Pre- and postsynaptic actions of baclofen: blockade of the late synaptically-evoked hyperpolarization of CA1 hippocampal neurones

Summary

Using intracellular recording techniques, the effects of β-p-chlorophenyl-GABA (baclofen) on passive membrane properties and postsynaptic potentials of CA1 pyramidal neurones were investigated. In experiments where only the hyperpolarizing action of baclofen was precluded by conventional current clamp techniques, 20 μM (±) baclofen blocked the early GABA-mediated IPSP and also a late hyperpolarization which, since it could be evoked by orthodromic stimulation subthreshold for spike firing, would not be expected to be produced by a Ca²⁺-activated increase in potassium conductance (AHP), but to be a transmitter-mediated event. In addition the conductance increase associated with this late IPSP evoked by subthreshold stimulation and also that associated with the AHP produced by spike activation were abolished. Baclofen also appeared to increase the duration of EPSPs, an event possibly related to loss of IPSPs. The hyperpolarization produced by baclofen was associated with an increased conductance of the resting membrane, an event possibly associated with an elevated potassium flux. To preclude this postsynaptic effect as a cause of reduced synaptic responses, tetraethylammonium chloride (TEA), a compound which decreases conductance and depolarizes the membrane of CA1 pyramidal neurones by a reduction of a ‘leak’ or resting potassium conductance (gK), was added to the bathing medium. A comparison of the effect of TEA on the hyperpolarizations with that of baclofen was undertaken since TEA also interferes with the increased gK evoked by Ca²⁺ inflow during spike activation. Whereas TEA reduced only an early phase of the postspike hyperpolarization possibly related to the AHP, baclofen abolished the remaining late IPSP. While loss of the AHP or IPSPs individually did not provoke additional spike activity, the abolition of both components promoted extra action potentials in response to synaptic excitation. Baclofen also increased the reduced conductance evoked by TEA towards control levels and caused membrane hyperpolarization. Thus baclofen is considered to evoke its postsynaptic effects through an increased membrane potassium conductance which TEA may also affect to reduce membrane conductance. The resultant uncontrolled hyperpolarization (even in the presence of TEA) occurring in inhibitory interneurones might contribute to the disinhibition recorded in this study.