Methamphetamine decreases calcium current density and alters paired-pulse facilitation of glutamate release in the mouse prefrontal cortex

B. GONZALEZ; J.A. MUÑIZ; C. RIVERO ECHETO; J. L. CADET; E. GARCIA-RILL; F. J. URBANO; V. BISAGNO

Washington

Congreso; Neuroscience 2014, SfN's 44rd annual meeting; 2014

SFN

Chronic use of methamphetamine (METH) leads to long-lasting cognitive dysfunction in humans and animal models. We have previously demonstrated that METH sub-chronic administration in mice induces deficits on visual memory retention 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 METH induced a reduction in ICa density in mPFC layer V pyramidal neurons both in vitro (bath-applied, 1 ?ÝM) and in mice treated repeatedly with METH (1 mg/Kg, daily for 7 days, evaluated after a 4-day withdraw period). Then, we analyzed CaMKII protein expression in mPFC tissue from single dose and repeated METH-treatment. We found that METH induced a decrease in pCaMKII /total CaMKII protein expression. We have also analyzed voltage-gated Ca2+ channels (Cav) mRNA expression and found that repeated METH caused a reduction in the 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. Glutamate receptor subunits mRNA expression AMPA Gria1 and Gria2 were increased in single dose and repeated METH-treated animals compared to controls, and no changes were observed 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, similarly to the robust reduction in voltage-gated Ca2+ currents density recorded from post-synaptic pyramidal neurons from METH treated animals. In addition, changes observed in high and low voltage calcium channel mRNA expression might represent compensatory changes generated by profound alterations induced by METH on calcium currents and glutamate transmission in the mPFC.