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Introduction

Clinical findings in autism and relevance of dysfunctional calcium signalling in
:

     Brain Development
     Neurotransmitters
     Hormones
     Motor/Sensory Disturbances
     Blood Brain Barrier
     Epilepsy/Seizures
     Immunity and Inflammation
     Gastrointestinal Issues
     Membrane Metabolism
     Oxidative Stress
     Mitochondrial Dysfunction
     Gender Differences

Dysregulating Factors:
     Genetic Factors
     Hypoxia/Ischemia
     Toxins
     Infectious Agents
     Other

Conclusion

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Summary of abnormal biomedical findings in autism





Motor and sensory disturbances in autism and role of calcium signalling



Individuals with autism often present with auditory, visual, tactile and oral sensory processing disorders, as well as various forms of motor difficulties, including dyspraxia (occasionally linked to low muscle tone), dystonia (involuntary, sustained muscle contractions) and ataxia [16940314, 17016677, 15514415, 16903124, 12639336]. Visual disturbances in autism often include abnormalities of colour perception [16598434] and weak visual coherence. Retinal dysfunction in autism has been suggested, as well as deficits in visual processing in dorsal cortex [3341467, 15958508]. Abnormal pain perception is sometimes present in autism, as well as self-injurious behaviour.

Dyspraxia is a disorder of coordination that can also be described as a difficulty with planning a sequence of coordinated movements, or in the case of ideo-motor dyspraxia, a difficulty with executing a known plan. Various areas of difficulty can include speech and language, fine motor control (eg handwriting or holding pencil in a correct way), poor spacial awareness and timing and balance of body movements and difficulty combining movements, poor physical play skills (throwing and catching a ball) and difficulty in manipulating small objects. Ataxia refers more specifically to a failure of muscle control in limbs, often resulting in a lack of balance and coordination and abnormal gait.

During development and growth motor neurons express multiple calcium channels that are thought to be involved in their development. The importance of LTCC and ryanodine-sensitive calcium channels in particular has been observed [16324742, 9758236]. Several types of ataxia in humans are results in mutations in genes encoding for calcium channels [16100538]. Rodent models with mutations in genes that incode for calcium channels exibit various forms of motor abnormalities, including ataxia and dystonia, as well as lower body weight [9882694, 12890513]. Administration of calcium channel agonist BAY K 8644 to wild-type mice in results in similar motor dysfunctions and dystonia, which could be reversed by applying LTCC blockers [10830422]. In addition, mice with mutation in genes that encode for calcium binding proteins also exibit significant deficits in motor coordination as well as sensory processing, suggesting the importance of intracellular calcium buffering and regulation in these functions [9037080, 12716955, 10220453]. Decreased expression of calcium binding proteins has also been suggested to be behind impaired motor function following hypobaric hypoxia [16169666] (see Treatments).

With regards to role of calcium homeostasis in auditory processing, LTCC located in inner ear hair cells are essential for auditory processing in mammals, and are involved in development of auditory system [15115817, 16828974, 14645476, 16567618, 15158080].

Animal models have shown that mice lacking a gene that encodes one subunit of LTCC exibit reduced auditory evoked behavioral responses [12890513, 15283975], whereas mice treated with calcium channel agonist BAY K 8644 exibit, alongside deficits in motor activity and coordination, a significantly increased sensitivity to to auditory stimulation, which can be reversed by dihydropyridine calcium channel antagonist nifedipine [2581145]. As with abovementioned motor neurons, again the importance of calcium buffering and calcium binding protein expression has been observed in auditory outer hair cells, in which they are thought to play a developmental role and in which cellular calcium overload as a result of acustic overstimmulation can be amplified in the absence of those proteins [16120789, 8867285].

Apart from motor and auditory abnormalities, another phenomenon observed following administration of calcium channel agonists to mice is the emergence of self-biting behaviour, which could be inhibited by pretreating the mice with dihydropyridine LTCC antagonists [10611367].

Development and refinement of retinal pathways is partially dependent on function of voltage gated calcium channels and calcium fluxes into, and within the cell. LTCC in particular are expressed in many neurons linked to retinal pathways during development [12101036, 2838315]. In animal models, development of the visual pathways is disrupted in mice with a disruption of a calcium channel subunit genes [11745616, 17033974].

In humans, several inherited retinal disorders have been associated with mutations in genes encoding for voltage gated calcium channels. For example, a mutation in a calcium channel gene Cacna1f that leads to retinal disorder and visual impairments has been observed in a family in New Zealand. Although female members of the family display visual impairments, the symptoms are more severe, and include abnormal colour vision, a symptom that is common in autism, in male family members. Five of the affected males exibit intellectual disability, with autism being present in three of those five individuals [15807819]. Perception of colour is linked to retinal cone cells, and calcium dynamics and functioning of LTCC plays a central role in those cells [12161344].

Animal studies have pointed to the role played by LTCC in fear conditioning and implications of these mechanisms in the treatment of anxiety and in emotional learning and plasticity [12724155].

Several calcium channels expressed in different types of neurons and at different locations have been implicated in pain perception and signalling [12832498, 1425934, 11520183, 15843607].







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