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Dynamic functions of GABA signaling during granule cell maturation.

Dieni CV, Chancey JH, Overstreet-Wadiche LS - Front Neural Circuits (2013)

Bottom Line: Thereafter robust synaptic inhibition enforces low spiking probability of granule cells in response to cortical excitatory inputs and maintains the sparse activity patterns characteristic of this brain region.Here we review these dynamic functions of GABA across granule cell maturation, focusing on the potential role of specific interneuron circuits at progressive developmental stages.We further highlight questions that remain unanswered about GABA signaling in granule cell development and excitability.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, University of Alabama at Birmingham Birmingham, AL, USA.

ABSTRACT
The dentate gyrus is one of the few areas of the brain where new neurons are generated throughout life. Neural activity influences multiple stages of neurogenesis, thereby allowing experience to regulate the production of new neurons. It is now well established that GABA(A) receptor-mediated signaling plays a pivotal role in mediating activity-dependent regulation of adult neurogenesis. GABA first acts as a trophic signal that depolarizes progenitors and early post mitotic granule cells, enabling network activity to control molecular cascades essential for proliferation, survival and growth. Following the development of glutamatergic synaptic inputs, GABA signaling switches from excitatory to inhibitory. Thereafter robust synaptic inhibition enforces low spiking probability of granule cells in response to cortical excitatory inputs and maintains the sparse activity patterns characteristic of this brain region. Here we review these dynamic functions of GABA across granule cell maturation, focusing on the potential role of specific interneuron circuits at progressive developmental stages. We further highlight questions that remain unanswered about GABA signaling in granule cell development and excitability.

No MeSH data available.


