Overexpression of the Type 1 Adenylyl Cyclase in the Forebrain Leads to Deficits of Behavioral Inhibition

Introduction

AC1 is a calcium/calmodulin-stimulated adenylyl cyclase that is predominantly expressed in the nervous system (Xia et al., 1991, 1993). AC1 is not stimulated by activation of Gs-coupled receptors alone but is synergistically potentiated by receptor activation paired with calcium (Wayman et al., 1994). Therefore, combinations of β-adrenergic agonists and free calcium maximally stimulate AC1 activity. AC1 is highly sensitive to intracellular free calcium and can be directly activated by Ca2+ and CaM in vivo (Choi et al., 1992) with half-maximal stimulation at 150-200 nm free Ca2+, concentrations just above resting free Ca2+ in neurons (Wang and Storm, 2003). Calcium-activated AC1 generates cAMP, which subsequently stimulates several downstream events required for synaptic long-term potentiation and memory consolidation (Sindreu et al., 2007).

Previous studies using AC1−/− mice have implicated AC1 in consolidation of long-term memory (Wu et al., 1995; Wong et al., 1999; Wieczorek et al., 2012), neuropathic pain (Wei et al., 2002), and drug addiction (Krishnan et al., 2008; DiRocco et al., 2009). In contrast, AC1+ mice have enhanced long-term potentiation (LTP) and impaired long-term depression (LTD; Wang and Zhang, 2012; Zhang and Wang, 2013), and exhibit increased recognition memory and superior remote contextual memory (Wang et al., 2004; Shan et al., 2008). Calcium-stimulated cyclase adenylyl activity in hippocampal membrane preparations from AC1+ mice is ∼2.5-fold higher than wild-type mice. In addition, PKA, MAP kinase, and CREB activities are also markedly elevated in AC1+ mice (Wang et al., 2004). Because AC1 couples intracellular free calcium to cAMP increases, AC1 is essential for several forms of synaptic plasticity (Choi et al., 1992; Villacres et al., 1998; Wang et al., 2011). For example, AC1+ mice exhibit enhanced LTP at the CA1-CA3 synapse in the hippocampus (Wang et al., 2004).

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AC1 generates cAMP in response to calcium influx through either NMDA receptors or voltage-gated calcium channels (Wang and Storm, 2003). Interestingly, dysfunction in NMDA receptors and voltage-gated calcium channels lead to a variety of psychiatric diseases (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013; Fromer et al., 2014). In addition, animal studies and a human genome-wide association study have implicated AC1 (Krishnan et al., 2008) and AC8 (Schaefer et al., 2000; Wolf et al., 2014) in mental disorders. Because calcium-cAMP signaling regulates neuronal activity, as well as mental states (Arnsten and Jin, 2012; Wolf et al., 2014), and AC1 is essential for potentiation of synaptic transmission upon vigorous electrical stimulation, we reasoned that increased expression of AC1 may cause deficits in behavioral inhibition. Here we report that AC1+ mice are hyperactive both in their home cage and in an open field. Moreover, AC1+ mice display reduced sociability as well as increased impulsivity. In contrast, AC1/8 double-knock-out mice are hypoactive, more social, and less impulsive. Together, these data indicate that increased expression of AC1 leads to hyperactivity and impaired behavioral inhibition.

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