Cell-intrinsic mechanisms underlying spontaneous activity in the mouse visual cortical slice: implications for...

In the Fmr1-knockout (KO) mouse model of fragile X syndrome (FXS), visual cortical slices exhibit enhanced persistent spiking following electrical stimulation in layer 5 (L5) when bathed with artificial cerebral spinal fluid (aCSF) emulating the ionic concentrations measured in vivo. This phenotype is of particular interest because it responds to several treatments that have been shown to correct a wide array of other disease phenotypes. However, the underlying mechanisms and physiological relevance of this hyperactivity phenotype are unknown in large part because of our incomplete understanding of the persistent spiking activity itself. In recordings from wild-type visual cortical slices, we find that extratelencephalic (ET) (but not intratelencephalic) L5 pyramidal neurons (PNs) are spontaneously active in physiological aCSF during pharmacological inhibition of ionotropic synaptic transmission. We show that this activity depends upon aCSF composition. Physiological divalent cation concentrations profoundly enhance the intrinsic excitability of ET L5 PNs in large part by altering the voltage dependence of the persistent sodium current (I_NaP). As a result, many ET PNs exhibit spontaneous, I_NaP-mediated activity. We show that the excitability and spontaneous activity of Fmr1-KO ET PNs are unchanged relative to WTs, indicating that the unstimulated Fmr1-KO L5 circuit is not spontaneously hyperactive in the absence of external input.NEW & NOTEWORTHY As extracellular divalent cation concentrations are reduced, neocortical slices become spontaneously active. Here, we show that these conditions enhance persistent sodium currents, driving intrinsically generated activity in a subclass of layer 5 neurons. This spontaneous activity is no different in Fmr1-knockout mice, however, pointing toward a crucial role for external input in eliciting a well-studied form of hyperactivity in Fmr1-knockout visual cortex.