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Genetic control of astrocyte function in neural circuits.

Jahn HM, Scheller A, Kirchhoff F - Front Cell Neurosci (2015)

Bottom Line: Furthermore, such genetic approaches have also been used to restore astrocyte function.In these studies two alternatives were employed to achieve proper genetic targeting of astrocytes: transgenes using the promoter of the human glial fibrillary acidic protein (GFAP) or homologous recombination into the glutamate-aspartate transporter (GLAST) locus.We will highlight their specific properties that could be relevant for their use.

View Article: PubMed Central - PubMed

Affiliation: Molecular Physiology, Center for Integrative Physiology and Molecular Medicine (CIPMM), University of Saarland Homburg, Germany.

ABSTRACT
During the last two decades numerous genetic approaches affecting cell function in vivo have been developed. Current state-of-the-art technology permits the selective switching of gene function in distinct cell populations within the complex organization of a given tissue parenchyma. The tamoxifen-inducible Cre/loxP gene recombination and the doxycycline-dependent modulation of gene expression are probably the most popular genetic paradigms. Here, we will review applications of these two strategies while focusing on the interactions of astrocytes and neurons in the central nervous system (CNS) and their impact for the whole organism. Abolishing glial sensing of neuronal activity by selective deletion of glial transmitter receptors demonstrated the impact of astrocytes for higher cognitive functions such as learning and memory, or the more basic body control of muscle coordination. Interestingly, also interfering with glial output, i.e., the release of gliotransmitters can drastically change animal's physiology like sleeping behavior. Furthermore, such genetic approaches have also been used to restore astrocyte function. In these studies two alternatives were employed to achieve proper genetic targeting of astrocytes: transgenes using the promoter of the human glial fibrillary acidic protein (GFAP) or homologous recombination into the glutamate-aspartate transporter (GLAST) locus. We will highlight their specific properties that could be relevant for their use.

No MeSH data available.


Related in: MedlinePlus

Genetic mouse models reveal a diversity of astrocyte functions affecting mouse behavior. (A) Astroglial cannabinoid receptors are involved in spatial memory formation (Han et al., 2012). (B) The ionotropic glutamate receptors on BG contribute to fine motor coordination (Saab et al., 2012). (C) Although the lack of the widely expressed transcriptional repressor MECP2 results in synapse loss, severe mental retardation and premature death, the astrocyte-specific re-expression restores several vital functions like motor activity (Lioy et al., 2011). (D) Impairment of astroglial ATP release perturbs sleep behavior and induces memory loss (Pascual et al., 2005; Halassa et al., 2009).
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Figure 2: Genetic mouse models reveal a diversity of astrocyte functions affecting mouse behavior. (A) Astroglial cannabinoid receptors are involved in spatial memory formation (Han et al., 2012). (B) The ionotropic glutamate receptors on BG contribute to fine motor coordination (Saab et al., 2012). (C) Although the lack of the widely expressed transcriptional repressor MECP2 results in synapse loss, severe mental retardation and premature death, the astrocyte-specific re-expression restores several vital functions like motor activity (Lioy et al., 2011). (D) Impairment of astroglial ATP release perturbs sleep behavior and induces memory loss (Pascual et al., 2005; Halassa et al., 2009).

Mentions: The functional role in working memory and its molecular signaling of the hippocampal CA3-CA1 synapse have been well characterized (Neves et al., 2008; Bannerman et al., 2014). A diversity of endogenous compounds is capable of modulating its transmission and thereby affecting our memory. Interestingly, one of the most abundant G-protein coupled receptors of the brain, the cannabinoid type-1 receptor (CB1R), has been detected on all hippocampal cell types (Marsicano and Lutz, 1999). Based on work performed on brain slices, endocannabinoids or the synthetic drug Δ9-tetrahydrocannabinol (THC), better known as marijuana, are thought to inhibit presynaptic transmitter release via CB1R activation, thereby depressing excitatory neurotransmission, and finally, impairing spatial working memory (Misner and Sullivan, 1999; Carlson et al., 2002; Takahashi and Castillo, 2006; Bajo et al., 2009; Schoeler and Bhattacharyya, 2013). Also in vivo THC was found to cause long-term depression (LTD; Hampson and Deadwyler, 2000; Mato et al., 2004; Madroñal et al., 2012). However, when the impact of CB1R was tested more selectively using genetically modified mice with cell-specific receptor deficiency, unexpectedly, it was the ablation of the astroglial (Figure 1H; GFAP-CreERT2 × floxed CB1R), but not the neuronal CB1R that completely abolished THC-dependent depression (Figure 2A; Han et al., 2012). For their analysis, the authors used mice with at least 4 weeks of time to allow efficient receptor protein degradation. Although 30% of CB1R protein could still be detected using immune-EM, the receptor function in modulating synaptic efficacy, i.e., LTD, was completely gone. In parallel, the mutant mice remained unaffected after THC injection when behaviorally tested in a variant of the Morris water maze. Thereby, this study demonstrates the pivotal role of astrocytes in modulating synaptic transmission and respective circuit-associated learning behavior.


