Allen Reference Atlas: A Digital Color Brain Atlas of the C57BL/6J Male Mouse.ByHong Wei Dong. Hoboken (New Jersey): John Wiley & Sons. $195.00 (spiral). ix + 366 p.; ill.; no index. 978‐0‐470‐05408‐6. [CD‐ROM included.] 2008.

The growing knowledge of the molecular anatomy of the human genome and the mechanisms of the gene expression, together with recent advances in molecular epidemiology, have nurtured an entirely different view of the complex relationships between genes and phenotype. This review begins with a brief description of the different types of molecular lesion that may occur in a particular gene sequence as well as the biological consequences that they originate. Then, a "molecular view" of various concepts of classical genetics is presented: dominance and recessiveness are discussed as a problem of cellular homeostasis whereas gene penetrance and expressivity are viewed as problems of variability, gene connectivity and functional pleiotropism. Based on these concepts a few final remarks focus on the relationship between genes and the environment and its enormous impact in the genesis of polygenic and multifactorial disorders.

From the genotype to the phenotype

Developmental alterations in firing properties of hippocampal CA1 inhibitory and excitatory neurons in a mouse model of Dravet syndrome.

Abstract Dravet syndrome is a severe epileptic encephalopathy caused primarily by haploinsufficiency of the SCN1A gene. Repetitive seizures can lead to endurable and untreatable neurological deficits. Whether this severe pathology is reversible after symptom onset remains unknown. To address this question, we generated a Scn1a conditional knock-in mouse model ( Scn1a Stop/+ ) in which Scn1a expression can be re-activated on-demand during the mouse lifetime. Scn1a gene disruption leads to the development of seizures, often associated with sudden unexpected death in epilepsy (SUDEP) and behavioral alterations including hyperactivity, social interaction deficits and cognitive impairment starting from the second/third week of age. However, we showed that Scn1a gene re-activation when symptoms were already manifested (P30) led to a complete rescue of both spontaneous and thermic inducible seizures, marked amelioration of behavioral abnormalities and normalization of hippocampal fast-spiking interneuron firing. We also identified dramatic gene expression alterations, including those associated with astrogliosis in Dravet syndrome mice, that, accordingly, were rescued by Scn1a gene expression normalization at P30. Interestingly, regaining of Na v 1.1 physiological level rescued seizures also in adult Dravet syndrome mice (P90) after months of repetitive attacks. Overall, these findings represent a solid proof-of-concept highlighting that disease phenotype reversibility can be achieved when Scn1a gene activity is efficiently reconstituted in brain cells. 

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Scn1a gene reactivation after symptom onset rescues pathological phenotypes in a mouse model of Dravet syndrome

https://www.nature.com/articles/s41467-021-27837-w.pdf

Objective Dravet syndrome (Dravet) is a severe childhood epileptic encephalopathy. The disease begins with a febrile stage, characterized by febrile seizures with otherwise normal development. Progression to the worsening stage features recurrent intractable seizures and the presentation of additional nonepileptic comorbidities, including global developmental delay, hyperactivity, and motor deficits. Later in life, at the stabilization stage, seizure burden decreases, whereas Dravet-associated comorbidities persist. To date, it remains debated whether the nonepileptic comorbidities result from severe epilepsy or represent an independent phenotypic feature. Methods Dravet mice (DS) faithfully recapitulate many clinical aspects of Dravet. Using wild-type (WT) and DS at different ages, we monitored multiple behavioral features as well as background electroencephalogram (EEG) activity during the different stages of Dravet epilepsy. Results Behavioral tests of WT and DS demonstrated that some deficits manifest already at the pre-epileptic stage, prior to the onset of convulsive seizures. These include motor impairment and hyperactivity in the open field. Deficits in cognitive functions were detected at the onset of severe spontaneous seizures. Power spectral analysis of background EEG activity, measured through development, showed that DS exhibit normal background oscillations at the pre-epileptic stage, a marked reduction in total power during the onset of severe epilepsy, and a subsequent smaller reduction later in life. Importantly, low EEG power at the stage of severe frequent convulsive seizures correlated with increased risk for premature death. Significance Our data provide a comprehensive developmental trajectory of Dravet epilepsy and Dravet-associated comorbidities in mice, under controlled settings, demonstrating that the convulsive seizures and some nonepileptic comorbidities may be uncoupled. Moreover, we report the existence of an inverse correlation, on average, between the power of background EEG and the severity of epileptic phenotypes, suggesting that such measurements may potentially serve as a biomarker for Dravet severity.