Related in: MedlinePlus

Modes of GABAR signaling during GC development. (A) Tonic signaling to Type I radial glial-like stem cells: Top, schematic depiction of whole cell patch clamp recording from mature granule cells (mGCs) or Type I GFP+ radial glial-like stem cells (RGLs) during photoactivation of PV+ interneurons expressing channelrhodopsin (ChR2). Middle, photoactivation of ChR2+PV+ interneurons (indicated by blue lines, 1 Hz) generates large synaptic currents in mature GCs that are blocked by the GABAR antagonist bicuculline (Bic). Bottom, photoactivation of ChR2+PV+ interneurons (blue bar, 8 Hz) generates small tonic currents in Type I RGLs that are blocked by bicuculline. Adapted from Song et al. (2012) with permission from Macmillan Publishers Ltd. Estimates for input resistance (IR) of Type I and Type II cells are from Fukuda et al. (2003). (B) Synaptic signaling to Type II neuroprogenitors: Top, schematic depiction of innervation of Type II cells by dentate interneurons. Middle, hilar stimulation evokes inward currents in Type II cells that are blocked by bicuculline. Bottom, the frequency of spontaneous activity in Type II cells is increased by bath application of 4-aminopyridine (4-AP; 100 μM), a potassium channel blocker that causes synchronous firing of dentate interneurons (Michelson and Wong, 1994; Markwardt et al., 2011). 4-AP-induced currents are blocked by tetrodotoxin (TTX). Insets show currents on an expanded time scale. Adapted from Tozuka et al. (2005) with permission from Elsevier. (C) Synaptic signaling to newborn GCs by Ivy/NG interneurons: Top, reconstructed Ivy/NG interneuron (red cell body and dendrites, black axon) from a paired recording with a POMC-GFP+ newborn GC (green). ML, molecular layer. Middle, current injection into presynaptic Ivy/NG cells evokes slow GPSCs in newborn GCs. The averaged unitary IPSC (green) is overlaid on individual currents (gray). From Markwardt et al. (2011). Bottom, bath application of 4-AP (100 μM) induces synaptic currents in newborn GCs that are blocked by picrotoxin (PTX). Insets show currents on expanded time scales [scale bars are 200 pA and 10 s (left) or 500 ms (right)]. From Markwardt et al. (2009). The estimate for IR of newborn GCs is from Overstreet et al. (2004). (D) Heterogeneous synaptic signaling to mature GCs: Top, schematic depiction showing that mature GCs are innervated by a variety of interneuron subtypes including Ivy/NG cells and perisomatic projecting interneurons. Ivy/NG cells also provide slow GABAergic inhibition to perisomatic-projecting interneurons. Middle, current injection in individual interneurons evokes either fast (left) or slow (right) uIPSCs in mature GCs, reflecting the heterogeneity of innervation. Bottom, spontaneous GPSCs in mature GCs arise from perisomatic-projecting interneurons (Soltesz et al., 1995). The frequency of sGPSCs is reduced by stimulation of the ML (arrows) that evokes slow NO711-sensitive IPSCs in mature GCs (insets) and perisomatic projecting interneurons (not shown). Together these results support the circuit diagram shown above. Scale in inset, 300 pA, 500 ms. Adapted from Markwardt et al. (2011). The estimate of IR for mature GCs is from Schmidt-Hieber et al. (2004) and Overstreet et al. (2004).
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Figure 2: Modes of GABAR signaling during GC development. (A) Tonic signaling to Type I radial glial-like stem cells: Top, schematic depiction of whole cell patch clamp recording from mature granule cells (mGCs) or Type I GFP+ radial glial-like stem cells (RGLs) during photoactivation of PV+ interneurons expressing channelrhodopsin (ChR2). Middle, photoactivation of ChR2+PV+ interneurons (indicated by blue lines, 1 Hz) generates large synaptic currents in mature GCs that are blocked by the GABAR antagonist bicuculline (Bic). Bottom, photoactivation of ChR2+PV+ interneurons (blue bar, 8 Hz) generates small tonic currents in Type I RGLs that are blocked by bicuculline. Adapted from Song et al. (2012) with permission from Macmillan Publishers Ltd. Estimates for input resistance (IR) of Type I and Type II cells are from Fukuda et al. (2003). (B) Synaptic signaling to Type II neuroprogenitors: Top, schematic depiction of innervation of Type II cells by dentate interneurons. Middle, hilar stimulation evokes inward currents in Type II cells that are blocked by bicuculline. Bottom, the frequency of spontaneous activity in Type II cells is increased by bath application of 4-aminopyridine (4-AP; 100 μM), a potassium channel blocker that causes synchronous firing of dentate interneurons (Michelson and Wong, 1994; Markwardt et al., 2011). 4-AP-induced currents are blocked by tetrodotoxin (TTX). Insets show currents on an expanded time scale. Adapted from Tozuka et al. (2005) with permission from Elsevier. (C) Synaptic signaling to newborn GCs by Ivy/NG interneurons: Top, reconstructed Ivy/NG interneuron (red cell body and dendrites, black axon) from a paired recording with a POMC-GFP+ newborn GC (green). ML, molecular layer. Middle, current injection into presynaptic Ivy/NG cells evokes slow GPSCs in newborn GCs. The averaged unitary IPSC (green) is overlaid on individual currents (gray). From Markwardt et al. (2011). Bottom, bath application of 4-AP (100 μM) induces synaptic currents in newborn GCs that are blocked by picrotoxin (PTX). Insets show currents on expanded time scales [scale bars are 200 pA and 10 s (left) or 500 ms (right)]. From Markwardt et al. (2009). The estimate for IR of newborn GCs is from Overstreet et al. (2004). (D) Heterogeneous synaptic signaling to mature GCs: Top, schematic depiction showing that mature GCs are innervated by a variety of interneuron subtypes including Ivy/NG cells and perisomatic projecting interneurons. Ivy/NG cells also provide slow GABAergic inhibition to perisomatic-projecting interneurons. Middle, current injection in individual interneurons evokes either fast (left) or slow (right) uIPSCs in mature GCs, reflecting the heterogeneity of innervation. Bottom, spontaneous GPSCs in mature GCs arise from perisomatic-projecting interneurons (Soltesz et al., 1995). The frequency of sGPSCs is reduced by stimulation of the ML (arrows) that evokes slow NO711-sensitive IPSCs in mature GCs (insets) and perisomatic projecting interneurons (not shown). Together these results support the circuit diagram shown above. Scale in inset, 300 pA, 500 ms. Adapted from Markwardt et al. (2011). The estimate of IR for mature GCs is from Schmidt-Hieber et al. (2004) and Overstreet et al. (2004).

