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

The neuromodulator histamine regulates key processes in many regions of both the adult and developing brain including the striatum. However, striatal innervation by histaminergic afferents is very sparse making the physiological sources of histamine controversial. Here potential sources of striatal histamine were investigated during early postnatal development and specifically in the second postnatal week, in acute mouse brain slices. Firstly, a combination of whole-cell patch-clamp recordings and optogenetic stimulation demonstrates that during this period exogenously applied histamine modulates the intrinsic properties of developing D1 and D2 striatal spiny projection neurons (SPNs) as well as synaptic transmission at afferents coming from the mPFC and visual cortex. Secondly, immunohistochemistry for histamine reveals a brain region proximal and caudal to striatum densely innervated by histaminergic axons and corresponding to the oval nucleus of the bed nucleus of stria terminalis (ovBNST). Thirdly, direct electrical stimulation of the ovBNST leads to significant and detectable levels of histamine in the striatum, as assessed by both fast scan cyclic voltammetry and fluorescent histamine sensors. Lastly, electrical stimulation of the ovBNST nucleus, at frequencies mimicking active histaminergic neurons, can release sufficient levels of histamine to modulate excitatory synaptic transmission from mPFC onto striatal SPNs by acting at histamine H3 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 boundaries and act as a paracrine neuromodulator. Significance statementHistamine is synthesized by neurons in the hypothalamic tuberomammillary nucleus (TMN) and released from their axons in many brain regions controlling key physiological processes. When dysregulated this can result in neurological and neurodevelopmental disorders such as Tourettes syndrome and OCD. To understand the physiological roles for histamine and to facilitate the generation of new therapeutic interventions it is key to define the sources of histamine and its mode of action. Here we provide evidence, using the developing striatum as an exemplar, that sources of histamine can lie beyond anatomical boundaries with histamine acting as a paracrine neuromodulator. This also has potential implications for our mechanistic understanding of deep brain stimulation of the BNST in treating severe Tourettes syndrome and OCD.