Dissection of Subicular Microcircuitry

The dysregulation of dopamine involved in psychosis associated with drug addiction and schizophrenia is commonly thought to be due to hyperactivity of the ventral subiculum. Dysregulation of the dopamine system can be a result of synaptic changes in subicular excitatory output to the nucleus accumbens (e.g. changes in synapse numbers and/or changes in pre- and post-synaptic signaling) and/or alterations in the local microcircuit of the subiculum - changes in inhibitory synaptic input onto regular and burst spiking excitatory pyramidal cells. In support of the latter, evidence form clincal and pre-clinical studies found that inhibitory neurons are altered in schizophrenia and/or drug addiction. Despite mounting evidence that implicates the subicular microcircuit in mental health disorders, very little is known regarding the cell-type specific connectivity, synaptic transmission properties and molecular identities of inhibitory neurons in this brain region (Fig 1). Interestingly, classic in-situ hybridization experiments revealed that in the hippocampus, neurexin-3 (a gene associated with drug addiction and schizophrenia) is robustly expressed in inhibitory neurons. Moreover, through recent preliminary next-generation RNA-sequencing, we found that transcriptional variants of Nrxn3 are differentially regulated in the two classes of inhibitory perisomatic basket cells in the hippocampus. Basket cells provide robust inhibition onto principle neurons and play a dominant role in establishing the excitatory to inhibitory balance of a local circuit. We hypothesize that transcriptional variants of Nrxn3 play a cell-type specific function to enable inhibitory synaptic transmission at distinct synapses within the subicular microcircuit. We  endeavor to provide the first characterization of the microcircuit with cell-type and synapse resolution and will explore if the cell-type specific differential regulation of major Nrxn3 variants confers unique function (Fig. 2). To test our hypotheses, we will employ novel Nrxn3 conditional mutant mice, electrophysiology from synaptically connected basket cell – pyramidal neuron pairs and next-generation single-cell RNA-sequencing.

Adapted from Freund and Katona, 2007

Figure 1. Microciruitry of the subiculum. Cartoon schematic highlights the proposed interactions between perisomatic basket cells and pyramidal neurons in the subiculum. ? represent uncharacterized cell-type specific connectivity.

Figure courtesy of Csaba Földy

Figure 2. Example traces of electrophysiologically defined GABergic perisomatic basket cells from CA1. A. Intrinsic spiking of PV+ fast-spiking basket cells (left) and example of synaptically conntected paired-recording (right). B. Intrinsic spiking of CCK+ regular spiking basket cells (left) and example of synaptically connected paired-recording (right). Action potential (top) and resulting IPSC (bottom) for each cell type. Note: examples are from the CA1 microcircuit because the subicular microcircuit has is poorly understood.