The T-type calcium channel antagonist Z944 disrupts prepulse inhibition in both epileptic and non-epileptic rats
Introduction
Low-voltage-activated T-type calcium channels contribute to the functioning of both normal physiological processes such as sleep and heart pacemaker activity, as well as the pathophysiological processes involved in absence epilepsy and neuropathic pain (Nelson et al., 2006, Cain and Snutch, 2013, Cheong and Shin, 2013, Crunelli et al., 2014, Mesirca et al., 2014). T-type calcium channels exhibit unique biophysical properties implicated in the generation of low-threshold spikes that can lead not only to the oscillatory behavior in the brain observed during sleep, but also the burst-firing observed during pathological events such as absence seizures (Cain and Snutch, 2010, Cain and Snutch, 2013).
The term sensorimotor gating describes the phenomenon of a weak sensory event inhibiting a motor response to a subsequent larger sensory event (Swerdlow et al., 2000). PPI is a form of sensorimotor gating that reflects the normal suppression of a startle reflex when an intense stimulus, such as a tone, is preceded by a weaker tone prestimulus (Swerdlow et al., 2000). PPI has high cross species validity between humans and rodents, face and predictive validity, ease of implementation, and reliability (Powell et al., 2012). Interestingly, disrupted PPI is observed in patients with psychiatric and neurological disorders such as schizophrenia, obsessive compulsive disorder, Huntington’s disease, temporal lobe epilepsy with psychosis, and Tourette’s syndrome (Braff et al., 2001, Castellanos et al., 1996, Geyer et al., 2001, Swerdlow et al., 1993, Swerdlow et al., 1995). Consistent with the neural circuits thought to be involved in these disorders (Swerdlow et al., 1992, Klarner et al., 1998), PPI is regulated by limbic and cortico-striato-pallido-pontine (CSPP) circuits (Koch and Schnitzler, 1997, Swerdlow et al., 2000, Fendt et al., 2001, Yeomans et al., 2006), areas in which T-type calcium channels are expressed (Talley et al., 1999).
Previous research has demonstrated that Cav 3.1 T-type channels in the thalamocortical circuit mediate forward suppression (sensory gating) of auditory cortex neurons, a phenomenon observed when a brief sound subsequently suppresses the neuronal responsiveness to a successive sound of equal magnitude presented within hundreds of milliseconds (Bayazitov et al., 2013). Investigation of the role of T-type calcium channels in mediating PPI is warranted for several reasons. First, there is a wide distribution of T-type calcium channel isoforms in the CSPP circuitry. Second, known disruptions in PPI are observed in disorders such as schizophrenia, obsessive compulsive disorder, Huntington’s disease, temporal lobe epilepsy with psychosis, and Tourette’s syndrome which are all characterized by CSPP abnormalities. Lastly, T-type channels are known to contribute to the suppression of neuronal responses to repetitive auditory stimuli. The recently developed drug, Z944, is a robust pan-T-type calcium channel blocker (Tringham et al., 2012) with demonstrated dose-dependent attenuation of absence seizures and the progression of amygdala kindling in rats, and pain in humans (Tringham et al., 2012, Lee, 2014, Casillas-Espinosa et al., 2015). With this in mind, the objective of the present study was to examine the dose-dependent effect of Z944 on PPI performance in three separate strains of rats (Wistar, GAERS, and NEC). The PPI protocol comprised a range of prepulse-pulse intervals (30, 50, 80, and 140 ms) and prepulse intensities (3, 6, and 12 dB) as it has been demonstrated in both clinical populations and rodents that PPI can fluctuate depending on the interaction of drug treatment with specific PPI protocol parameters (Ballendine et al., 2015, Chandna et al., 2015, Duncan et al., 2001, Howland et al., 2012, Pinnock et al., 2015, Swerdlow et al., 2016, Swerdlow et al., 2008). We expected to observe a dose-dependent alteration in PPI following Z944 treatment in the Wistar and NEC strains. GAERS are a well-described rodent model of childhood absence epilepsy that display a gain-of-function missense mutation in the Cav3.2 T-type calcium channel, R1584P (Powell et al., 2009). Given the observed gain-of-function of CaV3.2 channels in GAERS, we were uncertain as to whether PPI would be altered in this strain following treatment with Z944. We found that the highest dose of Z944 (10 mg/kg) had a profound effect on PPI in the Wistar and GAERS strains. Significant reductions in PPI in the Wistar and GAERS strains following Z944 treatment at varying prepulse intervals and intensities were observed with a dose-dependent effect on startle in the Wistar strain only.
Section snippets
Animals
Male Wistar rats (Charles River Laboratories, Quebec, Canada), and male and female rats from two related strains, GAERS and NEC (University of Saskatchewan Lab Animal Services Unit, Saskatoon, Canada) (Marks et al., 2016a, Marks et al., 2016b) were used for these experiments (Wistar N = 40, 8 per treatment group; NEC N = 60, 12 per treatment group; GAERS N = 60, 12 per treatment group). Wistar rats weighed 300–500 g throughout the course of testing; whereas NEC and GAERS weighed 170–350 g and 130–250 g,
Results
A four-way mixed factor ANOVA (Strain and Treatment as between measures factors and Prepulse-pulse interval and Prepulse Intensity as repeated measures factors) was initially run for all data. The main effect of Strain (F(2,145) = 2.20, p = 0.115) and the Strain by Treatment interaction (F(8,145) = 1.86, p = 0.071) were both non-significant. However, given the gain-of-function mutation of T-type calcium channels in the GAERS strain, and the trend toward a significant Strain by Treatment interaction,
Discussion
We investigated the effects of a recently developed high affinity, selective T-type calcium channel blocker, Z944, on startle and PPI in Wistar, NEC, and GAERS rats. The highest dose of Z944 tested (10 mg/kg) had a profound effect on PPI in the Wistar and GAERS strains. Significant reductions in PPI were observed following Z944 treatment at varying prepulse intervals and intensities with a dose-dependent effect on startle in the Wistar strain only (Fig. 1, Fig. 2, Fig. 4). Z944 also produced
Conclusions
Z944 had a profound effect on PPI in the Wistar and GAERS strains with significant reductions in PPI observed following Z944 treatment at varying prepulse intervals and intensities. The effects of Z944 in the NEC strain were less robust indicating genetic variation between rat strains may contribute to the effects of T-type calcium channel blockers on PPI. Next generation T-type calcium channel blockers have demonstrated promise in preclinical assays of antipsychotic-like activity. For example,
Acknowledgments
The research was supported by a Brain Canada Multi-Investigator Research Initiative Grant with matching support from Genome British Columbia, the Michael Smith Foundation for Health Research, and the Koerner Foundation (PI: TPS). Work in the laboratory of TPS is supported by an operating grant from the Canadian Institutes for Health Research (CIHR; #10677) and a Canada Research Chair in Biotechnology and Genomics-Neurobiology. Work in the laboratory of JGH is supported by an operating grant
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