Coloboma mouse mutant as an animal model of hyperkinesis and attention deficit hyperactivity disorder
Introduction
Attention deficit hyperactivity disorder (ADHD) is a major pediatric neuropsychiatric disorder affecting about 5% of school-aged children [1]. The three major symptoms of inattention, excess impulsivity, and uncontrolled hyperactivity that define ADHD reflect a wide constellation of age-inappropriate behaviors which tend to cluster, leading to the assignment of two subtypes of ADHD, inattention and hyperactivity/impulsivity. While affected children may independently present either subtype, the combined phenotype of inattention, impulsivity and hyperactivity appears to be most common. The behavioral impairments associated with ADHD are typically exhibited early in childhood, before the age of seven. Although the severity of these deficits, particularly hyperactivity, generally wane at adolescence, elements of these impairments persist in 50–80% of adolescents and 30–50% of adults [2], [3]. Considerable evidence from family studies, and twin and adoption studies has strongly suggested that ADHD is heritable (for review see [4]), although penetrance is clearly not complete. Taken together these observations suggest that as other complex neuropsychiatric disorders such as schizophrenia, ADHD is a multifaceted, likely heterogeneous disorder that arises from a variety of genetic interactions contributed by different gene loci. The genetic loci with contribute to the variable impairments of ADHD are thus likely to represent a collection of susceptibility or modulatory genes that initially influence development and consequently impact on information processing in the mature brain.
Despite compelling evidence for genetic heritance ADHD, few animal models of ADHD have emerged. However, characteristics of ADHD drawn from patient populations can be used to help identify certain elements of the disorder that may be modeled in animals, in particular rodents. For example, the observation that indirect dopamine agonists, particularly methylphenidate and d-amphetamine, effectively improve both behavioral deficits of hyperactivity and in classroom performance, together with the altered levels of dopamine metabolites in ADHD affected individuals (for example, see [5]) provides support for the notion that dopaminergic pathways are particularly affected in ADHD. Morphometric studies based on magnetic resonance imaging have, in fact, provided additional evidence for the involvement of prefrontal cortex-striatal systems, which receive strong dopaminergic input [6]. Recently, Barkley has proposed that the principal deficit in ADHD lies in executive functions performed by the prefrontal cortex to control the initiation of motor responses leading to impulsivity and hyperactivity [7]. Since prefrontal cortex receives modulatory input from the striatum, this again suggests a link between the circuitry of striatal and prefrontal dopaminergic pathways and behavioral deficits in ADHD. Studies examining the co-inheritance of polymorphic alleles of the dopamine reuptake transporter DAT1 and the dopamine D4 receptor DRD4 have identified specific alleles of these genes that may provide increased risk for ADHD (reviewed in Ref. [8]). While these findings still appear controversial ([9], and see Ref. [8]), they have provided specific gene targets to evaluate for a direct role in ADHD. It is of interest, therefore, that mice homozygous for the null DAT1 alleles, generated by homologous recombination gene “knock-out” technology, are spontaneously hyperactive. However, in the case of the DAT1 polymorphism associated with ADHD, this mutation lies outside the protein-coding region and within the 3′ untranslated portion of the mRNA. Thus it remains unclear how this might affect dopamine reuptake function in ADHD and correspond to the lack of dopamine transporter function in DAT1 knockout mice.
Several rat models displaying characteristics of ADHD have been described, including the genetic models based on the spontaneously hypertensive rat (SHR) [10] and Naples-Excitability (NHE) [11] lines, as well as neonatal lesions of the dopaminergic input to the striatum [12]. Behavioral and pharmacological studies have shown that such genetic and lesion models do faithfully reflect ADHD-associated deficits including, although not limited to, hyperkinesis (for example, [10], [13], [14]). However these models have been limited by the lack of precise mapping of genetic defects to trace in molecular mechanisms underlying brain dysfunctions relevant to ADHD. In contrast, studies in the mouse have benefited enormously from the vast collection of genetic information and great number of genetically defined mutants, which when coupled with the advance of transgenic technology, and more recently targeted gene disruption methods, provide an effective means to identify genes that influence behavior. Based on this genetic groundwork, investigations in the mouse that complement the pharmacological and behavioral insight gained in rat models can begin to unravel the complexities of gene expression and development that underlie neuropsychiatric diseases, such as ADHD.
Section snippets
The coloboma mutant mouse
Coloboma mutant mice display a variety of behavioral, neurophysiological and developmental deficits, of which a subset may be compared with those, presented by ADHD children. Although the Cm mutation is early embryonic lethal when homozygous [15], adult heterozygote mice (genotype, Cm/+) are viable but exhibit pronounced spontaneous hyperactive locomotor behavior, originally termed “circling,” as well as head bobbing, and a distinctive ocular dysmorphology leading to sunken and often closed
Deficiencies in SNAP-25 lead to dysregulation of activity and hyperkinesis
The role of SNAP-25 in mediating vesicular release of neurotransmitter suggested that it may be a candidate for neurophysiological dysfunction seen in Cm/+ mice. SNAP-25 (synaptosomal associated protein of 25 kD) is a nerve terminal protein which together with syntaxin 1a and VAMP-2 (synaptobrevin-2) form a highly stable ternary complex [26]. This complex is thought to form a direct link between transmitter laden synaptic vesicles and the plasma membrane at the site of fusion for exocytosis of
Hippocampal electrophysiology
Synaptic function in coloboma mutant and normal mice has been examined by electroencephalograph (EEG) and evoked potential recordings in hippocampus of anesthetized mice [32]. The advantage of this preparation is that the nervous system remains intact and can be examined for its response to external stimuli. The hippocampus, moreover, plays an important role in a variety of behaviors including learning and memory consolidation, but importantly also in the regulation of initiation of locomotor
Coloboma mutants exhibit selective deficits in dopaminergic transmission
Direct evidence for a disruption of dopaminergic transmission in Cm/+ mutant mice has been obtained using release assays from slice preparations in vitro [18]. In this study, calcium-dependent release of endogenous dopamine and serotonin (5-HT) from dorsal striatum, ventral, striatum (including olfactory tubercle and nuc. accumbens) and cortex was compared between Cm/+ and wild-type mice. In contrast to the significant KC1-induced release of dopamine from wild-type mice, no detectable
Acknowledgements
I would like to thank Philip Washbourne for comments on this manuscript. This work was supported by National Institutes of Heath grant MH48989.
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