Aberrant behavioral sensitization by methamphetamine in junctophilin-deficient mice

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Junctophilins (JPs) form junctional membrane complexes (JMCs) by linking the endoplasmic/sarcoplasmic reticulum (ER/SR) to the plasma membrane.
• Aberrant JMC function is implicated in various neurological disorders.

Purpose of the Study:

• To investigate the role of junctophilins (JPs) in methamphetamine (METH)-induced behavioral sensitization and synaptic plasticity.
• To elucidate the molecular mechanisms underlying METH response in the corticostriatal circuits.

Main Methods:

• Generation and analysis of double-knockout mice lacking JP3 and JP4 (JP-DKO).
• Assessment of striatal glutamatergic population spikes (PS) and long-term potentiation/depression (LTP/LTD) following METH administration.
• Evaluation of calcineurin (CaN) and CaMKII activity, including autophosphorylation, via immunoblotting.
• Pharmacological inhibition of CaN and SK channels.

Main Results:

• JP-DKO mice exhibited impaired METH-induced behavioral sensitization and failed to convert LTD to LTP in the corticostriatal pathway.
• LTP impairment in JP-DKO mice was rescued by FK506 (CaN inhibitor) but not apamin (SK channel inhibitor).
• METH treatment increased CaMKII autophosphorylation in control mice but not in JP-DKO mice, correlating with impaired sensitization and elevated CaN activity.

Conclusions:

• Junctophilins JP3 and JP4 are crucial for normal METH-induced behavioral sensitization and synaptic plasticity.
• Altered calcineurin and CaMKII activity in the striatum of JP-DKO mice underlies the observed deficits in METH response.
• Targeting JP-mediated pathways may offer novel therapeutic strategies for substance use disorders.