Short‐term treatment with the GABA_A receptor antagonist pentylenetetrazole produces a sustained pro‐cognitive benefit in a mouse model of Down's syndrome

Abstract

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

Nest building is impaired in the Ts65Dn mouse model of Down syndrome and rescued by blocking 5HT2a receptors

“…3 month old Ts65Dn mice treated daily with PTZ 0.3 mg kg À1 show improved long term object memory for a sustained period of time (Colas et al, 2013). This drug regimen did not produce nesting behavior improvement: nesting scores found after a test with a 12 h delay in a novel environment for PTZ treated mice within the time window of improved cognition (two weeks post treatment) were 1 ± 1 for TS and 5 ± 1 for 2N and were significantly different (n = 8 per genotype, Mann-Whitney vs 2N, p < .01).…”

“…We previously showed that chronic daily treatment with pentylenetetrazole (PTZ), a GABA receptor-A antagonist, at very low doses, resulted in improved cognition and neural plasticity in young Ts65Dn mice (Colas et al, 2013;Fernandez et al, 2007). In the course of this study, 2N and Ts65Dn mice were treated daily with either vehicle or PTZ 0.3 mg kg À1 for 2 weeks and subjected to the nesting test describe above in a novel environment 15 days after the end of the treatment regimen, the time window corresponding to improved cognition in Ts65Dn.…”

“…Ts65Dn mice have been used to develop and test potential pharmacotherapies for improving memory in DS (Colas et al, 2013;Ruparelia, Pearn, & Mobley, 2012). Besides memory, however, additional cognitive aspects of DS have been scarcely studied in mice (Rueda, Florez, & Martinez-Cue, 2012).…”

Synaptic Pathology of Down Syndrome

“…Importantly, these studies were performed in adult mice indicating that trisomy does not permanently damage these circuits. Our recent studies showing that PTZ is efficacious in mice from 2 to 18 months support this concept (Colas et al 2012). A principle concern of this strategy is that at high doses PTZ can induce seizure or reduce the threshold for seizure via "kindling" (Mason and Cooper 1972).…”

Modeling of human brain diseases in experiments on rodents (brief overview)

“…Снижение тормозных влияний со стороны ГАМК-ергической системы достигали путем воздей-ствия на ГАМК-ергическую передачу. Это было либо введение антагониста ГАМК-рецептора пентилентетра-зола [48], либо действие селективных антагонистов α5-субъединицы рецептора, что улучшало показатели научения и памяти у этих животных. Эти данные гово-рят о хорошей перспективе клинических испытаний такого рода препаратов [35; 44].…”