151.02/AA15 - "Methamphetamine decreases calcium current density and alters paired-pulse facilitation of glutamate release in the mouse prefrontal cortex.?

GONZALEZ B; MUÑIZ JA; RIVERO-ECHETO C; CADET JL; GARCIA-RILL E; URBANO FJ; BISAGNO V

Washington, DC

Congreso; 2014 SOCIETY FOR NEUROSCIENCE MEETING, Washington D.C., Nov. 15-19.; 2014

Society for Neuroscience

Chronic use of methamphetamine (METH) leads to long-lasting cognitive dysfunction in humans and animal models. We previously demonstrated that sub-chronic administration of METH in mice induces deficits in visual memory through a mechanism that involves blunted novelty-induced ERK signaling in the medial prefrontal cortex (mPFC). In the present study, we evaluated different components of mPFC circuitry by analyzing total Ca2+ current density and glutamate synaptic transmission using electrophysiological (whole-cell patch clamp in slices) and molecular (western blot and qPCR) techniques in METH-treated and control mice. We found that there was METH-induced a reduction in ICa density in mPFC layer V pyramidal neurons in vitro (bath-applied, 1 μM). Similar observations were observed in mice treated repeatedly with METH (1 mg/Kg, daily for 7 days, evaluated after a 4-day withdrawal). Then, we analyzed the expression of CaMKII protein in mPFC tissue from single dose and repeated METH-treatment. These METH treatments caused decreased pCaMKII /total CaMKII protein expression. Further analyses showed that repeated METH caused a reduction in low voltage T type Cacna1g (Cav3.1) and Cacna1i (Cav3.3) subunits, concomitant with increases in Cacna1h (Cav3.2) and high voltage P/Q type Cacna1a (Cav2.1). Moreover, repeated METH also induced paired-pulse facilitation of glutamate release compared to controls, suggesting reduced presynaptic probability of glutamate release onto layer V pyramidal mPFC neurons. The mRNA expression of glutamate receptor subunits, AMPA Gria1 and Gria2, were increased in single dose and repeated METH-treated animals compared to controls but there were no changes in NMDA subunits, Grin1 and Grin2A. Our results suggest that METH-induced changes might be mediated by a reduction in presynaptic Ca2+ current density at glutamatergic terminals, in a fashion similar to the robust reduction in voltage-gated Ca2+ current density recorded from post-synaptic pyramidal neurons in METH-treated animals. In addition, changes observed in high and low voltage calcium channel and glutamate receptor mRNA expression might represent compensatory changes generated by profound alterations produced by METH on calcium currents and glutamate transmission in the mPFC.