Spinal reflexes are mediated by synaptic connections between sensory afferents and motor neurons [1][2][3] . The organization of these circuits exhibits several levels of specificity. Only certain classes of proprioceptive sensory neurons make direct, monosynaptic, connections with motor neurons 4 . Those that do are bound by rules of motor pool specificity -they form strong connections with motor neurons supplying the same muscle, but avoid motor pools supplying antagonistic muscles 1,[5][6][7] . This pattern of connectivity is initially accurate and is maintained in the absence of activity 8 , implying that wiring specificity relies on the matching of recognition molecules on the surface of sensory and motor neurons. But determinants of fine synaptic specificity here, as in most regions of the central nervous system (CNS), have yet to be defined. To address the origins of synaptic specificity in these reflex circuits we have used molecular genetic methods to manipulate recognition proteins expressed by subsets of sensory and motor neurons. We show here that a recognition system involving expression of Sema3e by selected motor neuron pools, and its high-affinity receptor PlexinD1 by proprioceptive sensory neurons, is a critical determinant of synaptic specificity in sensory-motor circuits. Changing the profile of Sema3e-PlexinD1 signaling in sensory or motor neurons results in functional and anatomical rewiring of monosynaptic connections, but does not alter motor pool specificity. Our findings indicate that patterns of monosynaptic connectivity in this prototypic CNS circuit are constructed through a recognition program based on repellent signaling.Several observations led us to focus on the potential contribution of the class 3 semaphorin Sema3e and its receptors as mediators of sensory-motor synaptic specificity. Sema3e is expressed by a restricted set of brachial motor neurons and can serve as a bifunctional ligand, eliciting repellent responses through engagement of PlexinD1 and attractant responses through interactions with a Neuropilin-1/PlexinD1 receptor complex 9-12 . Moreover, Sema3e expression is lost, and the pattern of monosynaptic sensory-motor connections altered, in mice mutant for Pea3, an ETS transcription factor expressed by several brachial motor neuron pools 11, 13 . We analyzed the role of Sema3e and its receptors in two sensory-motor reflex arcs. In one reflex arc that supplies the triceps (Tri) forelimb muscle, motor neurons receive monosynaptic input from Tri sensory afferents 13 . But in a second, atypical, reflex arc that controls the cutaneous maximus (Cm) muscle, motor neurons fail to receive monosynaptic input from Cm afferents [13][14][15] . Cm motor neurons also lack monosynaptic input from Tri proprioceptive neurons, or from any other proprioceptive afferents, and conversely, Tri motor neurons lack monosynaptic input from Cm proprioceptive afferents 13 . The contrasting circuitry of these two reflex arcs permitted us to examine monosynaptic connectivity between proprioce...

In Huntington's disease (HD), whether transneuronal spreading of mutant huntingtin (mHTT) occurs and its contribution to non-cell autonomous damage in brain networks is largely unknown. We found mHTT spreading in three different neural network models: human neurons integrated in the neural network of organotypic brain slices of HD mouse model, an ex vivo corticostriatal slice model and the corticostriatal pathway in vivo. Transneuronal propagation of mHTT was blocked by two different botulinum neurotoxins, each known for specifically inactivating a single critical component of the synaptic vesicle fusion machinery. Moreover, healthy human neurons in HD mouse model brain slices displayed non-cell autonomous changes in morphological integrity that were more pronounced when these neurons bore mHTT aggregates. Altogether, our findings suggest that transneuronal propagation of mHTT might be an important and underestimated contributor to the pathophysiology of HD.

Chadman, K. K. et al. Minimal aberrant behavioral phenotypes of neuroligin-3 R451C knockin mice.

Motor circuits in the spinal cord integrate information from various sensory and descending pathways to control appropriate motor behavior. Recent work has revealed that target-derived retrograde signaling mechanisms act to influence sequential assembly of motor circuits through combinatorial action of genetic and experience-driven programs. These parallel activities imprint somatotopic information at the level of the spinal cord in precisely interconnected circuits and equip animals with motor circuits capable of reacting to changing demands throughout life.