Convulsive seizures and some behavioral comorbidities are uncoupled in the Scn1a A1783V Dravet syndrome mouse model.

Tuftsin-phosphorylcholine attenuate experimental autoimmune encephalomyelitis.

Dravet Syndrome (Dravet) is a severe childhood epileptic encephalopathy. The disease begins around the age of six months, with a febrile stage, characterized by febrile seizures with otherwise normal development. By the end of the first year of life, the disease progresses to the worsening stage, featuring recurrent intractable seizures and the appearance of additional comorbidities, including global developmental delay, cognitive deficits, hyperactivity and motor problems. Later, in early school years, Dravet reaches the stabilization stage, in which seizure burden decreases, while Dravet-associated comorbidities persist. Dravet syndrome mouse models (DS) faithfully recapitulate the three stages of the human syndrome. Here, we performed power spectral analyses of background EEG activity in DS and their wild-type (WT) littermates, demonstrating disease stage-related alterations. Specifically, while the febrile stage activity resembled that of WT mice, we observed a marked reduction in total power during the worsening stage and a smaller reduction during the stabilization stage. Moreover, low EEG power at the worsening stage correlated with increased risk for premature death, suggesting that such measurements can potentially be used as a marker for Dravet severity. With normal development at the febrile stage and the presentation of developmental delay at the worsening stage, the contribution of recurrent seizures to the emergence of Dravet-associated comorbidities is still debated. Thus, we further characterized the behavior of WT and DS mice during the different stages of Dravet. At the febrile stage, despite their normal background EEG patterns, DS mice already demonstrated motor impairment and hyperactivity in the open field, that persisted to the worsening and stabilization stages. Conversely, clear evidence for deficits in working memory emerged later in life, during the worsening stage. These results indicate that despite the mild epilepsy at the febrile stage, DS development is already altered, suggesting that the pathophysiological mechanisms governing the appearance of some Dravet behavioral comorbidities may be independent of the epileptic phenotype. Highlights Reduction in background EEG power in Dravet Low EEG power correlates with the risk of premature death Motor deficits and hyperactivity are evident as early as the febrile stage Cognitive deficits and detection of increased anxiety begin at the worsening stage

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Early EEG and behavioral alterations in Dravet mice

Objective Dravet syndrome (Dravet) is a rare and severe form of developmental epileptic encephalopathy. First-line treatment for DS patients includes valproic acid (VA) or clobazam with or without stiripentol (CLB+STP), while sodium channel blockers like carbamazepine (CBZ) or lamotrigine (LTG) are contraindicated. As patients are rarely seizure-free, drug therapy focuses on reducing the seizure burden, as reported by caregivers. In addition to their effect on epileptic phenotypes, antiseizure medications (ASMs) were shown to modify the properties of background neuronal activity. Nevertheless, little is known about these background properties alternations in Dravet. Methods Utilizing Dravet mice (DS, Scn1aA1783V/WT), we tested the acute effect of several ASMs on background electrocorticography (ECoG) activity and frequency of interictal spikes. Results Compared to wild-type mice, background ECoG activity in DS had lower power and reduced phase coherence, which was not corrected by any of the tested ASMs. However, acute administration of Dravet-recommended drugs, including VA or a combination of CLB+STP, caused, in most mice, a reduction of frequency of interictal spikes, alongside an increase in the relative contribution of the beta frequency band. Conversely, CBZ and LTG increased the frequency of interictal spikes with no effect on background spectral properties. Moreover, we uncovered a correlation between the reduction in interictal spike frequency, the drug-induced effect on the power of background activity, and a spectral shift toward higher frequency bands. Significance These data provide a comprehensive analysis of the effect of selected ASMs on the properties of background neuronal oscillations and highlight a possible correlation between their effect on epilepsy and background activity. Thus, examining these properties, following an acute administration, may be used as an additional tool for rapid evaluation of the therapeutic potential of ASMs. Key Points Reduced background power and phase coherence in Dravet mice DS-recommended medicines (VA, CLB+STP) increase the relative beta power DS-contraindicated drugs (CBZ, LTG) do not cause spectral changes Correlation between reduction in background power and interictal spike frequency Correlation between theta to beta bands ratio and interictal spike frequency

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Shir Quinn

Papers

Convulsive seizures and some behavioral comorbidities are uncoupled in the Scn1a A1783V Dravet syndrome mouse model.

Tuftsin-phosphorylcholine attenuate experimental autoimmune encephalomyelitis.

Early EEG and behavioral alterations in Dravet mice

Acute effect of antiseizure drugs on background oscillations in Scn1a A1783V Dravet syndrome mouse model