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Neurabin contributes to hippocampal long-term potentiation and contextual fear memory.

Wu LJ, Ren M, Wang H, Kim SS, Cao X, Zhuo M - PLoS ONE (2008)

Bottom Line: Highly enriched in the dendritic spine, neurabin is important for spine morphogenesis and synaptic formation.However, less is known about the role of neurabin in hippocampal plasticity and its possible effect on behavioral functions.Our results indicate that neurabin regulates contextual fear memory and LTP in hippocampal CA1 pyramidal neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of Toronto, Toronto, Onatrio, Canada.

ABSTRACT
Neurabin is a scaffolding protein that interacts with actin and protein phosphatase-1. Highly enriched in the dendritic spine, neurabin is important for spine morphogenesis and synaptic formation. However, less is known about the role of neurabin in hippocampal plasticity and its possible effect on behavioral functions. Using neurabin knockout (KO) mice, here we studied the function of neurabin in hippocampal synaptic transmission, plasticity and behavioral memory. We demonstrated that neurabin KO mice showed a deficit in contextual fear memory but not auditory fear memory. Whole-cell patch clamp recordings in the hippocampal CA1 neurons showed that long-term potentiation (LTP) was significantly reduced, whereas long-term depression (LTD) was unaltered in neurabin KO mice. Moreover, increased AMPA receptor but not NMDA receptor-mediated synaptic transmission was found in neurabin KO mice, and is accompanied by decreased phosphorylation of GluR1 at the PKA site (Ser845) but no change at the CaMKII/PKC site (Ser831). Pre-conditioning with LTD induction rescued the following LTP in neurabin KO mice, suggesting the loss of LTP may be due to the saturated synaptic transmission. Our results indicate that neurabin regulates contextual fear memory and LTP in hippocampal CA1 pyramidal neurons.

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Rescue of LTP by preconditioning with LTD induction but not by forskolin treatment in neurabin KO mice.A, In the presence of forskolin (10 µM), LTP is induced in hippocampal CA1 neurons with pairing protocol in wild-type (n = 7) but not in neurabin KO mice (n = 8). The insets show averages of six EPSCs at baseline response and 30 min after LTP induction (arrow). Right panel shows the statistical result of LTP reduction in neurabin KO mice in the presence of forskolin. The dashed lines indicate the mean basal synaptic response. B, Pre-conditioning with LTD induction rescued LTP in neurabin KO mice (n = 9). The insets show averages of six EPSCs at baseline response (thick dark traces), 10 min (thin dark traces) after LTD induction (arrow) and 30 min (gray traces) after LTP induction (arrow). Right panel showing LTP in both wild-type (n = 5) and neurabin KO mice after preconditioning with LTD induction. The dashed lines indicate the mean basal synaptic response.
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pone-0001407-g005: Rescue of LTP by preconditioning with LTD induction but not by forskolin treatment in neurabin KO mice.A, In the presence of forskolin (10 µM), LTP is induced in hippocampal CA1 neurons with pairing protocol in wild-type (n = 7) but not in neurabin KO mice (n = 8). The insets show averages of six EPSCs at baseline response and 30 min after LTP induction (arrow). Right panel shows the statistical result of LTP reduction in neurabin KO mice in the presence of forskolin. The dashed lines indicate the mean basal synaptic response. B, Pre-conditioning with LTD induction rescued LTP in neurabin KO mice (n = 9). The insets show averages of six EPSCs at baseline response (thick dark traces), 10 min (thin dark traces) after LTD induction (arrow) and 30 min (gray traces) after LTP induction (arrow). Right panel showing LTP in both wild-type (n = 5) and neurabin KO mice after preconditioning with LTD induction. The dashed lines indicate the mean basal synaptic response.

Mentions: At least two mechanisms may underlie the loss of LTP observed in neurabin KO mice. First, the reduced phosphorylation of GluR1p845 in the neurabin KO may affect activity-dependent AMPA receptor contribution to LTP. Second, the synaptic responses may be saturated and simply could not undergo activity-dependent potentiation. To test the first idea, we examined whether forskolin, an adenylyl cyclase activator, could rescue the loss of LTP by increasing PKA activities and therefore phosphorylation of GluR1 at Ser845 site. Perfusion of forskolin (10 µM) for 10 minutes significantly increased AMPA EPSCs in hippocampal CA1 neurons in wild-type mice (180.9±20.6 % of control; n = 5, P<0.05, paired t-test) (Fig. S2). Similar increase was also observed in neurabin KO mice (168.5±21.5 % of control; n = 5, P>0.05 compared with wild-type mice, unpaired t-test). LTP induced by the pairing protocol was then studied in the presence of forskolin in both groups (Fig. 5A). We found that LTP could be observed in wild-type mice (135.9±10.0 % of baseline response, n = 7, P>0.05 compared with control LTP, unpaired t-test). However, LTP is still significantly impaired in the neurabin KO mice in the presence of forskolin (98.0±9.4 % of baseline response, n = 8, P<0.05 compared with wild-type, unpaired t-test) (Fig. 5A). Therefore, increasing cAMP-PKA activity could not rescue the loss of LTP in neurabin KO mice.