Mentions: Radial glial cells (Type I cells) that express nestin are the putative neural stem cells of the adult DG (Seri et al., 2001; Bonaguidi et al., 2012). Located in the subgranular zone (Figures 1 and 2), Type I cells express the glial marker GFAP and have astrocytic properties including low input resistance and a resting potential near the K+ equilibrium potential (Filippov et al., 2003; Fukuda et al., 2003). Two reports indicate that Type I cells have functional GABARs that respond to high concentrations of exogenously applied GABA (Wang et al., 2005; Song et al., 2012), although GABA-evoked currents were not detected in another study (Tozuka et al., 2005). Type I cells do not have GABA synaptic innervation since both electrical stimulation and light-driven activation of parvalbumin (PV)-expressing interneurons fail to evoke synaptic currents (Figure 2A; Song et al., 2012). However, Song et al. (2012) proposed that tonic currents mediated by γ2-GABARs promote quiescence since knockout of the γ2 GABAR enhanced proliferation of Type I cells. Repression of stem cell proliferation by tonic GABAR signaling is likewise supported by the increased proliferation of progenitors seen in germline α4 GABAR knockout mice that have impaired tonic GABAR signaling in adult-generated progeny (Duveau et al., 2011). Tonic GABAR signaling in mature GCs is typically mediated by α4β2δ GABARs (Farrant and Nusser, 2005), but δ-GABAR subunit knockout mice did not have any of the deficits seen in the α4 knockout (Duveau et al., 2011). Thus, GABARs involved in tonic signaling in progenitors may be different than those of mature GCs. Indeed, γ2-GABAR subunits are typically associated with phasic GABAergic signaling since the γ2 subunit is essential for clustering receptors at synaptic sites (Essrich et al., 1998). It will be important to establish the mechanism by which tonic GABAR signaling through γ2 or α4 subunits contributes to stem cell proliferation, since the characteristics of Ca2+ influx generated by tonic depolarization of low-input resistance Type I cells will likely be distinct from Ca2+ transients generated by phasic GABAR signaling to later stage progenitors and newborn GCs that have high input resistance.


Dynamic functions of GABA signaling during granule cell maturation.

Dieni CV, Chancey JH, Overstreet-Wadiche LS - Front Neural Circuits (2013)

