| Popis: |
Postsynaptic Density Protein-95 (PSD-95) is a major scaffolding protein in the excitatory postsynaptic density and regulator of synaptic maturation by interacting and recruiting N-methyl-D-aspartic acid (NMDA) and [alpha]- amino-3-hydroxy-5-methyl-4-isox-azolpropionic acid (AMPA) receptors. PSD-95 deficiency has been linked to cognitive and learning deficits implicated in neurodevelopmental disorders such as autism and schizophrenia. In previous studies shown within the hippocampus, PSD-95 deficiency causes a significant reduction in the excitatory response at the postsynaptic membrane. However, little is known whether PSD-95 deficiency will affect gamma-aminobutyric acid (GABA)ergic inhibitory synapses in the medial prefrontal cortex (mPFC). Using a PSD-95 transgenic mouse model (PSD-95 +/-), we study how PSD-95 deficiency affects GABAA receptor expression and function in the mPFC of adolescent mice. Using Western blot, we show a significant decrease in protein expression levels of PSD-95 in the PSD-95 +/- mouse, confirming sufficient reduction of the protein. Our results also show a significant increase in the GABAA receptor subunit [alpha]1 and a trending increase in the subunits [alpha]2. We utilized whole-cell patch clamp to record spontaneous inhibitory postsynaptic currents (sIPSCs) as a measure of GABA-mediated current in layer 5 pyramidal neurons of the mPFC. We found significant increases in sIPSC frequency and amplitude in PSD-95+/- mice. In addition, we show a decrease of evoked excitatory postsynaptic currents (eEPSCs) and a significant increase in evoked IPSCs (eIPSCs), leading to a significant decrease in the excitatory-to-inhibitory balance in PSD-95+/- mice. Our study suggests that PSD-95 deficiency causes an increase in the inhibitory response in the mPFC due to an increase in GABA receptor presence and function, consequently leading to a shift in the excitatory/inhibitory balance. This study will provide novel insights into the importance of GABAergic transmission in the mPFC in response to PSD-95 deficiency and its potential link with cognitive and learning deficits associated with autism and schizophrenia. |