Neurabin contributes to hippocampal long-term potentiation and contextual fear memory.

Wu LJ, Ren M, Wang H, Kim SS, Cao X, Zhuo M - PLoS ONE (2008)

Rescue of LTP by preconditioning with LTD induction but not by forskolin treatment in neurabin KO mice.A, In the presence of forskolin (10 µM), LTP is induced in hippocampal CA1 neurons with pairing protocol in wild-type (n = 7) but not in neurabin KO mice (n = 8). The insets show averages of six EPSCs at baseline response and 30 min after LTP induction (arrow). Right panel shows the statistical result of LTP reduction in neurabin KO mice in the presence of forskolin. The dashed lines indicate the mean basal synaptic response. B, Pre-conditioning with LTD induction rescued LTP in neurabin KO mice (n = 9). The insets show averages of six EPSCs at baseline response (thick dark traces), 10 min (thin dark traces) after LTD induction (arrow) and 30 min (gray traces) after LTP induction (arrow). Right panel showing LTP in both wild-type (n = 5) and neurabin KO mice after preconditioning with LTD induction. The dashed lines indicate the mean basal synaptic response.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2169299&req=5

pone-0001407-g005: Rescue of LTP by preconditioning with LTD induction but not by forskolin treatment in neurabin KO mice.A, In the presence of forskolin (10 µM), LTP is induced in hippocampal CA1 neurons with pairing protocol in wild-type (n = 7) but not in neurabin KO mice (n = 8). The insets show averages of six EPSCs at baseline response and 30 min after LTP induction (arrow). Right panel shows the statistical result of LTP reduction in neurabin KO mice in the presence of forskolin. The dashed lines indicate the mean basal synaptic response. B, Pre-conditioning with LTD induction rescued LTP in neurabin KO mice (n = 9). The insets show averages of six EPSCs at baseline response (thick dark traces), 10 min (thin dark traces) after LTD induction (arrow) and 30 min (gray traces) after LTP induction (arrow). Right panel showing LTP in both wild-type (n = 5) and neurabin KO mice after preconditioning with LTD induction. The dashed lines indicate the mean basal synaptic response.
Mentions: At least two mechanisms may underlie the loss of LTP observed in neurabin KO mice. First, the reduced phosphorylation of GluR1p845 in the neurabin KO may affect activity-dependent AMPA receptor contribution to LTP. Second, the synaptic responses may be saturated and simply could not undergo activity-dependent potentiation. To test the first idea, we examined whether forskolin, an adenylyl cyclase activator, could rescue the loss of LTP by increasing PKA activities and therefore phosphorylation of GluR1 at Ser845 site. Perfusion of forskolin (10 µM) for 10 minutes significantly increased AMPA EPSCs in hippocampal CA1 neurons in wild-type mice (180.9±20.6 % of control; n = 5, P<0.05, paired t-test) (Fig. S2). Similar increase was also observed in neurabin KO mice (168.5±21.5 % of control; n = 5, P>0.05 compared with wild-type mice, unpaired t-test). LTP induced by the pairing protocol was then studied in the presence of forskolin in both groups (Fig. 5A). We found that LTP could be observed in wild-type mice (135.9±10.0 % of baseline response, n = 7, P>0.05 compared with control LTP, unpaired t-test). However, LTP is still significantly impaired in the neurabin KO mice in the presence of forskolin (98.0±9.4 % of baseline response, n = 8, P<0.05 compared with wild-type, unpaired t-test) (Fig. 5A). Therefore, increasing cAMP-PKA activity could not rescue the loss of LTP in neurabin KO mice.

Bottom Line: Highly enriched in the dendritic spine, neurabin is important for spine morphogenesis and synaptic formation.However, less is known about the role of neurabin in hippocampal plasticity and its possible effect on behavioral functions.Our results indicate that neurabin regulates contextual fear memory and LTP in hippocampal CA1 pyramidal neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of Toronto, Toronto, Onatrio, Canada.

ABSTRACT
Neurabin is a scaffolding protein that interacts with actin and protein phosphatase-1. Highly enriched in the dendritic spine, neurabin is important for spine morphogenesis and synaptic formation. However, less is known about the role of neurabin in hippocampal plasticity and its possible effect on behavioral functions. Using neurabin knockout (KO) mice, here we studied the function of neurabin in hippocampal synaptic transmission, plasticity and behavioral memory. We demonstrated that neurabin KO mice showed a deficit in contextual fear memory but not auditory fear memory. Whole-cell patch clamp recordings in the hippocampal CA1 neurons showed that long-term potentiation (LTP) was significantly reduced, whereas long-term depression (LTD) was unaltered in neurabin KO mice. Moreover, increased AMPA receptor but not NMDA receptor-mediated synaptic transmission was found in neurabin KO mice, and is accompanied by decreased phosphorylation of GluR1 at the PKA site (Ser845) but no change at the CaMKII/PKC site (Ser831). Pre-conditioning with LTD induction rescued the following LTP in neurabin KO mice, suggesting the loss of LTP may be due to the saturated synaptic transmission. Our results indicate that neurabin regulates contextual fear memory and LTP in hippocampal CA1 pyramidal neurons.

Show MeSH
Related in: MedlinePlus