d-Cycloserine improves sociability in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorders with altered Ras/Raf/ERK1/2 signaling

Abstract

The genetically inbred BTBR T+ Itpr3tf/J (BTBR) mouse is a proposed model of autism spectrum disorders (ASDs). Similar to several syndromic forms of ASDs, mTOR activity may be enhanced in this mouse strain as a result of increased Ras signaling. Recently, d-cycloserine, a partial glycineB site agonist that targets the NMDA receptor, was shown to improve the sociability of the Balb/c mouse strain, another proposed genetically inbred model of ASDs. NMDA receptor activation is an important regulator of mTOR signaling activity. Given the ability of d-cycloserine to improve the sociability of the Balb/c mouse strain and the regulatory role of the NMDA receptor in mTOR signaling, we wondered if d-cycloserine would improve the impaired sociability of the BTBR mouse strain. d-Cycloserine (320 mg/kg, ip) improved measures of sociability in a standard sociability paradigm and spontaneous grooming that emerged during social interaction with an ICR stimulus mouse in the BTBR strain; however, similar effects were observed in the Swiss Webster comparator strain, raising questions about their strain-selectivity. Importantly, the profile of d-cycloserine's effects on both measures of sociability and stereotypies is consistent with that of a desired medication for ASDs; specifically, a desired medication would not improve sociability at the expense of worsening stereotypic behaviors or vice versa.

Neurobiology of rodent self-grooming and its value for translational neuroscience

“…For example, cholinergic agents (which may be useful in correcting postulated cholinergic deficits in ASD 97,98 and/or some of its clinical symptoms 99 ) reduce self-grooming 19 and other ASD-like behaviours 100 in BTBR mice. Furthermore, repetitive self-grooming behaviour in BTBR mice is rescued by the inhibition of glutamatergic metabotropic mGluR5 receptors 90,101 and by the stimulation of NMDA receptors by d -cycloserine 102 (which has also been shown to ameliorate some behavioural deficits in individuals with ASD 103,104 ). Environmental enrichment reduces the duration, but not the rigid patterning, of abnormal self-grooming in BTBR mice 33 .…”

The α7 nicotinic acetylcholine receptor: A mediator of pathogenesis and therapeutic target in autism spectrum disorders and Down syndrome

“…Immunostaining of cerebella from patients with AD with anti-Aȕ 1-42 antibodies showed numerous diffuse amyloid plaques in the molecular layer; this was not observed in control cerebella. In the AD cerebella, Purkinje neurons contained numerous positively-immunostained a n u s c r i p t 33 in the thin distal branches of the Purkinje cell dendritic tree and also accumulated at bifurcation points of dendritic branches. Based on a visually-observed relationship between densely packed Aȕ 1-42 -containing granules or "plugs" within the dendritic tree and density of diffuse amyloid plaques in the molecular layer, the authors hypothesized that the "plugs" eventually rupture the dendritic membrane leading to extracellular deposition and formation of diffuse amyloid plaques [49].…”

“…In vitro evidence from primary cortical neuron cultures of E17-19 Į7-KO and wild-type mice was also consistent with an effect of ablated Į 7 nAChR expression on maturation of GABAergic neurons. The Į7-KO mice were also shown to have diminished expression of NMDA receptors and diminished levels of D-serine, an endogenous glycinergic co-agonist; importantly, NMDA receptor hypofunction is independently associated with ASD [27,[29][30][31][32][33]. Thus, given the important relationships between normal function of Į 7 nAChR-and NMDA receptor-mediated neurotransmission and the synchronized oscillatory output of pyramidal cell neurons, it is not surprising that defective transduction of the acetylcholine signal is implicated in the pathogenesis of ASD [2,10,23,27,28].…”

Translational Mouse Models of Autism: Advancing Toward Pharmacological Therapeutics

“…In assays of sociability, discussed below, the inbred strains A/J, BALB/cByJ (BALB), BTBR T + Itpr3 tf /J (BTBR), C58/J (C58), and 129S1/SvImJ mice exhibited lack of sociability, as compared to inbred mouse strains with high sociability, such as C57BL/6J (B6) and FVB/NJ mice (Brodkin 2007; Moy et al 2007; Yang et al 2007; McFarlane et al 2008; Moy et al 2008b). Additionally, several mouse strains, such as BTBR and C58, also display overt motoric stereotypies or repetitive behaviors, including jumping, digging, and high levels of self-grooming and marble burying (Bolivar et al 2007; Moy et al 2007; Panksepp et al 2007; McFarlane et al 2008; Moy et al 2008b; Yang et al 2009; Pobbe et al 2010; Ryan et al 2010; Silverman et al 2010a; Wohr et al 2011a; Yang et al 2012a; Burket et al 2013; Fairless et al 2013; Silverman et al 2013; Han et al 2014). Of these, BTBR has been the most extensively characterized and well-replicated for ASD-related behaviors.…”