Genetic control of astrocyte function in neural circuits.

Jahn HM, Scheller A, Kirchhoff F - Front Cell Neurosci (2015)

Genetic mouse models reveal a diversity of astrocyte functions affecting mouse behavior. (A) Astroglial cannabinoid receptors are involved in spatial memory formation (Han et al., 2012). (B) The ionotropic glutamate receptors on BG contribute to fine motor coordination (Saab et al., 2012). (C) Although the lack of the widely expressed transcriptional repressor MECP2 results in synapse loss, severe mental retardation and premature death, the astrocyte-specific re-expression restores several vital functions like motor activity (Lioy et al., 2011). (D) Impairment of astroglial ATP release perturbs sleep behavior and induces memory loss (Pascual et al., 2005; Halassa et al., 2009).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4538289&req=5

Figure 2: Genetic mouse models reveal a diversity of astrocyte functions affecting mouse behavior. (A) Astroglial cannabinoid receptors are involved in spatial memory formation (Han et al., 2012). (B) The ionotropic glutamate receptors on BG contribute to fine motor coordination (Saab et al., 2012). (C) Although the lack of the widely expressed transcriptional repressor MECP2 results in synapse loss, severe mental retardation and premature death, the astrocyte-specific re-expression restores several vital functions like motor activity (Lioy et al., 2011). (D) Impairment of astroglial ATP release perturbs sleep behavior and induces memory loss (Pascual et al., 2005; Halassa et al., 2009).
Mentions: The functional role in working memory and its molecular signaling of the hippocampal CA3-CA1 synapse have been well characterized (Neves et al., 2008; Bannerman et al., 2014). A diversity of endogenous compounds is capable of modulating its transmission and thereby affecting our memory. Interestingly, one of the most abundant G-protein coupled receptors of the brain, the cannabinoid type-1 receptor (CB1R), has been detected on all hippocampal cell types (Marsicano and Lutz, 1999). Based on work performed on brain slices, endocannabinoids or the synthetic drug Δ9-tetrahydrocannabinol (THC), better known as marijuana, are thought to inhibit presynaptic transmitter release via CB1R activation, thereby depressing excitatory neurotransmission, and finally, impairing spatial working memory (Misner and Sullivan, 1999; Carlson et al., 2002; Takahashi and Castillo, 2006; Bajo et al., 2009; Schoeler and Bhattacharyya, 2013). Also in vivo THC was found to cause long-term depression (LTD; Hampson and Deadwyler, 2000; Mato et al., 2004; Madroñal et al., 2012). However, when the impact of CB1R was tested more selectively using genetically modified mice with cell-specific receptor deficiency, unexpectedly, it was the ablation of the astroglial (Figure 1H; GFAP-CreERT2 × floxed CB1R), but not the neuronal CB1R that completely abolished THC-dependent depression (Figure 2A; Han et al., 2012). For their analysis, the authors used mice with at least 4 weeks of time to allow efficient receptor protein degradation. Although 30% of CB1R protein could still be detected using immune-EM, the receptor function in modulating synaptic efficacy, i.e., LTD, was completely gone. In parallel, the mutant mice remained unaffected after THC injection when behaviorally tested in a variant of the Morris water maze. Thereby, this study demonstrates the pivotal role of astrocytes in modulating synaptic transmission and respective circuit-associated learning behavior.

Bottom Line: Furthermore, such genetic approaches have also been used to restore astrocyte function.In these studies two alternatives were employed to achieve proper genetic targeting of astrocytes: transgenes using the promoter of the human glial fibrillary acidic protein (GFAP) or homologous recombination into the glutamate-aspartate transporter (GLAST) locus.We will highlight their specific properties that could be relevant for their use.

View Article: PubMed Central - PubMed

Affiliation: Molecular Physiology, Center for Integrative Physiology and Molecular Medicine (CIPMM), University of Saarland Homburg, Germany.

ABSTRACT
During the last two decades numerous genetic approaches affecting cell function in vivo have been developed. Current state-of-the-art technology permits the selective switching of gene function in distinct cell populations within the complex organization of a given tissue parenchyma. The tamoxifen-inducible Cre/loxP gene recombination and the doxycycline-dependent modulation of gene expression are probably the most popular genetic paradigms. Here, we will review applications of these two strategies while focusing on the interactions of astrocytes and neurons in the central nervous system (CNS) and their impact for the whole organism. Abolishing glial sensing of neuronal activity by selective deletion of glial transmitter receptors demonstrated the impact of astrocytes for higher cognitive functions such as learning and memory, or the more basic body control of muscle coordination. Interestingly, also interfering with glial output, i.e., the release of gliotransmitters can drastically change animal's physiology like sleeping behavior. Furthermore, such genetic approaches have also been used to restore astrocyte function. In these studies two alternatives were employed to achieve proper genetic targeting of astrocytes: transgenes using the promoter of the human glial fibrillary acidic protein (GFAP) or homologous recombination into the glutamate-aspartate transporter (GLAST) locus. We will highlight their specific properties that could be relevant for their use.

No MeSH data available.


Related in: MedlinePlus