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.
At a glance
- Corticostriatal connectivity and its role in disease. Nat. Rev. Neurosci. 14, 278–291 (2013).
- Antagonistic but not symmetric regulation of primary motor cortex by basal ganglia direct and indirect pathways. Neuron 86, 1174–1181 (2015). &
- Early postnatal development of the monkey neostriatum: a Golgi and ultrastructural study. J. Comp. Neurol. 190, 303–331 (1980). , &
- Postnatal development of identified medium-sized caudate spiny neurons in the cat. Brain Res. 389, 47–62 (1986). , , &
- Postnatal development of the rat neostriatum: electrophysiological, light- and electron-microscopic studies. Dev. Neurosci. 20, 125–145 (1998). , , &
- Corrigendum: Recurrent network activity drives striatal synaptogenesis. Nature 489, 326–326 (2012). , , , &
- Caudate nucleus is enlarged in high-functioning medication-naive subjects with autism. Biol. Psychiatry 62, 262–266 (2007). , , , &
- Repetitive and self-injurious behaviors: associations with caudate volume in autism and fragile X syndrome. J. Neurodev. Disord. 5, 12 (2013). , , , &
- Changes in the developmental trajectories of striatum in autism. Biol. Psychiatry 66, 327–333 (2009). et al.
- Changes in the development of striatum are involved in repetitive behavior in autism. Biol. Psychiatry 76, 405–411 (2014). et al.
- Autism spectrum disorders. Neuron 28, 355–363 (2000). , , &
- Changing views of basal ganglia circuits and circuit disorders. Clin. EEG Neurosci. 41, 61–67 (2010). &
- Advances in autism genetics: on the threshold of a new neurobiology. Nat. Rev. Genet. 9, 341–355 (2008). &
- Modeling autism by SHANK gene mutations in mice. Neuron 78, 8–27 (2013). &
- Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat. Genet. 39, 25–27 (2007). et al.
- Novel de novo SHANK3 mutation in autistic patients. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 150B, 421–424 (2009). et al.
- Shank expression is sufficient to induce functional dendritic spine synapses in aspiny neurons. J. Neurosci. 25, 3560–3570 (2005). et al.
- Autism-associated mutations in ProSAP2/Shank3 impair synaptic transmission and neurexin-neuroligin-mediated transsynaptic signaling. J. Neurosci. 32, 14966–14978 (2012). et al.
- SHANK3 overexpression causes manic-like behavior with unique pharmacogenetic properties. Nature 503, 72–77 (2013). et al.
- Importance of Shank3 protein in regulating metabotropic glutamate receptor 5 (mGluR5) expression and signaling at synapses. J. Biol. Chem. 286, 34839–34850 (2011). et al.
- Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction and social communication. Mol. Autism 1, 15 (2010). et al.
- Reduced excitatory neurotransmission and mild autism-relevant phenotypes in adolescent Shank3 null mutant mice. J. Neurosci. 32, 6525–6541 (2012). et al.
- Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472, 437–442 (2011). et al.
- Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum. Mol. Genet. 20, 3093–3108 (2011). et al.
- Anatomical characterization of Cre driver mice for neural circuit mapping and manipulation. Front. Neural Circuits 8, 76 (2014). et al.
- Selective acquisition of AMPA receptors over postnatal development suggests a molecular basis for silent synapses. Nat. Neurosci. 2, 31–36 (1999). et al.
- Developmental presence and disappearance of postsynaptically silent synapses on dendritic spines of rat layer 2/3 pyramidal neurons. J. Physiol. (Lond.) 586, 1519–1527 (2008). , &
- Early motor activity drives spindle bursts in the developing somatosensory cortex. Nature 432, 758–761 (2004). et al.
- Timing and location of synaptic inputs determine modes of subthreshold integration in striatal medium spiny neurons. J. Neurosci. 27, 8967–8977 (2007). , &
- Decreased probability of neurotransmitter release underlies striatal long-term depression and postnatal development of corticostriatal synapses. Proc. Natl. Acad. Sci. USA 94, 2665–2670 (1997). &
- Ion channel development, spontaneous activity, and activity-dependent development in nerve and muscle cells. Physiol. Rev. 85, 883–941 (2005). &
- Neuromodulation of excitatory synaptogenesis in striatal development. eLife 4, e10111 (2015). et al.
- Anatomic and molecular development of corticostriatal projection neurons in mice. Cereb. Cortex 24, 293–303 (2014). , , , &
- A conserved switch in sensory processing prepares developing neocortex for vision. Neuron 67, 480–498 (2010). et al.
- Electrical activity patterns and the functional maturation of the neocortex. Eur. J. Neurosci. 34, 1677–1686 (2011). , &
- Postnatal development of intrinsic and synaptic properties transforms signaling in the layer 5 excitatory neural network of the visual cortex. J. Neurosci. 31, 9526–9537 (2011). &
- Dichotomous anatomical properties of adult striatal medium spiny neurons. J. Neurosci. 28, 10814–10824 (2008). , &
- A role for correlated spontaneous activity in the assembly of neural circuits. Neuron 80, 1129–1144 (2013). , , &
- Concerted action of zinc and ProSAP/Shank in synaptogenesis and synapse maturation. EMBO J. 30, 569–581 (2011). et al.
- Sensory integration in mouse insular cortex reflects GABA circuit maturation. Neuron 83, 894–905 (2014). , , , &
- The non-human primate striatum undergoes marked prolonged remodeling during postnatal development. Front. Cell. Neurosci. 8, 294 (2014). &
- Magnetoencephalographic patterns of epileptiform activity in children with regressive autism spectrum disorders. Pediatrics 104, 405–418 (1999). et al.
- Circuit level defects in the developing neocortex of Fragile X mice. Nat. Neurosci. 16, 903–909 (2013). , , &
- Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis. Neuron 78, 510–522 (2013). et al.
- Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 147, 235–246 (2011). et al.
- Autistic-like behaviour in Scn1a+/− mice and rescue by enhanced GABA-mediated neurotransmission. Nature 489, 385–390 (2012). et al.
- Longitudinal patterns of repetitive behavior in toddlers with autism. J. Child Psychol. Psychiatry 55, 945–953 (2014). et al.
- Motor stereotypies in children with autism and other developmental disorders. Dev. Med. Child Neurol. 51, 30–38 (2009). et al.
- Stereotypies in autism: a video demonstration of their clinical variability. Front. Integr. Neurosci. 6, 121 (2012). &
- Nonautistic motor stereotypies: clinical features and longitudinal follow-up. Pediatr. Neurol. 38, 267–272 (2008). , &
- Bursts and recurrences of bursts in the spike trains of spontaneously active striate cortex neurons. J. Neurophysiol. 53, 926–939 (1985). &
- Supplementary Figure 1: Correlated oEPSC peak amplitude recorded at Vh=−70 and −20 mV. (39 KB)
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. (81 KB)
(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. (44 KB)
(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. (73 KB)
(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. (80 KB)
(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. (63 KB)
(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. (53 KB)
(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).