavior. We show that, in the ␤2 ؊/؊ mutant, the high-order spatiotemporal organization of locomotor behavior, together with conflict resolution and social interaction, is selectively dissociated from low-level, more automatic motor behaviors. Such deficits in executive functions resemble the rigid and asocial behavior found in some psychopathological disorders such as autism and attention deficit hyperactivity disorder. N icotine and nicotinic agonists enhance cognitive and psychomotor behaviors in various species (1-5). Conversely, nicotinic antagonists (6, 7) and loss of nicotinic acetylcholine receptors (nAChRs) under various pathological conditions impair cognitive performance (8-10). These pharmacological actions of nicotine are mediated by a variety of nAChR subtypes with different distribution patterns in the brain (11,12). To unravel their respective contribution to brain functions, mice lacking defined nAChR subunits have been generated (for a review see ref. 13).Brain nAChRs are pentameric oligomers composed of protein subunits arranged in various combinations of ␣ (2-9) and ␤ (2-4). The principal combinations that predominate in the brain are ␣4␤2 and ␣7 subunits (13,14). Mice lacking the ␤2 subunits show abnormal passive avoidance (15) and impaired nicotine self-administration (16) and drug discrimination (17) and exhibit a reduced nociceptive response to nicotine (18) and decreased visual acuity (19). On the other hand, general spatial memory tested in the water-maze task is not affected (9).The aim of this article is to explore the contribution of nAChRs to complex cognitive functions referred to as executive processes. The management of these processes provides the maintenance of goal representation, the appropriate adaptation of behavior in a changing environment, the organization of sequences of actions over time, and the inhibition of prepotent or previous responses (20). Former work in humans and animals has shown that these processes require prefrontal and͞or cingulate activation (21-24). Behavioral protocols known to rely on the integrity of these structures were adapted to mice.We developed an automated analytical procedure for locomotor behavior (25) in the mouse. This method makes possible the distinction and quantitative evaluation of high-level executive components from low-level motor behavior. Furthermore, to study an index of adapted responses to a context that potentially leads to conflict resolution, we designed a procedure aimed at the distinction between several types of sequential behaviors in a social context. Interestingly, the ''supervisory planning'' organization of mouse locomotor behavior and conflict resolution were found selectivel...

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Section: Discussionmentioning

confidence: 99%

“…Conversely, nicotinic antagonists (6,7) and loss of nicotinic acetylcholine receptors (nAChRs) under various pathological conditions impair cognitive performance (8)(9)(10). These pharmacological actions of nicotine are mediated by a variety of nAChR subtypes with different distribution patterns in the brain (11,12).…”

mentioning

confidence: 99%

Executive and social behaviors under nicotinic receptor regulation

Granon

Fauré

Changeux

2003

Proc. Natl. Acad. Sci. U.S.A.

154

164

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“…Abnormalities in cortical nicotinic binding have been demonstrated in several neurodevelopmental conditions, including autism (Perry et al, 2001;Martin-Ruiz et al, 2004), epilepsy (Picard et al, 2006), and schizophrenia (Breese et al, 2000;Marutle et al, 2001). In the human brain, nicotinic binding is highest toward the end of gestation (Court et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Developmental Excitation of Corticothalamic Neurons by Nicotinic Acetylcholine Receptors

Kassam¹,

Herman²,

Goodfellow³

et al. 2008

J. Neurosci.

129

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In this study, we show robust nicotinic excitation of pyramidal neurons in layer VI of prefrontal cortex. This layer contains the corticothalamic neurons, which gate thalamic activity and play a critical role in attention. Our experiments tested nicotinic excitation across postnatal development, using whole-cell recordings in prefrontal brain slices from rats. These experiments showed that layer VI neurons have peak nicotinic currents during the first postnatal month, a time period of intensive cortical development in rodents. We demonstrate that these currents are mediated directly by postsynaptic nicotinic receptors and can be suppressed by a competitive antagonist of ␣ 4 ␤ 2 * nicotinic receptors. To record from identified corticothalamic neurons, we performed stereotaxic surgery to label the neurons projecting to medial dorsal thalamus. As hypothesized, recordings from these retrogradely labeled neurons in layer VI showed prominent nicotinic currents. Finally, we examined the effects of the drug nicotine on layer VI neurons and probed for the potential involvement of the accessory subunit, ␣ 5 , in their receptors. A level of nicotine similar to that found in the blood of smokers elicits a stable inward current in layer VI neurons, yet this exposure desensitizes ϳ50% of the subsequent current elicited by acetylcholine. An allosteric modulator of ␣ 4 ␤ 2 ␣ 5 receptors resulted in a 2.5-fold potentiation of submaximal nicotinic currents. This result is consistent with the expression of the relatively rare ␣ 5 nicotinic subunit in layer VI. In summary, we show that layer VI corticothalamic neurons can be strongly excited during development by an unusual subtype of nicotinic receptor.

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“…Elevated levels of BDNF were found in postmortem brain tissue from adults with autism [Perry et al, 2001] and concentrations different from those in controls have been found in peripheral blood of adults and children diagnosed with autism [Connolly et al, 2006;Enstrom et al, 2008;Hashimoto et al, 2006;Miyazaki et al, 2004]. The two studies that have examined BDNF levels in neonatal specimens from individuals later diagnosed with autism have yielded inconsistent results [Nelson et al, 2001[Nelson et al, , 2006.…”

Section: Introductionmentioning

confidence: 99%

Brain‐derived neurotrophic factor and autism: maternal and infant peripheral blood levels in the Early Markers for Autism (EMA) study

et al. 2008

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To investigate levels of brain-derived neurotrophic factor (BDNF) in mid-pregnancy and neonatal blood specimens as early biologic markers for autism, we conducted a population-based case-control study nested within the cohort of infants born from July 2000 to September 2001 to women who participated in the prenatal screening program in Orange County, CA. Cases (n 5 84) were all children receiving services for autism at the Regional Center of Orange County. Two comparison groups from the same study population were included: children with mental retardation or developmental delay (n 5 49) receiving services at the same regional center, and children not receiving services for developmental disabilities, randomly sampled from the California birth certificate files (n 5 159), and frequency matched to autism cases on sex, birth year, and birth month. BDNF concentrations were measured in archived mid-pregnancy and neonatal blood specimens drawn during routine prenatal and newborn screening using a highly sensitive bead-based assay (Luminex, Biosource Human BDNF Antibody Bead Kit, Invitrogen-Biosource, Carlsbad, CA). The concentration of BDNF in maternal mid-pregnancy and neonatal specimens was similar across all three study groups. These data do not support previous findings of an association between BDNF and autism and suggest that the concentration of BDNF during critical periods of early neurodevelopment is not likely to be a useful biomarker for autism susceptibility.

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Cholinergic Activity in Autism: Abnormalities in the Cerebral Cortex and Basal Forebrain

Abstract: These neurochemical abnormalities implicate the cholinergic system in developmental disorders such as autism and suggest the potential for intervention based on cholinergic receptor modulation.

Cited by 345 publications

References 45 publications

Executive and social behaviors under nicotinic receptor regulation

Executive and social behaviors under nicotinic receptor regulation

Developmental Excitation of Corticothalamic Neurons by Nicotinic Acetylcholine Receptors

Brain‐derived neurotrophic factor and autism: maternal and infant peripheral blood levels in the Early Markers for Autism (EMA) study

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