Histamine originating from the BNST modulates corticostriatal synaptic transmission during early postnatal development

The neuromodulator histamine regulates key processes in many circuits of the adult and developing brain, including striatum. However, striatal innervation by histaminergic afferents is very sparse making the physiological sources of histamine unclear. Here sources of striatal histamine were investigated during early postnatal development and specifically during the second postnatal week in mice of either sex. Firstly, a combination of patch-clamp recording and optogenetic stimulation in brain slices demonstrates that during this period exogenously applied histamine modulates both the intrinsic properties of developing D 1 and D 2 striatal spiny projection neurons (SPNs) and synaptic transmission at afferents coming from the mPFC and visual cortex. Secondly, immunohistochemistry for histamine reveals a brain region adjacent to the caudal striatum densely innervated by histaminergic axons and corresponding to the oval nucleus of bed nucleus of stria terminalis (ovBNST). Thirdly, electrical stimulation of the ovBNST leads to significant and detectable levels of histamine in striatum, as assessed by fast scan cyclic voltammetry and fluorescent histamine sensors in brain slices as well as in vivo. Lastly, electrical stimulation of the ovBNST nucleus, at frequencies mimicking normal active histamine neurons, can release sufficient levels of histamine to modulate excitatory synaptic transmission from mPFC onto striatal SPNs through histamine H 3 receptors. Together, these results provide evidence for the existence of the ovBNST as an extrastriatal source of histamine during early brain development and postulates a new view of the modus operandi of histamine in that it can cross anatomical and functional boundaries and act as a paracrine neuromodulator. Significance statement The neuromodulator histamine is synthesized by neurons located in the tuberomammillary nucleus (TMN) of the hypothalamus and is released from their axons in many brain regions. There the histaminergic system regulates many key processes, and has been shown to be dysregulated in a variety of neurological and neurodevelopmental disorders. Key to understanding the physiological roles of histamine and to generate possible interventions when dysregulated is to know both the local sources of histamine and its mode of action. Using the striatum as an exemplar we provide here the first evidence that sources of histamine may lie outside of anatomical boundaries and that histamine can act as a paracrine neuromodulator during early brain development contrasting with many other neuromodulators.