Fig. 5.

Free intracellular Ca²⁺ and Ca²⁺-dependent signaling in Myk/⁺ mice. (A) Mean resting intracellular ([Ca²⁺]_i) is stably elevated in cortical cells cultured from Myk/⁺ (n = 47) than +/+ mice (n = 19), as measured by the ratio of fura-2 fluorescence emission upon 340-nm and 380-nm excitation (P < 0.01). (B) Myk/⁺ cortical neurons show a prolonged peak in [Ca²⁺]_i compared with +/+ in response to bath superfusion of 10 μM glutamate (Glu). (C) When normalized to baseline [Ca²⁺]_i, glutamate-evoked [Ca²⁺]_i transients were prolonged in neurons from Myk/⁺ compared with neurons from +/+ (D) Immunoreactivity of p-Akt1/2/3 and p-ERK1/2 was elevated in Myk/⁺ compared with +/+ hippocampus. Transgenic overexpression of NKA α3 in Myk/⁺/Tg mice did not alter hippocampal levels of p-ERK1/2 but reduced p-Akt1/2/3. +/+, n = 8 (Akt, ERK); Myk/+, n = 11 (Akt), n = 10 (ERK); Myk/+/Tg, n = 5 (Akt, ERK). (E) Model of NKA α3 signaling at the synapse in +/+ and Myk/⁺ mice. Myk/⁺ mice have reduced NKA activity that augments [Ca²⁺]_i and activation of p-ERK and p-Akt. These intracellular signals may independently, additively or synergistically contribute to behavioral phenotypes of mania. All data are presented as means ± SEM, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 compared with +/+ mice, ⁺⁺P < 0.01 compared with Myk/⁺/Tg mice.