Modes of GABAR signaling during GC development. (A) Tonic signaling to Type I radial glial-like stem cells: Top, schematic depiction of whole cell patch clamp recording from mature granule cells (mGCs) or Type I GFP+ radial glial-like stem cells (RGLs) during photoactivation of PV+ interneurons expressing channelrhodopsin (ChR2). Middle, photoactivation of ChR2+PV+ interneurons (indicated by blue lines, 1 Hz) generates large synaptic currents in mature GCs that are blocked by the GABAR antagonist bicuculline (Bic). Bottom, photoactivation of ChR2+PV+ interneurons (blue bar, 8 Hz) generates small tonic currents in Type I RGLs that are blocked by bicuculline. Adapted from Song et al. (2012) with permission from Macmillan Publishers Ltd. Estimates for input resistance (IR) of Type I and Type II cells are from Fukuda et al. (2003). (B) Synaptic signaling to Type II neuroprogenitors: Top, schematic depiction of innervation of Type II cells by dentate interneurons. Middle, hilar stimulation evokes inward currents in Type II cells that are blocked by bicuculline. Bottom, the frequency of spontaneous activity in Type II cells is increased by bath application of 4-aminopyridine (4-AP; 100 μM), a potassium channel blocker that causes synchronous firing of dentate interneurons (Michelson and Wong, 1994; Markwardt et al., 2011). 4-AP-induced currents are blocked by tetrodotoxin (TTX). Insets show currents on an expanded time scale. Adapted from Tozuka et al. (2005) with permission from Elsevier. (C) Synaptic signaling to newborn GCs by Ivy/NG interneurons: Top, reconstructed Ivy/NG interneuron (red cell body and dendrites, black axon) from a paired recording with a POMC-GFP+ newborn GC (green). ML, molecular layer. Middle, current injection into presynaptic Ivy/NG cells evokes slow GPSCs in newborn GCs. The averaged unitary IPSC (green) is overlaid on individual currents (gray). From Markwardt et al. (2011). Bottom, bath application of 4-AP (100 μM) induces synaptic currents in newborn GCs that are blocked by picrotoxin (PTX). Insets show currents on expanded time scales [scale bars are 200 pA and 10 s (left) or 500 ms (right)]. From Markwardt et al. (2009). The estimate for IR of newborn GCs is from Overstreet et al. (2004). (D) Heterogeneous synaptic signaling to mature GCs: Top, schematic depiction showing that mature GCs are innervated by a variety of interneuron subtypes including Ivy/NG cells and perisomatic projecting interneurons. Ivy/NG cells also provide slow GABAergic inhibition to perisomatic-projecting interneurons. Middle, current injection in individual interneurons evokes either fast (left) or slow (right) uIPSCs in mature GCs, reflecting the heterogeneity of innervation. Bottom, spontaneous GPSCs in mature GCs arise from perisomatic-projecting interneurons (Soltesz et al., 1995). The frequency of sGPSCs is reduced by stimulation of the ML (arrows) that evokes slow NO711-sensitive IPSCs in mature GCs (insets) and perisomatic projecting interneurons (not shown). Together these results support the circuit diagram shown above. Scale in inset, 300 pA, 500 ms. Adapted from Markwardt et al. (2011). The estimate of IR for mature GCs is from Schmidt-Hieber et al. (2004) and Overstreet et al. (2004).
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Figure 2: Modes of GABAR signaling during GC development. (A) Tonic signaling to Type I radial glial-like stem cells: Top, schematic depiction of whole cell patch clamp recording from mature granule cells (mGCs) or Type I GFP+ radial glial-like stem cells (RGLs) during photoactivation of PV+ interneurons expressing channelrhodopsin (ChR2). Middle, photoactivation of ChR2+PV+ interneurons (indicated by blue lines, 1 Hz) generates large synaptic currents in mature GCs that are blocked by the GABAR antagonist bicuculline (Bic). Bottom, photoactivation of ChR2+PV+ interneurons (blue bar, 8 Hz) generates small tonic currents in Type I RGLs that are blocked by bicuculline. Adapted from Song et al. (2012) with permission from Macmillan Publishers Ltd. Estimates for input resistance (IR) of Type I and Type II cells are from Fukuda et al. (2003). (B) Synaptic signaling to Type II neuroprogenitors: Top, schematic depiction of innervation of Type II cells by dentate interneurons. Middle, hilar stimulation evokes inward currents in Type II cells that are blocked by bicuculline. Bottom, the frequency of spontaneous activity in Type II cells is increased by bath application of 4-aminopyridine (4-AP; 100 μM), a potassium channel blocker that causes synchronous firing of dentate interneurons (Michelson and Wong, 1994; Markwardt et al., 2011). 4-AP-induced currents are blocked by tetrodotoxin (TTX). Insets show currents on an expanded time scale. Adapted from Tozuka et al. (2005) with permission from Elsevier. (C) Synaptic signaling to newborn GCs by Ivy/NG interneurons: Top, reconstructed Ivy/NG interneuron (red cell body and dendrites, black axon) from a paired recording with a POMC-GFP+ newborn GC (green). ML, molecular layer. Middle, current injection into presynaptic Ivy/NG cells evokes slow GPSCs in newborn GCs. The averaged unitary IPSC (green) is overlaid on individual currents (gray). From Markwardt et al. (2011). Bottom, bath application of 4-AP (100 μM) induces synaptic currents in newborn GCs that are blocked by picrotoxin (PTX). Insets show currents on expanded time scales [scale bars are 200 pA and 10 s (left) or 500 ms (right)]. From Markwardt et al. (2009). The estimate for IR of newborn GCs is from Overstreet et al. (2004). (D) Heterogeneous synaptic signaling to mature GCs: Top, schematic depiction showing that mature GCs are innervated by a variety of interneuron subtypes including Ivy/NG cells and perisomatic projecting interneurons. Ivy/NG cells also provide slow GABAergic inhibition to perisomatic-projecting interneurons. Middle, current injection in individual interneurons evokes either fast (left) or slow (right) uIPSCs in mature GCs, reflecting the heterogeneity of innervation. Bottom, spontaneous GPSCs in mature GCs arise from perisomatic-projecting interneurons (Soltesz et al., 1995). The frequency of sGPSCs is reduced by stimulation of the ML (arrows) that evokes slow NO711-sensitive IPSCs in mature GCs (insets) and perisomatic projecting interneurons (not shown). Together these results support the circuit diagram shown above. Scale in inset, 300 pA, 500 ms. Adapted from Markwardt et al. (2011). The estimate of IR for mature GCs is from Schmidt-Hieber et al. (2004) and Overstreet et al. (2004).
Mentions: Radial glial cells (Type I cells) that express nestin are the putative neural stem cells of the adult DG (Seri et al., 2001; Bonaguidi et al., 2012). Located in the subgranular zone (Figures 1 and 2), Type I cells express the glial marker GFAP and have astrocytic properties including low input resistance and a resting potential near the K+ equilibrium potential (Filippov et al., 2003; Fukuda et al., 2003). Two reports indicate that Type I cells have functional GABARs that respond to high concentrations of exogenously applied GABA (Wang et al., 2005; Song et al., 2012), although GABA-evoked currents were not detected in another study (Tozuka et al., 2005). Type I cells do not have GABA synaptic innervation since both electrical stimulation and light-driven activation of parvalbumin (PV)-expressing interneurons fail to evoke synaptic currents (Figure 2A; Song et al., 2012). However, Song et al. (2012) proposed that tonic currents mediated by γ2-GABARs promote quiescence since knockout of the γ2 GABAR enhanced proliferation of Type I cells. Repression of stem cell proliferation by tonic GABAR signaling is likewise supported by the increased proliferation of progenitors seen in germline α4 GABAR knockout mice that have impaired tonic GABAR signaling in adult-generated progeny (Duveau et al., 2011). Tonic GABAR signaling in mature GCs is typically mediated by α4β2δ GABARs (Farrant and Nusser, 2005), but δ-GABAR subunit knockout mice did not have any of the deficits seen in the α4 knockout (Duveau et al., 2011). Thus, GABARs involved in tonic signaling in progenitors may be different than those of mature GCs. Indeed, γ2-GABAR subunits are typically associated with phasic GABAergic signaling since the γ2 subunit is essential for clustering receptors at synaptic sites (Essrich et al., 1998). It will be important to establish the mechanism by which tonic GABAR signaling through γ2 or α4 subunits contributes to stem cell proliferation, since the characteristics of Ca2+ influx generated by tonic depolarization of low-input resistance Type I cells will likely be distinct from Ca2+ transients generated by phasic GABAR signaling to later stage progenitors and newborn GCs that have high input resistance.

