Expression of GABA signaling molecules KCC2, NKCC1, and GAD1 in cortical development and schizophrenia

ArticleinThe Journal of Neuroscience : The Official Journal of the Society for Neuroscience 31(30):11088-95 · July 2011with58 Reads
Impact Factor: 6.34 · DOI: 10.1523/JNEUROSCI.1234-11.2011 · Source: PubMed

GABA signaling molecules are critical for both human brain development and the pathophysiology of schizophrenia. We examined the expression of transcripts derived from three genes related to GABA signaling [GAD1 (GAD67 and GAD25), SLC12A2 (NKCC1), and SLC12A5 (KCC2)] in the prefrontal cortex (PFC) and hippocampal formation of a large cohort of nonpsychiatric control human brains (n = 240) across the lifespan (from fetal week 14 to 80 years) and in patients with schizophrenia (n = 30-31), using quantitative RT-PCR. We also examined whether a schizophrenia risk-associated promoter SNP in GAD1 (rs3749034) is related to expression of these transcripts. Our studies revealed that development and maturation of both the PFC and hippocampal formation are characterized by progressive switches in expression from GAD25 to GAD67 and from NKCC1 to KCC2. Previous studies have demonstrated that the former leads to GABA synthesis, and the latter leads to switching from excitatory to inhibitory neurotransmission. In the hippocampal formation, GAD25/GAD67 and NKCC1/KCC2 ratios are increased in patients with schizophrenia, reflecting a potentially immature GABA physiology. Remarkably, GAD25/GAD67 and NKCC1/KCC2 expression ratios are associated with rs3749034 genotype, with risk alleles again predicting a relatively less mature pattern. These findings suggest that abnormalities in GABA signaling critical to brain development contribute to genetic risk for schizophrenia.

    • "Likewise, Berry and coworkers found that prenatally stress rats, at adolescence showed not only a reduction in social interest and in the affiliative behaviors but also decreased hippocampal expression levels of BDNF, a neurotrophin playing a pivotal role in neuronal development as well as synaptic plasticity, emotionality and cognitive abilities (Cirulli & Alleva, 2009 ). These effects were also associated to a specific change in the hippocampal NKCC1/ KCC2 ratio (two genes related to GABA signaling), suggesting an imbalance between neuronal inhibitory and excitatory mechanisms possibly related to an immature GABA system (Hyde et al., 2011). Most intriguingly, the authors also provide evidence that, for a prenatally stressed rat, the interaction with a nonstressed control subject leads to an improvement in sociality suggesting that the social environment could be exploited for nonpharmacological therapeutic intervention (Berry et al., in press). "
    [Show abstract] [Hide abstract] ABSTRACT: Schizophrenia is a devastating psychiatric disorder. Despite many efforts, we are still far from being able to picture the complexity of its neurobiology, which greatly limits our ability for intervention. In this chapter, the concept of schizophrenia as a neurodevelopmental disorder will be introduced, depicting important interactions taking place between the individual genetic background and early life insults, leading toward psychopathology. Animal models of prenatal stress, which show behavioral deficits and changes in biochemical pathways disrupted in schizophrenia patients, will be described. The mechanisms—so far elucidated—through which activation of the stress system can modulate brain function and behavior in a long-term perspective will be discussed. Animal models of early life stress have greatly contributed to our understanding of how vulnerability to stress becomes “embedded” into brain physiology and can be very useful in the future to unravel phenotypic heterogeneity, including dynamic epigenetic changes, directing environmental, and/or pharmacological interventions.
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    • "More experiments are clearly needed to fully explore how activity-driven downregulation of KCC2 membrane stability may affect plasticity rules at glutamatergic synapses. In addition to activity-induced changes at the posttranslational level, KCC2 expression is also down-regulated in a variety of pathological conditions ranging from epilepsy (Rivera et al., 2004; Jin et al., 2005; Miles et al., 2012; Pallud et al., 2014), stroke (Jaenisch et al., 2010), to schizophrenia (Hyde et al., 2011) and autism (Tyzio et al., 2014). These conditions are associated with increased neuronal activity, which is often assumed to reflect reduced GABAergic signaling due to altered chloride extrusion. "
    [Show abstract] [Hide abstract] ABSTRACT: Expression of the neuronal K/Cl transporter KCC2 is tightly regulated throughout development and by both normal and pathological neuronal activity. Changes in KCC2 expression have often been associated with altered chloride homeostasis and GABA signaling. However, recent evidence supports a role of KCC2 in the development and function of glutamatergic synapses through mechanisms that remain poorly understood. Here we show that suppressing KCC2 expression in rat hippocampal neurons precludes long-term potentiation of glutamatergic synapses specifically by preventing activity-driven membrane delivery of AMPA receptors. This effect is independent of KCC2 transporter function and can be accounted for by increased Rac1/PAK- and LIMK-dependent cofilin phosphorylation and actin polymerization in dendritic spines. Our results demonstrate that KCC2 plays a critical role in the regulation of spine actin cytoskeleton and gates long-term plasticity at excitatory synapses in cortical neurons
    Full-text · Article · Dec 2015 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    • "A point worth of emphasis is that CCCs are gaining an increasing amount of interest as potential drug targets ( Töllner et al. 2014 ), especially with regard to the design of novel anticonvulsant drugs (Löscher et al. 2013a, 2013b). In this context, our data on the fetal onset of KCC2 expression in human supraspinal brain structures (see also Vanhatalo et al. 2005; Bayatti et al. 2008; Robinson et al. 2010; Hyde et al. 2011) refute the view (cf. Dzhala et al. 2005) that the poor efficacy of anticonvulsants in the term human neonate is attributable to a lack of KCC2. "
    [Show abstract] [Hide abstract] ABSTRACT: Work on rodents demonstrated that steep upregulation of KCC2, a neuron-specific Cl(-) extruder of cation-chloride cotransporter (CCC) family, commences in supraspinal structures at around birth, leading to establishment of hyperpolarizing GABAergic responses. We describe spatiotemporal expression profiles of the entire CCC family in human brain. KCC2 mRNA was observed already at 10th postconceptional week (PCW) in amygdala, cerebellum, and thalamus. KCC2-immunoreactive (KCC2-ir) neurons were abundant in subplate at 18 PCW. By 25 PCW, numerous subplate and cortical plate neurons became KCC2-ir. The mRNA expression profiles of α- and β-isoforms of Na-K ATPase, which fuels cation-chloride cotransport, as well of tropomyosin receptor kinase B (TrkB), which promotes developmental upregulation of KCC2, were consistent with data from studies on rodents about their interactions with KCC2. Thus, in human brain, expression of KCC2 and its functionally associated proteins begins in early fetal period. Our work facilitates translation of results on CCC functions from animal studies to human and refutes the view that poor efficacy of anticonvulsants in the term human neonate is attributable to the lack of KCC2. We propose that perinatally low threshold for activation of Ca(2+)-dependent protease calpain renders neonates susceptible to downregulation of KCC2 by traumatic events, such as perinatal hypoxia ischemia.
    Full-text · Article · Oct 2015 · Cerebral Cortex
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