Effects of GAD Deletions in Knockout Mice

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Mice lacking GAD67 die shortly after birth, presumably as a result of cleft palate. Their brains contain only 7% of the GABA concentration of control brains and about 20% of the GAD activity. Morphological

analyses of their brains reveal no major abnormalities, but no detailed anatomical or electrophysiological studies of embryonic structures from GAD67 knockouts have been reported.

Mice lacking GAD65 appear to develop normally but are abnormally sensitive to seizures, particularly in a mouse line that is genetically susceptible to insulin-dependent diabetes mellitus. Perhaps significantly, these mice exhibit both humoral and cellular immune responses to both GAD65 and GAD67.

Mice lacking GAD65 have a lowered capacity for depolarization-dependent GABA release in vivo. The GAD65 knockout mice also show impaired experience-dependent plasticity, as determined in monocular deprivation experiments. GAD65 may be selectively important in providing GABA to fill secretory vesicles and support exocytotic release of GABA. For example, GAD65 knockout mice cannot release normal amounts of GABA during and immediately after sustained stimulation of the retina or hippocampus. Moreover, in contrast to wild-type mice, these GAD65 knockout mice show no increase in the probability of GABA release after tetanic stimulation of the hippocampus. Although GAD67-synthesized GABA can evidently be packaged into release vesicles under conditions of low demand, GAD67 alone seems to be unable to support the high-efficiency reloading of GABA vesicles required for normal function during conditions of high demand.

Mice lacking both forms of GAD die at birth, presumably from cleft palate. Although these mice have no detectable GABA, there do not appear to be any gross histological abnormalities in their brains. Therefore, GABA's role as a developmental molecule may be redundant, at least in some respects.

GABA occurs in cultured hippocampal neurons as well as in cells transfected with the GABA transporter and in a pancreatic cell line. Evidence from knockout mice suggests that GAD67-synthesized GABA may not be effectively packaged into vesicles. Therefore, it either remains in the cytosol (where it is available for the GABA shunt) or crosses the plasma membrane via the GABA transporter.

Extrasynaptic GABA (either released via GAT or leaked from the synapse) could interact with extra-synaptic GABA receptors. Such diffuse GABA would cause inhibition diffuse with kinetics different from those at the synapse. Such inhibition would depend on the kinetics of GABA release, diffusion, reuptake, and degradation as well as on receptor composition.

Diffuse GABA could act in a paracrine manner on extrasynaptic GABAa receptors. Such receptors have been documented electrophysiologically in studies of GABA "spillover" in cerebellar synapses and microscopically by EM immunocytochemistry. The effect of such paracrine action would be to suppress neuronal firing in cells within damaged circuits. Sustained inhibition could allow the plastic remodeling of neural circuits, such as occurs during the retraining of the spinal cord. According to this view, paracrine GABA, synthesized primarily by GAD67, could serve a "reset" function, giving the cells of damaged but plastic circuits the time to recover from challenge or injury. Observed parallel increases in GAD67 and extracellular GABA in the hippocampus of kainate-treated rats are consistent with this view. Therefore, GAD67 may contribute to a relatively slow mode of paracrine function, whereas GAD65 may be mainly responsible for the synthesis of GABA that participates in rapid point-to-point signaling.

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