Abstract
Some autistic individuals exhibit abnormal development of the caudate nucleus and associative cortical areas, suggesting potential dysfunction of cortico-basal ganglia (BG) circuits. Using optogenetic and electrophysiological approaches in mice, we identified a narrow postnatal period that is characterized by extensive glutamatergic synaptogenesis in striatal spiny projection neurons (SPNs) and a concomitant increase in corticostriatal circuit activity. SPNs during early development have high intrinsic excitability and respond strongly to cortical afferents despite sparse excitatory inputs. As a result, striatum and corticostriatal connectivity are highly sensitive to acute and chronic changes in cortical activity, suggesting that early imbalances in cortical function alter BG development. Indeed, a mouse model of autism with deletions in Shank3 (Shank3B−/−) shows early cortical hyperactivity, which triggers increased SPN excitatory synapse and corticostriatal hyperconnectivity. These results indicate that there is a tight functional coupling between cortex and striatum during early postnatal development and suggest a potential common circuit dysfunction that is caused by cortical hyperactivity.
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Acknowledgements
We thank I. Oldenburg for help with in vivo recordings and analysis and J. Levasseur and R. Pemberton for mouse genotyping and colony management. We thank S. da Silva, C. Deister and the members of the Sabatini laboratory for helpful discussions and critical reading of the manuscript. R.T.P. was supported by the Alice and Joseph Brooks fellowship and the Nancy Lurie Marks clinical and research fellowship in autism. Y.K. was supported by the Leonard and Isabelle Goldenson Research Fellowship and the Nancy Lurie Marks Family Foundation. This work was supported by the National Institute of Neurological Disorders and Stroke (NS046579, to B.L.S.) and the Nancy Lurie Marks Foundation.
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R.T.P. and B.L.S. conceived the study and wrote the manuscript. R.T.P. carried out in vivo recordings and analyzed the data. R.T.P., W.W. and Y.K. carried out in vitro slice recordings and R.T.P. analyzed the data. D.M.C. performed the behavioral experiments and dendritic spine imaging and analysis.
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Supplementary Figure 1 Correlated oEPSC peak amplitude recorded at Vh=−70 and −20 mV.
Average oEPSC peak amplitude recorded in P14 SPNs of Rbp4-Cre;ChR2f/f mice at Vh=−70 and −20 mV. Note the linear relationship between oEPSCs recorded under the two conditions across a wide range of oEPSC amplitudes.
Supplementary Figure 2 Average cortical and striatal multi-unit responses to optogenetic stimulation of Rbp4-Cre;ChR2f/f mice.
(a) Peri-stimulus time histogram (5 ms bin) of APs fired by P10−11 (black) and P14−16 (red) cortical and (b) striatal units in response to extracranial optogenetic stimulation of Rbp4-Cre;ChR2f/f mice with 100 pulses of 473 nm light (blue rectangle). Shaded regions represent ± SEM. Arrows point to time bin with peak firing rate. Note the 5 ms shift in response latency of striatal units from P10−11 to P14−16.
Supplementary Figure 3 Similar presynaptic release properties in WT and Shank3B−/− SPNs across development.
(a) Example traces of eEPSCs evoked in SPNs of P14 WT and Shank3B−/− mice in response to paired electrical pulses (P1 and P2) with 50 ms ISI. (b) Mean ± SEM ratio of eEPSC amplitude in response to the paired stimulation pulses (P2/P1) in P14 and (c) P9 WT and Shank3B−/− SPNs.
Supplementary Figure 4 Increased Rbp4+ excitatory input onto Shank3B−/− SPNs during early development.
(a) Experimental diagram depicting whole cell recordings in P14 SPNs of dorsomedial striatum in acute brain slices of Shank3B−/−;Rbp4-Cre;ChR2-YFPf/wt mice and optogenetic fiber stimulation using whole field illumination (blue cone). Scale bar, 1 mm. (b) Representative traces of AMPAR oEPSCs recorded in SPNs of Shank3B+/− or Shank3B−/− mice under voltage clamp (Vh= -70 mV) in response to brief pulses of 473 nm laser light (blue rectangle). (c) Mean oEPSC peak amplitude ± SEM recorded in Shank3B+/− or Shank3B−/− SPNs. (d) Pair-wise comparison of average oEPSC amplitude in animals recorded in (c). Note that SPNs from Shank3B−/− animals have consistently larger oEPSC amplitude compared to SPNs from Shank3B+/− heterozygous littermates.
Supplementary Figure 5 Similar intrinsic excitability of WT and Shank3B−/− SPNs at P13−14.
(a) Mean ± SEM current-voltage (I-V) relationship in WT and KO SPNs. (b) Mean spike threshold potential (c) rheobase current (d) Vrest and (e) Current-firing rate (I-F) plot of WT and KO SPNs recorded at P13−14. Error bars represent ± SEM.
Supplementary Figure 6 Decreased locomotion of AAV-Cre injected vGATf/f mice.
(a) Heat map representing locomotion of vGATf/f mice (control) and vGATf/f littermates injected with AAV-Cre-EGFP (Cre) in an open chamber for 15 min. Color scale represents normalized time spent at each location. Scale bar, 10 cm. (b) Mean average velocity ± SEM of control and Cre injected vGATf/f animals. (c) Mean average time moving ± SEM of control and Cre injected vGATf/f animals. (d) Mean average total distance moved ± SEM of control and Cre injected vGATf/f animals.
Supplementary Figure 7 Similar PPR of eEPSC in SPNs of vGATf/f (control) and vGATf/f mice injected with AAV-Cre-EGFP.
(a) Example traces of eEPSCs evoked in SPNs of control and Cre-injected littermates in response to paired electrical pulses (P1 and P2) with 50 ms ISI. (b) Mean ± SEM ratio of eEPSC amplitude in response to the paired stimulation pulses (P2/P1).
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Peixoto, R., Wang, W., Croney, D. et al. Early hyperactivity and precocious maturation of corticostriatal circuits in Shank3B−/− mice. Nat Neurosci 19, 716–724 (2016). https://doi.org/10.1038/nn.4260
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DOI: https://doi.org/10.1038/nn.4260