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Roles of KChIP1 in the regulation of GABA-mediated transmission and behavioral anxiety.

Xia K, Xiong H, Shin Y, Wang D, Deerinck T, Takahashi H, Ellisman MH, Lipton SA, Tong G, Descalzi G, Zhang D, Zhuo M, Zhang Z - Mol Brain (2010)

Bottom Line: Its physiological function, however, remains largely unknown.We report that KChIP1 is predominantly expressed at GABAergic synapses of a subset of parvalbumin-positive neurons in the brain.Forced expression of KChIP1 in cultured hippocampal neurons increased the frequency of miniature inhibitory postsynaptic currents (mIPSCs), reduced paired pulse facilitation of autaptic IPSCs, and decreases potassium current density.

View Article: PubMed Central - HTML - PubMed

Affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, China.

ABSTRACT
K+ channel interacting protein 1 (KChIP1) is a neuronal calcium sensor (NCS) protein that interacts with multiple intracellular molecules. Its physiological function, however, remains largely unknown. We report that KChIP1 is predominantly expressed at GABAergic synapses of a subset of parvalbumin-positive neurons in the brain. Forced expression of KChIP1 in cultured hippocampal neurons increased the frequency of miniature inhibitory postsynaptic currents (mIPSCs), reduced paired pulse facilitation of autaptic IPSCs, and decreases potassium current density. Furthermore, genetic ablation of KChIP1 potentiated potassium current density in neurons and caused a robust enhancement of anxiety-like behavior in mice. Our study suggests that KChIP1 is a synaptic protein that regulates behavioral anxiety by modulating inhibitory synaptic transmission, and drugs that act on KChIP1 may help to treat patients with mood disorders including anxiety.

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KChIP1 KO mice display enhanced anxiety-like behavior. a: In the light/dark test, KChIP1 KO mice (n = 6) spent significantly less time in the light compartment compared to WT controls (n = 5) (*P < 0.05.). b: In the open field test, KChIP1 KO mice had significantly less ambulatory counts compared to WT controls (n = 7). (* P < 0.02). c: KChIP1 KO mice (n = 9) travelled significantly less within the centre area compared to WT controls (n = 7). d: In the elevated plus maze test, KChIP1 KO mice (n = 9) spent significantly less time in the open arms to WT mice (n = 7), however e: KChIP1 KO mice (n = 9) made similar amount of entries into the arms compared to WT controls (n = 7) (* P < 0.05). f: In a rota-rod test for motor performance, KChIP1 KO mice (n = 6) exhibited similar falling latencies as WT control mice (n = 6). g: On a thermal hot plate test, KChIP1 KO mice (n = 6) displayed similar latencies for nociceptive behavior display as WT control mice (n = 6). h: In a tail flick assay, KChIP1 KO mice (n = 6) displayed similar latencies for tail flicks as WT control mice (n = 6).
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Figure 7: KChIP1 KO mice display enhanced anxiety-like behavior. a: In the light/dark test, KChIP1 KO mice (n = 6) spent significantly less time in the light compartment compared to WT controls (n = 5) (*P < 0.05.). b: In the open field test, KChIP1 KO mice had significantly less ambulatory counts compared to WT controls (n = 7). (* P < 0.02). c: KChIP1 KO mice (n = 9) travelled significantly less within the centre area compared to WT controls (n = 7). d: In the elevated plus maze test, KChIP1 KO mice (n = 9) spent significantly less time in the open arms to WT mice (n = 7), however e: KChIP1 KO mice (n = 9) made similar amount of entries into the arms compared to WT controls (n = 7) (* P < 0.05). f: In a rota-rod test for motor performance, KChIP1 KO mice (n = 6) exhibited similar falling latencies as WT control mice (n = 6). g: On a thermal hot plate test, KChIP1 KO mice (n = 6) displayed similar latencies for nociceptive behavior display as WT control mice (n = 6). h: In a tail flick assay, KChIP1 KO mice (n = 6) displayed similar latencies for tail flicks as WT control mice (n = 6).

