Synaptic transmission is generally considered to fall into two categories- excitatory and inhibitory. In the hippocampus the major excitatory transmitter is glutamate, and the major inhibitory transmitter is GABA. Binding of an excitatory transmitter to its postsynaptic receptor leads to a depolarization of the postsynaptic cell, and binding of an inhibitory transmitter generally leads to a hyperpolarization of the postsynaptic cell. Currently the lab is using whole-cell voltage-clamp recording from guinea pig hippocampal slices to investigate a novel action of GABA: sometimes synaptic release of GABA leads to a depolarization of the postsynaptic cell. Our research has shown that the depolarizing action of GABA in adults is due to a bicarbonate (rather than Cl-) conductance. Currently the lab is investigating whether this conductance is mediated through a new GABA receptor-channel (Could there be a GABAD receptor-channel?). In addition, the physiological role of the GABA-mediated depolarization is being investigated. For example, certain hippocampal interneurons may be able to use synaptic GABA release to inhibit pyramidal cells while at the same time using GABA release to excite one another.
Figure 1. Intracellular chloride and bicarbonate ion concentrations can determine the polarity sequence of the biphasic giant GABA-mediated postsynaptic current (GPSC). The GPSC consists of the GABAA component (normally an outward current at potentials near rest) followed by the GABAD component (normally an inward current at potentials near rest.) Responses were recorded using whole-cell voltage-clamp from CA3 pyramidal cells in slices of guinea pig hippocampus in the presence of 4-aminopyridine with ionotropic glutamate receptors and the GABAB receptor blocked. GPSCs were evoked with a bipolar stimulating electrode placed in the hilus. For a detailed description of the methods see Perkins and Wong (1996).
A. GABA response recorded using a recording pipette solution which included 20 mM Cl- and 102 mM HCO3-. At this concentration of intracellular Cl-, the GABAA component of the GPSC is outward at this potential. On the other hand, the high concentration of intracellular bicarbonate ion accentuates the inwardness of the GABAD component of the GPSC. Holding potential was -48 mV.
B. GABA response recorded using a recording pipette solution which included 40 mM Cl- and 6 mM HCO3-. This high concentration of intracellular Cl- causes the GABAA component of the GPSC to be inward at this potential, and the low concentration of intracellular HCO3- causes the GABAD component of the GPSC to be outward at this potential. Holding potential was -40 mV.
Perkins, K. L., and Wong, R. K. S. (1996). Ionic basis of the postsynaptic depolarizing GABA response in hippocampal pyramidal cells. J. Neurophysiol. 76, 3886-3894.
Chen, Q. X., Perkins, K. L., Choi, D. W., and Wong, R. K. S. (1997). Secondary activation of a cation conductance is responsible for NMDA toxicity in acutely isolated hippocampal neurons. J. Neurosci. 17, 4032-4036.
Perkins, K. L. and Wong, R. K. S. (1997). The depolarizing GABA response. Can. J. Physiol. Pharmacol.75, 516-519.
Perkins, K. L. (1999). Cl- accumulation does not account for the depolarizing phase of the synaptic GABA response in hippocampal pyramidal cells. J. Neurophysiol. 82, 768-777.
Perkins, K. L. (2002). GABA application to hippocampal CA3 or CA1 stratum lacunosum-moleculare excites an interneuron network. J. Neurophysiol. 87, 1404-1414.
Kantrowitz, J. T., Francis, N. N., Salah, A., and Perkins, K. L. (2005). Synaptic depolarizing GABA response in adults is excitatory and proconvulsive when GABAB receptors are blocked. J. Neurophysiol. 93, 2656-2667.
Perkins, K.L. (2006). Cell-attached voltage-clamp and current-clamp recording and stimulation techniques in brain slices. J. Neurosci. Meth. 154, 1-18.
Salah, A. and Perkins, K.L. (2008). Effects of subtype-selective group I mGluR antagonists on synchronous activity induced by 4-aminopyridine/CGP 55845 in adult guinea pig hippocampal slices. Neuropharmacology 55, 47-54.
Salah, A. and Perkins, K.L. (2011). Persistent ictal-like activity in rat entorhinal/perirhinal cortex following washout of 4-aminopyridine. Epilepsy Research 94, 163 - 176.
Arranz AM, Perkins KL, Irie F, Lewis DP, Hrabe J, Xiao F, Itano N, Kimata K, Hrabetova S, and Yamaguchi Y. (2014). Hyaluronan Deficiency Due to Has3 Knock-out Causes Altered Neuronal Activity and Seizures via Reduction in Brain Extracellular Space. J. Neurosci. 34, 6164-6176.
Sally Dricks, Graduate Student