Abstract
Human mutations of the Na+-activated K+ channel Slack (KCNT1) are associated with epilepsy and intellectual disability. Accordingly, Slack knockout mice (Slack−/−) exhibit cognitive flexibility deficits in distinct behavioral tasks. So far, however, the underlying causes as well as the role of Slack in hippocampus-dependent memory functions remain enigmatic. We now report that infant (P6–P14) Slack−/− lack both hippocampal LTD and LTP, likely due to impaired NMDA receptor (NMDAR) signaling. Postsynaptic GluN2B levels are reduced in infant Slack−/−, evidenced by lower amplitudes of NMDAR-meditated excitatory postsynaptic potentials. Low GluN2B affected NMDAR-mediated Ca2+-influx, rendering cultured hippocampal Slack−/−neurons highly insensitive to the GluN2B-specific inhibitor Ro 25-6981. Furthermore, dephosphorylation of the AMPA receptor (AMPAR) subunit GluA1 at S845, which is involved in AMPAR endocytosis during homeostatic and neuromodulator-regulated plasticity, is reduced after chemical LTD (cLTD) in infant Slack−/−. We additionally detect a lack of mGluR-induced LTD in infant Slack−/−, possibly caused by upregulation of the recycling endosome-associated small GTPase Rab4 which might accelerate AMPAR recycling from early endosomes. Interestingly, LTP and mGluR LTD, but not LTD and S845 dephosphorylation after cLTD are restored in adult Slack−/−. This together with normalized expression levels of GluN2B and Rab4 hints to developmental “restoration” of LTP expression despite Slack ablation, whereas in infant and adult brain, NMDAR-dependent LTD induction depends on this channel. Based on the present findings, NMDAR and vesicular transport might represent novel targets for the therapy of intellectual disability associated with Slack mutations. Consequently, careful modulation of hippocampal Slack activity should also improve learning abilities.
Highlights
Intellectual disability (ID) is a heterogeneous neurodevelopmental disorder affecting 1–3% of the population [1]
We could induce significant longterm depression (LTD) in hippocampi derived from infant Slack+/+ but not Slack−/− mice (Fig. 1A), which is in accordance with impaired reversal learning of adult Slack−/− in the previously performed Morris Water Maze (MWM) [5]
We could observe significant long-term potentiation (LTP) in infant Slack+/+, but surprisingly not in Slack−/− (Fig. 1B), suggesting that synaptic plasticity is more severely affected in infant than in adult Slack−/−
Summary
Intellectual disability (ID) is a heterogeneous neurodevelopmental disorder affecting 1–3% of the population [1]. It is characterized by reduced intellectual (IQ < 70) and adaptive. Slack is broadly expressed in brain [5, 12,13,14], spinal cord and peripheral sensory neurons [15,16,17]. Malfunctions in synaptic plasticity are thought to underlie ID [24] Both LTP and LTD have been most intensively studied in the hippocampus, a brain region involved in spatial and declarative learning and memory [26], where both mechanisms were shown to be impaired in different models of ID [27,28,29,30]. Very little is known about the role of Slack in hippocampal synaptic plasticity
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