Neuronal deletion of CaV1.2 is associated with sex-specific behavioral phenotypes in mice

Abstract

The gene CACNA1C, which encodes the pore forming subunit of the L-type calcium channel CaV1.2, is associated with increased risk for neuropsychiatric disorders including schizophrenia, autism spectrum disorder, major depression, and bipolar disorder. Previous rodent work identified that loss or reduction of CaV1.2 results in cognitive, affective, and motor deficits. Most previous work has either included non-neuronal cell populations (haploinsufficient and Nestin-Cre) or investigated a discrete neuronal cell population (e.g. CaMKII-Cre, Drd1-Cre), but few studies have examined the effects of more broad neuron-specific deletion of CaV1.2. Additionally, most of these studies did not evaluate for sex-specific effects or used only male animals. Here, we sought to clarify whether there are sex-specific behavioral consequences of neuron-specific deletion of CaV1.2 (neuronal CaV1.2 cKO) using Syn1-Cre-mediated conditional deletion. We found that neuronal CaV1.2 cKO mice have normal baseline locomotor function but female cKO mice display impaired motor performance learning. Male neuronal CaV1.2 cKO display impaired startle response with intact pre-pulse inhibition. Male neuronal CaV1.2 cKO mice did not display normal social preference, whereas female neuronal CaV1.2 cKO mice did. Neuronal CaV1.2 cKO mice displayed impaired associative learning in both sexes, as well as normal anxiety-like behavior and hedonic capacity. We conclude that deletion of neuronal CaV1.2 alters motor performance, acoustic startle reflex, and social behaviors in a sex-specific manner, while associative learning deficits generalize across sexes. Our data provide evidence for both sex-specific and sex-independent phenotypes related to neuronal expression of CaV1.2.

Different Purkinje cell pathologies cause specific patterns of progressive ataxia in mice

“…Loss of Purkinje cell function can, therefore, by itself explain the development of ataxic gait. Clear signs of tremor and dystonia, which both can occur in patients with cerebellar damage (Diener et al, 1984; Deuschl et al, 2000; Neychev et al, 2008; Shakkottai et al, 2017; Nikolov et al, 2019; Dankova et al, 2020; Manto et al, 2020; Pan et al, 2020; Giannì et al, 2022; Klomp et al, 2022; Brown et al, 2023), were absent in our mice. Although we did not specifically test for tremor or dystonia, so that subtle signs may have been overlooked, this may imply that tremor and dystonia rely less on the contribution of malfunctioning Purkinje cells than does ataxic gait.…”

“…Following up on the demonstration that the ErasmusLadder enables the differentiation between cerebellar mutants in cross sectional studies (Van Der Giessen et al, 2008; Renier et al, 2010; Schonewille et al, 2011; van der Vaart et al, 2011; Baudouin et al, 2012; Saab et al, 2012; Vinueza Veloz et al, 2012; Galliano et al, 2013; Marques et al, 2015; Vinueza Veloz et al, 2015; Ha et al, 2016; Peter et al, 2016; Rahmati et al, 2016; French et al, 2018; Prekop et al, 2018; Sathyanesan et al, 2018; Sayed-Zahid et al, 2019; Wu et al, 2019; Almeida et al, 2020; Grasselli et al, 2020; Haify et al, 2020; Namdar et al, 2020; Peter et al, 2020; Blot et al, 2021; Lang-Ouellette et al, 2021; Vacher et al, 2021; White et al, 2021; Kaiser et al, 2022; Klomp et al, 2022; Lauffer et al, 2022; Ottenhoff et al, 2022; Birkisdóttir et al, 2023a; Fang et al, 2023) (Table S1), in this study we aimed to probe the ErasmusLadder as a tool for quantifying disease onset and progression in cerebellar disease models. We examined two mouse lines displaying progressive Purkinje cell degeneration, and followed their behavioral performance from early to severe symptomatic stages.…”

Sex-specific mechanisms underlie long-term potentiation at hippocampus-nucleus accumbens synapses

“…Zhou & Sheng, 2013). For example, neuronal deletion of L-type VGCCs impairs motor performance learning and increases contextual and emotional memory loss only in female mice (Klomp et al, 2022; Zanos et al, 2015). Moreover, Cacna1c , which encodes the Ca v 1.2 subunit of the L-type VGCC, is a risk gene associated with multiple mood disorders (Bigos et al, 2010; Dedic et al, 2018; Jiang et al, 2023; Moon et al, 2018; Sklar et al, 2008).…”