¹National Center of Neurology and Psychiatry, National Center of Neurology and Psychiatry, Tokyo, Japan, ²Harvard Medical School/VA Boston Healthcare Systeme, Psychiatry, West Roxbury, United States

Background: Schizophrenic (Sz) patients exhibit deficits in sensory gating and a reduction in waxing and waning 8-15 Hz cortical oscillations occurring during non-REM (NREM) sleep, so-called sleep spindles. Sleep spindles are thought to be generated by the GABAergic neurons of the thalamic reticular nucleus (TRN), most of which contain the calcium-binding protein, parvalbumin (PV). In addition, TRN is also considered to play a critical role in sensory information processing. The expression of the GABA synthetic enzyme, glutamate decarboxylase 67 (GAD67), is decreased in cortical PV GABAergic neurons of Sz brains examined postmortem. Thus, one possible explanation for the spindle deficit in Sz is a parallel reduction of GAD67 levels in TRN neurons.

Aims & Objectives: Thus, here we selectively deleted GAD67 in the TRN and tested the effect on sleep spindles and sensory gating.

Method: We reduced GAD67 levels in TRN neurons by injecting an adeno-associated virus (AAV) constitutively expressing a Cre recombinase-Green fluorescence protein (GFP) fusion protein (AAV-CreGFP) into TRN (AP -0.6; ML ±1.45; DV -3.25) of heterozygous GAD67 floxed mice. The time course of reduction in GAD67 after viral injection was evaluated by immunohistochemistry. EEG activity from frontal cortex AP 1.5, ML 1.0 and nuchal muscle EMG were recorded and sleep-wake states were analyzed in 4 s epochs. A custom-designed script (Matlab) was used to detect individual spindles (10-15Hz) during NREM sleep.

Results: TRN-GAD67 heterozygous mice exhibit reduced spindle density and abnormal prepulse inhibition.

Discussion & Conclusions: Our results suggest GAD67 floxed mice are a useful tool to test whether reduced levels of GAD67 levels in TRN results in decreased spindle density and prepulse inhibition, similar to the findings observed in schizophrenia patients. Furthermore, such a model may be useful in the future for dissecting out the molecular and cellular mechanisms underlying the schizophrenia pathophysiology.