An Atypical Rett Syndrome Phenotype Due to a Novel Missense Mutation in CACNA1A.

BACKGROUND: Some typical and atypical Rett syndrome patients lack known genetic mutations. Mutations in the P/Q type calcium channel CACNA1A have been implicated in epileptic encephalopathy, familial hemiplegic migraine, episodic ataxia 2, and spinocerebellar ataxia 6, but not Rett syndrome. Patient Description: The authors describe a female patient with developmental regression and a de novo, likely pathogenic mutation in CACNA1A who meets 3 of 4 main criteria (stereotypic hand movements, loss of purposeful hand movements, gait disturbance), and 6 of 11 supportive criteria (impaired sleep, abnormal tone, vasomotor disturbance, scoliosis, growth retardation, and screaming spells) for atypical Rett syndrome. Furthermore, she resembles the early seizure variant of Rett syndrome. Previously, 3 children with similar CACNA1A mutations have been reported, but a Rett syndrome phenotype has not been described. CONCLUSION: CACNA1A mutations should be considered in children presenting with an atypical Rett syndrome phenotype, specifically, the early seizure variant.

PTEN knockdown alters dendritic spine/protrusion morphology, not density.

Mutations in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) are implicated in neuropsychiatric disorders including autism. Previous studies report that PTEN knockdown in neurons in vivo leads to increased spine density and synaptic activity. To better characterize synaptic changes in neurons lacking PTEN, we examined the effects of shRNA knockdown of PTEN in basolateral amygdala neurons on synaptic spine density and morphology by using fluorescent dye confocal imaging. Contrary to previous studies in the dentate gyrus, we find that knockdown of PTEN in basolateral amygdala leads to a significant decrease in total spine density in distal dendrites. Curiously, this decreased spine density is associated with increased miniature excitatory postsynaptic current frequency and amplitude, suggesting an increase in number and function of mature spines. These seemingly contradictory findings were reconciled by spine morphology analysis demonstrating increased mushroom spine density and size with correspondingly decreased thin protrusion density at more distal segments. The same analysis of PTEN conditional deletion in the dentate gyrus demonstrated that loss of PTEN does not significantly alter total density of dendritic protrusions in the dentate gyrus, but does decrease thin protrusion density and increases density of more mature mushroom spines. These findings suggest that, contrary to previous reports, PTEN knockdown may not induce de novo spinogenesis, but instead may increase synaptic activity by inducing morphological and functional maturation of spines. Furthermore, behavioral analysis of basolateral amygdala PTEN knockdown suggests that these changes limited only to the basolateral amygdala complex may not be sufficient to induce increased anxiety-related behaviors.

Delayed reduction of hippocampal synaptic transmission and spines following exposure to repeated subclinical doses of organophosphorus pesticide in adult mice.

Agricultural and household organophosphorus (OP) pesticides inhibit acetylcholinesterase (AchE), resulting in increased acetylcholine (Ach) in the central nervous system. In adults, acute and prolonged exposure to high doses of AchE inhibitors causes severe, clinically apparent symptoms, followed by lasting memory impairments and cognitive dysfunction. The neurotoxicity of repeated environmental exposure to lower, subclinical doses of OP pesticides in adults is not as well studied. However, repeated exposure to acetylcholinesterase inhibitors, such as chlorpyrifos (CPF), pyridostigmine, and sarin nerve agent, has been epidemiologically linked to delayed onset symptoms in Gulf War Illness and may be relevant to environmental exposure in farm workers among others. We treated adult mice with a subclinical dose (5 mg/kg) of CPF for 5 consecutive days and investigated hippocampal synaptic transmission and spine density early (2-7 days) and late (3 months) after CPF administration. No signs of cholinergic toxicity were observed at any time during or after treatment. At 2-7 days after the last injection, we found increased synaptic transmission in the CA3-CA1 region of the hippocampus of CPF-treated mice compared with controls. In contrast, at 3 months after CPF administration, we observed a 50% reduction in synaptic transmission likely due to a corresponding 50% decrease in CA1 pyramidal neuron synaptic spine density. This study is the first to identify a biphasic progression of synaptic abnormalities following repeated OP exposure and suggests that even in the absence of acute cholinergic toxicity, repeated exposure to CPF causes delayed persistent damage to the adult brain in vivo.