Down syndrome (DS) is a developmental disorder caused by a third chromosome 21 in humans (Trisomy 21) leading to neurological deficits and cognitive impairment. Studies in mouse models of DS suggest that cognitive deficits in the adult are associated with deficits in synaptic learning and memory mechanisms, however it is unclear whether alterations in the early wiring and refinement of neuronal circuits contribute to these deficits. Here, we show that early developmental refinement of visual circuits is perturbed in mouse models of Down syndrome. Specifically, we find excessive eye-specific segregation of retinal axons in the dorsal lateral geniculate nucleus (dLGN). Indeed, the degree of refinement scales with defects in the “Down syndrome critical region” (DSCR) in a dose-dependent manner. We further identify Dscam, a gene within the DSCR, as a regulator of eye-specific segregation of retinogeniculate projections. While Dscam is not the sole gene in the DSCR contributing to enhanced refinement in trisomy, Dscam dosage clearly regulates cell spacing and dendritic fasciculation in a specific class of retinal ganglion cells Thus, altered developmental refinement of visual circuits that occurs prior to sensory experience is likely to contribute to visual impairment in individuals with Down syndrome.

BACKGROUND AND PURPOSEDown's syndrome is a common genetic cause of intellectual disability, for which there are no drug therapies. Mechanistic studies in a model of Down's syndrome [Ts65Dn (TS) mice] demonstrated that impaired cognitive function was due to excessive neuronal inhibitory tone. These deficits were normalized by low doses of GABAA receptor antagonists in adult animals. In this study, we explore the therapeutic potential of pentylenetetrazole, a GABAA receptor antagonist with a history of safe use in humans. EXPERIMENTAL APPROACHLong-term memory was assessed by the novel object recognition test in different cohorts of TS mice after a delay following a short-term chronic treatment with pentylenetetrazole. Seizure susceptibility, an index of treatment safety, was studied by means of EEG, behaviour and hippocampus morphology. EEG spectral analysis was used as a bio-marker of the treatment. KEY RESULTSPTZ has a wide therapeutic window (0.03-3 mg·kg −1 ) that is >10-1000-fold below its seizure threshold and chronic pentylenetetrazole treatment did not lower the seizure threshold. Short-term, low, chronic dose regimens of pentylenetetrazole elicited long-lasting (>1 week) normalization of cognitive function in young and aged mice. Pentylenetetrazole effectiveness was dependent on the time of treatment; cognitive performance improved after treatment during the light (inactive) phase, but not during the dark (active) phase. Chronic pentylenetetrazole treatment normalized EEG power spectra in TS mice. CONCLUSIONS AND IMPLICATIONSLow doses of pentylenetetrazole were safe, produced long-lasting cognitive improvements and have the potential of fulfilling an unmet therapeutic need in Down's syndrome. AbbreviationsGABAAR-α5, GABAA receptor containing α-5

Black SW; Morairty SR; Fisher SP; Chen TM; Warrier DR; Kilduff TS. Almorexant promotes sleep and exacerbates cataplexy in a murine model of narcolepsy. SLEEP 2013;36(3):325-336.

We have previously demonstrated that Type I neuronal nitric oxide synthase (nNOS)-expressing neurons are sleep-active in the cortex of mice, rats, and hamsters. These neurons are known to be GABAergic, to express Neuropeptide Y (NPY) and, in rats, to co-express the Substance P (SP) receptor NK1, suggesting a possible role for SP in sleep/wake regulation. To evaluate the degree of co-expression of nNOS and NK1 in the cortex among mammals, we used double immunofluorescence for nNOS and NK1 and determined the anatomical distribution in mouse, rat, and squirrel monkey cortex. Type I nNOS neurons co-expressed NK1 in all three species although the anatomical distribution within the cortex was species-specific. We then performed in vitro patch clamp recordings in cortical neurons in mouse and rat slices using the SP conjugate tetramethylrhodamine-SP (TMR-SP) to identify NK1-expressing cells and evaluated the effects of SP on these neurons. Bath application of SP (0.03–1 μM) resulted in a sustained increase in firing rate of these neurons; depolarization persisted in the presence of tetrodotoxin. These results suggest a conserved role for SP in the regulation of cortical sleep-active neurons in mammals.

Cortical interneurons, immunoreactive for neuronal nitric oxide synthase (nNOS) and the receptor NK1, express the functional activity marker Fos selectively during sleep. NREM sleep 'pressure' is hypothesized to accumulate during waking and to dissipate during sleep. We reported previously that the proportion of Fos þ cortical nNOS/NK1 neurons is correlated with established electrophysiological markers of sleep pressure. As these markers covary with the amount of NREM sleep, it remained unclear whether cortical nNOS/NK1 neurons are activated to the same degree throughout NREM sleep or whether the extent of their activation is related to the sleep pressure that accrued during the prior waking period. To distinguish between these possibilities, we used hypnotic medications to control the amount of NREM sleep in rats while we varied prior wake duration and the resultant sleep pressure. Drug administration was preceded by 6 h of sleep deprivation (SD) ('high sleep pressure') or undisturbed conditions ('low sleep pressure'). We find that the proportion of Fos þ cortical nNOS/NK1 neurons was minimal when sleep pressure was low, irrespective of the amount of time spent in NREM sleep. In contrast, a large proportion of cortical nNOS/NK1 neurons was Fos þ when an equivalent amount of sleep was preceded by SD. We conclude that, although sleep is necessary for cortical nNOS/NK1 neuron activation, the proportion of cells activated is dependent upon prior wake duration.