Abstract:The common co-occurrence of autism and epilepsy suggests that certain neurobiological mechanisms are shared between these disorders. In particular, the profusion of novel genetic mutations being discovered in autism and epilepsy points to abnormalities in synapse formation and function that alter the balance between neuronal excitation and inhibition. Animal models can be informative in sorting out the medical and behavioral complexities in autism and epilepsy and the relationship between them. As mechanistic … Show more
“…The E/I balance is determined by the number and function of excitatory glutamatergic synapses, inhibitory GABAergic synapses, and ion conductances. An increase in the E/I ratio is thought to be a common mechanism in autism spectrum disorders, responsible for the cognitive, learning and memory, sensory, motor deficits, behavioral and social dysfunction (Nelson and Valakh, 2015; Stafstrom and Benke, 2015; Uzunova et al, 2016). An increase in E and/or decrease in I also underlies seizure predisposition (Shao et al, 2019).…”
Section: The Functional Roles Of Syngap1mentioning
SYNGAP1 is a gene that encodes the cytosolic protein SYNGAP1 (SYNaptic GTPase Activating Protein), an essential component of the postsynaptic density at excitatory glutamatergic neurons. SYNGAP1 plays critical roles in synaptic development, structure, function, and plasticity. Mutations in SYNGAP1 result in a neurodevelopmental disorder termed Mental retardation‐type 5 (MRD5, OMIM #612621) with a phenotype consisting of intellectual disability, motor impairments, and epilepsy, attesting to the importance of this protein for normal brain development. Here we review the clinical and pathophysiological aspects of SYNGAP1 mutations with a focus on their effect on synaptogenesis, neural circuit function, and cellular plasticity. We conclude by comparing the molecular pathogenesis of SYNGAP1 mutations with those of another neurodevelopmental disorder that affects dendritic function and cellular plasticity, fragile X syndrome. Insights into the molecular similarities and differences underlying these disorders could lead to rationale therapy development.
“…The E/I balance is determined by the number and function of excitatory glutamatergic synapses, inhibitory GABAergic synapses, and ion conductances. An increase in the E/I ratio is thought to be a common mechanism in autism spectrum disorders, responsible for the cognitive, learning and memory, sensory, motor deficits, behavioral and social dysfunction (Nelson and Valakh, 2015; Stafstrom and Benke, 2015; Uzunova et al, 2016). An increase in E and/or decrease in I also underlies seizure predisposition (Shao et al, 2019).…”
Section: The Functional Roles Of Syngap1mentioning
SYNGAP1 is a gene that encodes the cytosolic protein SYNGAP1 (SYNaptic GTPase Activating Protein), an essential component of the postsynaptic density at excitatory glutamatergic neurons. SYNGAP1 plays critical roles in synaptic development, structure, function, and plasticity. Mutations in SYNGAP1 result in a neurodevelopmental disorder termed Mental retardation‐type 5 (MRD5, OMIM #612621) with a phenotype consisting of intellectual disability, motor impairments, and epilepsy, attesting to the importance of this protein for normal brain development. Here we review the clinical and pathophysiological aspects of SYNGAP1 mutations with a focus on their effect on synaptogenesis, neural circuit function, and cellular plasticity. We conclude by comparing the molecular pathogenesis of SYNGAP1 mutations with those of another neurodevelopmental disorder that affects dendritic function and cellular plasticity, fragile X syndrome. Insights into the molecular similarities and differences underlying these disorders could lead to rationale therapy development.
“…Thus, the balance between excitation and inhibition must satisfy constraints assuring normal oscillatory behavior. Abnormalities in this balance in the cortical circuitry have been associated with neurological disorders, such as autism and epilepsy [ 30 , 31 ].…”
Let a neuronal population be composed of an excitatory group interconnected to an inhibitory group. In the Wilson-Cowan model, the activity of each group of neurons is described by a first-order nonlinear differential equation. The source of the nonlinearity is the interaction between these two groups, which is represented by a sigmoidal function. Such a nonlinearity makes difficult theoretical works. Here, we analytically investigate the dynamics of a pair of coupled populations described by the Wilson-Cowan model by using a linear approximation. The analytical results are compared to numerical simulations, which show that the trajectories of this fourth-order dynamical system can converge to an equilibrium point, a limit cycle, a two-dimensional torus, or a chaotic attractor. The relevance of this study is discussed from a biological perspective.
“…The reason for anterior callosotomy in Patient 2 was simply the preference of patient’s family, as they were concerned about the risks of disconnection syndrome.13 The etiology of epilepsy was unclear in both patients. However, as both were patients with autism spectrum disorder and epilepsy, shared underlying neurobiological mechanisms might have been involved,14 such as genetic issues15 or mammalian target of the rapamycin pathway.16Figure 1Shoulder dislocation in Patient 2. A normal glenoid cavity conforms to the red circle.…”
Purpose
Treatment options appear lacking for patients with epileptic seizure-induced shoulder dislocations who are not candidates for shoulder and focus resection surgeries. To reduce shoulder joint dislocations caused by epileptic seizures and simultaneously reduce the frequency and intensity of seizures, we performed corpus callosotomy for two patients with medically intractable epilepsy that induced repetitive shoulder joint dislocations.
Materials and methods
A 21-year-old man (Patient 1) with bilateral temporal lobe epilepsy [Focal onset impaired awareness seizure (FIAS), 1/month; focal to bilateral tonic-clonic seizure (BTCS), 1/2–3 months], autism and intellectual disorder and a 34-year-old man (Patient 2) with left multi-lobar epilepsy (BTCS, 3–4/month; status epilepticus, 1/2–3 months), autism and intellectual disorder had suffered from repetitive seizure-induced shoulder dislocations (1/2–3 months for Patient 1; 3–4/month for Patient 2). Due to frequent seizures and uncooperativeness, they were not candidates for shoulder joint dislocation surgery. They were also not candidates for focus resection surgery due to multiple foci and uncooperativeness for invasive monitoring. We performed corpus callosotomy for both patients.
Results
Postoperatively, frequencies of both shoulder dislocations (2 in 5 years of follow-up for Patient 1; 1 in 5 months of follow-up for Patient 2) and epileptic seizures were drastically reduced.
Conclusions
For patients who are not candidates for focus resection and shoulder joint surgeries but who suffer from frequent shoulder joint dislocations, corpus callosotomy could be a treatment of last resort.
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