Altered excitability and glutamatergic synaptic transmission in the medium spiny neurons of the nucleus accumbens in mice deficient in the heparan sulfate endosulfatase Sulf1

Sulf1 is an extracellular sulfatase that regulates cell signaling by removing 6- O -sulfates from heparan sulfate. Although the roles of Sulf1 in neural development have been studied extensively, its functions in the adult brain remain largely unknown. Here, we report the effects of Sulf1 disruption on the neuronal properties of the medium spiny neurons (MSNs) in the nucleus accumbens (NAc) shell, one of the regions highly expressing Sulf1 . We separately labeled MSNs expressing dopamine D1 receptors (D1-MSNs) or D2 receptors (D2-MSNs) by injecting adult male Drd1-Cre and Drd2-Cre mice with a Cre-dependent AAV vector expressing a red fluorescent protein, mCherry, and examined their electrophysiological properties by means of whole-cell patch-clamp recording. In the D2-MSNs, Sulf1 disruption led to drastic changes in neural firing responses to depolarizing current injections: in the Sulf1 knockout mice, the rheobase was smaller than in the wild-type mice, but the number of action potentials elicited by depolarization did not increase at larger current injections. In the D1-MSNs, Sulf1 disruption resulted in more depolarized resting membrane potentials and increase in the AMPA/NMDA ratio. These results suggest that Sulf1 is essential for regulation of neuronal excitability and glutamatergic transmission of NAc MSNs in adult mice and implicate the potential roles of Sulf1 in NAc circuit activity, reward-aversion behaviors, and psychiatric disorders such as schizophrenia and drug addiction. Significance Statement Heparan sulfate plays critical roles in neural differentiation, axon guidance, synaptogenesis, and neurotransmission. Sulf1 is an extracellular sulfatase that removes 6- O -sulfate from heparan sulfate, thereby regulating various cellular functions. Although its roles during development have been studied extensively, its functions in the adult brain remain largely unknown. Here, we examined the electrophysiological properties of medium spiny neurons in the nucleus accumbens shell of adult mice by means of whole-cell patch-clamp recording. We found that Sulf1 disruption led to changes in neuronal excitability and glutamatergic transmission in medium spiny neurons. This study demonstrates the roles of the Sulf1 gene in neuronal activities at the cellular level, providing an important clue toward understanding the functions of Sulf1 in the adult brain.