Mentions: Given our observations that KChIP1 potentiates presynaptic GABA release and that benzodiazepines, commonly used for the relief of anxiety, are thought to act by enhancing the action of the inhibitory transmitter GABA, we investigated the possible role of KChIP1 in anxiety-like behavior and compared KChIP1 KO and WT mice in a battery of anxiety related tasks. In the light/dark emergence task, where a box is separated into light and dark compartments, KChIP1 KO mice spent a significantly smaller percentage of the time in the light compartment (17.72 ± 3.98 sec, n = 6) compared to WT mice (28.51 ± 3.16 sec, n = 5; P < 0.05) (Fig 7a) and also made significantly fewer crossings between compartments (14.33 ± 2.75, n = 6) compared with WT mice (38.8 ± 5.08 sec, n = 5; P < 0.005) (not shown). In the open field paradigm, KChIP1 KO mice displayed significantly less activity after 25 minutes (57 ± 10.92 sec, n = 9) and 30 minutes (83.33 ± 15.02 sec, n = 9) compared to WT mice (192.67 ± 27.92 sec, n = 9; P < 0.005) and (202.43 ± 38.92 sec, n = 9 P < 0.02) respectively (Fig. 7b). Furthermore, KChIP1 KO mice travelled significantly less in the centre area (512.14 ± 160.64 sec, n = 9) compared to control mice (1351.75 ± 221.55 sec; n = 7; P < 0.05) (Fig. 7c). In the elevated plus maze task, KChIP1 KO mice spent a significantly smaller percentage of the time in the open arms (7.81 ± 1.56 sec, n = 9) compared to WT mice (13.57 ± 2.04 n = 7; P < 0.05) (Fig. 7d). Importantly, total number of entries did not differ between KChIP1 KO and WT mice (Fig 7e), confirming that the results are not due to alterations in motor ability.


Roles of KChIP1 in the regulation of GABA-mediated transmission and behavioral anxiety.

Xia K, Xiong H, Shin Y, Wang D, Deerinck T, Takahashi H, Ellisman MH, Lipton SA, Tong G, Descalzi G, Zhang D, Zhuo M, Zhang Z - Mol Brain (2010)

KChIP1 KO mice display enhanced anxiety-like behavior. a: In the light/dark test, KChIP1 KO mice (n = 6) spent significantly less time in the light compartment compared to WT controls (n = 5) (*P < 0.05.). b: In the open field test, KChIP1 KO mice had significantly less ambulatory counts compared to WT controls (n = 7). (* P < 0.02). c: KChIP1 KO mice (n = 9) travelled significantly less within the centre area compared to WT controls (n = 7). d: In the elevated plus maze test, KChIP1 KO mice (n = 9) spent significantly less time in the open arms to WT mice (n = 7), however e: KChIP1 KO mice (n = 9) made similar amount of entries into the arms compared to WT controls (n = 7) (* P < 0.05). f: In a rota-rod test for motor performance, KChIP1 KO mice (n = 6) exhibited similar falling latencies as WT control mice (n = 6). g: On a thermal hot plate test, KChIP1 KO mice (n = 6) displayed similar latencies for nociceptive behavior display as WT control mice (n = 6). h: In a tail flick assay, KChIP1 KO mice (n = 6) displayed similar latencies for tail flicks as WT control mice (n = 6).
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Related In: Results  -  Collection