Bottom Line: Thereafter robust synaptic inhibition enforces low spiking probability of granule cells in response to cortical excitatory inputs and maintains the sparse activity patterns characteristic of this brain region.Here we review these dynamic functions of GABA across granule cell maturation, focusing on the potential role of specific interneuron circuits at progressive developmental stages.We further highlight questions that remain unanswered about GABA signaling in granule cell development and excitability.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, University of Alabama at Birmingham Birmingham, AL, USA.

ABSTRACT
The dentate gyrus is one of the few areas of the brain where new neurons are generated throughout life. Neural activity influences multiple stages of neurogenesis, thereby allowing experience to regulate the production of new neurons. It is now well established that GABA(A) receptor-mediated signaling plays a pivotal role in mediating activity-dependent regulation of adult neurogenesis. GABA first acts as a trophic signal that depolarizes progenitors and early post mitotic granule cells, enabling network activity to control molecular cascades essential for proliferation, survival and growth. Following the development of glutamatergic synaptic inputs, GABA signaling switches from excitatory to inhibitory. Thereafter robust synaptic inhibition enforces low spiking probability of granule cells in response to cortical excitatory inputs and maintains the sparse activity patterns characteristic of this brain region. Here we review these dynamic functions of GABA across granule cell maturation, focusing on the potential role of specific interneuron circuits at progressive developmental stages. We further highlight questions that remain unanswered about GABA signaling in granule cell development and excitability.

No MeSH data available.


Related in: MedlinePlus