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Published on: March 23, 2011
Loss of intracellular FGF14 (iFGF14) increases excitability of mature hippocampal pyramidal neurons
Joseph L Ransdell1, Yarimar Carrasquillo2, Marie K Bosch2
1Cardiovascular Division, Departments of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Abstract:
Mutations in FGF14, which encodes intracellular fibroblast growth factor 14 (iFGF14), have been linked to spinocerebellar ataxia type 27 (SCA27), a multisystem disorder associated with deficits in motor coordination and cognitive function. Mice lacking iFGF14 (Fgf14-/-) display similar phenotypes, and we have previously shown that the deficits in motor coordination reflect reduced excitability of cerebellar Purkinje neurons, owing to a hyperpolarizing shift in the voltage-dependence of voltage-gated Na+ (Nav) current steady-state inactivation. Here, we present the results of experiments designed to test the hypothesis that loss of iFGF14 also attenuates the intrinsic excitability of mature hippocampal pyramidal neurons. Current-clamp recordings from CA1 pyramidal neurons in acute in vitro slices, however, revealed that evoked repetitive firing rates were higher in Fgf14-/- than in wild type (WT) cells. Also, in contrast with Purkinje neurons, voltage-clamp recordings demonstrated that the loss of iFGF14 did not affect the voltage dependence of steady-state inactivation of the Nav currents in CA1 pyramidal neurons. In addition, in contrast with results reported for neonatal (rat) hippocampal pyramidal neurons in dissociated cell culture, immunohistochemical experiments revealed that loss of iFGF14 does not disrupt the localization or alter the normalized distribution of α-Nav1.6 or α-ankyrin G labeling along the axon initial segments (AIS) of mature hippocampal CA1 neurons in situ. However, the integrated intensities of α-Nav1.6 labeling were significantly higher along the AIS of Fgf14-/-, compared with WT, adult hippocampal CA1 pyramidal neurons, consistent with the marked increase in the excitability of CA1 neurons with the loss of iFGF14.
Insights
Loss of intracellular fibroblast growth factor 14 (iFGF14) increases excitability in hippocampal neurons, unlike its effect on cerebellar neurons. This suggests iFGF14 plays distinct roles in different neuronal populations.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Mutations in FGF14 cause spinocerebellar ataxia type 27 (SCA27), a disorder affecting motor coordination and cognition.
- iFGF14 (intracellular fibroblast growth factor 14) deficiency in mice leads to motor coordination deficits.
- Previous studies linked these deficits to reduced excitability in cerebellar Purkinje neurons due to altered Nav current inactivation.
Purpose of the Study:
- To investigate the role of iFGF14 in the intrinsic excitability of mature hippocampal pyramidal neurons.
- To determine if iFGF14 deficiency affects Nav current properties in hippocampal neurons.
- To examine the impact of iFGF14 loss on Nav channel localization at the axon initial segment (AIS) of hippocampal neurons.
Main Methods:
- Whole-cell patch-clamp recordings (current-clamp and voltage-clamp) from CA1 pyramidal neurons in acute hippocampal slices.
- Immunohistochemistry to assess the localization and distribution of Nav1.6 and Ankyrin G at the AIS.
- Comparison of Fgf14-/- mice with wild-type (WT) littermates.
Main Results:
- Hippocampal CA1 pyramidal neurons from Fgf14-/- mice exhibited higher firing rates compared to WT.
- Loss of iFGF14 did not alter the voltage-dependence of steady-state inactivation of Nav currents in CA1 neurons.
- While Nav1.6 and Ankyrin G localization at the AIS was unaffected, Nav1.6 labeling intensity was significantly increased in Fgf14-/- neurons.
Conclusions:
- iFGF14 deficiency enhances the intrinsic excitability of mature hippocampal CA1 pyramidal neurons.
- The mechanism differs from that in Purkinje neurons, as Nav current inactivation is not affected.
- Increased Nav1.6 expression at the AIS may underlie the enhanced excitability in iFGF14-deficient hippocampal neurons, indicating cell-type-specific functions of iFGF14.