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Show All Figures
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Figure 7: KChIP1 KO mice display enhanced anxiety-like behavior. a: In the light/dark test, KChIP1 KO mice (n = 6) spent significantly less time in the light compartment compared to WT controls (n = 5) (*P < 0.05.). b: In the open field test, KChIP1 KO mice had significantly less ambulatory counts compared to WT controls (n = 7). (* P < 0.02). c: KChIP1 KO mice (n = 9) travelled significantly less within the centre area compared to WT controls (n = 7). d: In the elevated plus maze test, KChIP1 KO mice (n = 9) spent significantly less time in the open arms to WT mice (n = 7), however e: KChIP1 KO mice (n = 9) made similar amount of entries into the arms compared to WT controls (n = 7) (* P < 0.05). f: In a rota-rod test for motor performance, KChIP1 KO mice (n = 6) exhibited similar falling latencies as WT control mice (n = 6). g: On a thermal hot plate test, KChIP1 KO mice (n = 6) displayed similar latencies for nociceptive behavior display as WT control mice (n = 6). h: In a tail flick assay, KChIP1 KO mice (n = 6) displayed similar latencies for tail flicks as WT control mice (n = 6).
Mentions: Given our observations that KChIP1 potentiates presynaptic GABA release and that benzodiazepines, commonly used for the relief of anxiety, are thought to act by enhancing the action of the inhibitory transmitter GABA, we investigated the possible role of KChIP1 in anxiety-like behavior and compared KChIP1 KO and WT mice in a battery of anxiety related tasks. In the light/dark emergence task, where a box is separated into light and dark compartments, KChIP1 KO mice spent a significantly smaller percentage of the time in the light compartment (17.72 ± 3.98 sec, n = 6) compared to WT mice (28.51 ± 3.16 sec, n = 5; P < 0.05) (Fig 7a) and also made significantly fewer crossings between compartments (14.33 ± 2.75, n = 6) compared with WT mice (38.8 ± 5.08 sec, n = 5; P < 0.005) (not shown). In the open field paradigm, KChIP1 KO mice displayed significantly less activity after 25 minutes (57 ± 10.92 sec, n = 9) and 30 minutes (83.33 ± 15.02 sec, n = 9) compared to WT mice (192.67 ± 27.92 sec, n = 9; P < 0.005) and (202.43 ± 38.92 sec, n = 9 P < 0.02) respectively (Fig. 7b). Furthermore, KChIP1 KO mice travelled significantly less in the centre area (512.14 ± 160.64 sec, n = 9) compared to control mice (1351.75 ± 221.55 sec; n = 7; P < 0.05) (Fig. 7c). In the elevated plus maze task, KChIP1 KO mice spent a significantly smaller percentage of the time in the open arms (7.81 ± 1.56 sec, n = 9) compared to WT mice (13.57 ± 2.04 n = 7; P < 0.05) (Fig. 7d). Importantly, total number of entries did not differ between KChIP1 KO and WT mice (Fig 7e), confirming that the results are not due to alterations in motor ability.

Bottom Line: Its physiological function, however, remains largely unknown.We report that KChIP1 is predominantly expressed at GABAergic synapses of a subset of parvalbumin-positive neurons in the brain.Forced expression of KChIP1 in cultured hippocampal neurons increased the frequency of miniature inhibitory postsynaptic currents (mIPSCs), reduced paired pulse facilitation of autaptic IPSCs, and decreases potassium current density.

View Article: PubMed Central - HTML - PubMed

Affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, China.

ABSTRACT
K+ channel interacting protein 1 (KChIP1) is a neuronal calcium sensor (NCS) protein that interacts with multiple intracellular molecules. Its physiological function, however, remains largely unknown. We report that KChIP1 is predominantly expressed at GABAergic synapses of a subset of parvalbumin-positive neurons in the brain. Forced expression of KChIP1 in cultured hippocampal neurons increased the frequency of miniature inhibitory postsynaptic currents (mIPSCs), reduced paired pulse facilitation of autaptic IPSCs, and decreases potassium current density. Furthermore, genetic ablation of KChIP1 potentiated potassium current density in neurons and caused a robust enhancement of anxiety-like behavior in mice. Our study suggests that KChIP1 is a synaptic protein that regulates behavioral anxiety by modulating inhibitory synaptic transmission, and drugs that act on KChIP1 may help to treat patients with mood disorders including anxiety.

Show MeSH
Related in: MedlinePlus