Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia

In the prefrontal cortex of subjects with schizophrenia, markers of the synthesis and re-uptake of GABA appear to be selectively altered in a subset of interneurons that includes chandelier cells. Determining the effect of these disturbances in presynaptic GABA markers on inhibitory signaling requires knowledge of the status of GABA(A) receptors at the postsynaptic targets of chandelier cells, the axon initial segments (AIS) of pyramidal neurons. Because the alpha(2) subunit of the GABA(A) receptor is preferentially localized at pyramidal neuron AIS, we quantified alpha(2) subunit immunoreactive AIS in tissue sections containing prefrontal cortex area 46 from 14 matched triads of subjects with schizophrenia, subjects with major depression and control subjects. Systematic, random sampling revealed that the mean number of alpha(2)-labeled AIS per mm(2) in subjects with schizophrenia was significantly (P = 0.007) increased by 113% compared to control subjects and non-significantly increased compared to subjects with major depression. Furthermore, within subjects with schizophrenia, the density of alpha(2)-labeled AIS was negatively correlated (r = -0.49, P = 0.038) with the density of chandelier axon terminals immunoreactive for the GABA membrane transporter. These data suggest that GABA(A) receptors are up-regulated at pyramidal neuron AIS in response to deficient GABA neuro-transmission at chandelier axon terminals in schizophrenia. Thus, disturbances in inhibition at the chandelier neuron-pyramidal neuron synapse may be a critical component of prefrontal cortical dysfunction in schizophrenia.