Chemogenetic activation of CRF neurons as a model of chronic stress produces sex-specific physiological and behavioral effects.

Trauma and chronic stress exposure are the strongest predictors of lifetime neuropsychiatric disease presentation. These disorders often have significant sex biases, with females having higher incidences of affective disorders such as major depression, anxiety, and PTSD. Understanding the mechanisms by which stress exposure heightens disease vulnerability is essential for developing novel interventions.

Parvalbumin subtypes of cerebellar Purkinje cells contribute to differential intrinsic firing properties.

Purkinje cells (PCs) are central to cerebellar information coding and appreciation for the diversity of their firing patterns and molecular profiles is growing. Heterogeneous subpopulations of PCs have been identified that display differences in intrinsic firing properties without clear mechanistic insight into what underlies the divergence in firing parameters. Although long used as a general PC marker, we report that the calcium binding protein parvalbumin labels a subpopulation of PCs, based on high and low expression, with a conserved distribution pattern across the animals examined.

Regulation of Neural Circuit Development by Cadherin-11 Provides Implications for Autism.

Autism spectrum disorder (ASD) is a neurologic condition characterized by alterations in social interaction and communication, and restricted and/or repetitive behaviors. The classical Type II cadherins cadherin-8 (Cdh8, CDH8) and cadherin-11 (Cdh11, CDH11) have been implicated as autism risk gene candidates. To explore the role of cadherins in the etiology of autism, we investigated their expression patterns during mouse brain development and in autism-specific human tissue.

Dynamic Recovery from Depression Enables Rate Encoding in Inhibitory Synapses.

Parvalbumin-expressing fast-spiking interneurons (PV-INs) control network firing and the gain of cortical response to sensory stimulation. Crucial for these functions, PV-INs can sustain high-frequency firing with no accommodation. However, PV-INs also exhibit short-term depression (STD) during sustained activation, largely due to the depletion of synaptic resources (vesicles).

Tomosyn regulates the small RhoA GTPase to control the dendritic stability of neurons and the surface expression of AMPA receptors.

Tomosyn, a protein encoded by syntaxin-1-binding protein 5 (STXBP5) gene, has a well-established presynaptic role in the inhibition of neurotransmitter release and the reduction of synaptic transmission by its canonical interaction with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor machinery. However, the postsynaptic role of tomosyn in dendritic arborization, spine stability, and trafficking of ionotropic glutamate receptors remains to be elucidated. We used short hairpin RNA to knock down tomosyn in mouse primary neurons to evaluate the postsynaptic cellular function and molecular signaling regulated by tomosyn.

Developmental Disruption of GABAR-Meditated Inhibition in Cntnap2 KO Mice.

GABA released from presynaptic sites induces short-lived phasic inhibition mediated by synaptic GABA receptors (GABARs) and longer-duration tonic inhibition mediated by extrasynaptic GABA or GABA receptors (GABARs). A number of studies have found that contactin-associated protein 2 (Cntnap2) knockout (KO) mice, a well-established mouse model of autism, exhibit reduced interneuron numbers and aberrant phasic inhibition. However, little is known about whether tonic inhibition is disrupted in Cntnap2 KO mice and when the disruption of inhibition begins to occur during postnatal development.

Pharmacological Activators of the NR4A Nuclear Receptors Enhance LTP in a CREB/CBP-Dependent Manner.

Nr4a nuclear receptors contribute to long-term memory formation and are required for long-term memory enhancement by a class of broad-acting drugs known as histone deacetylase (HDAC) inhibitors. Understanding the molecular mechanisms that regulate these genes and identifying ways to increase their activity may provide novel therapeutic approaches for ameliorating cognitive dysfunction. In the present study, we find that Nr4a gene expression after learning requires the cAMP-response element binding (CREB) interaction domain of the histone acetyltransferase CREB-binding protein (CBP).

The NR4A orphan nuclear receptors mediate transcription-dependent hippocampal synaptic plasticity.

Memory consolidation and long-term potentiation require activity-dependent gene transcription, coordinated by an array of transcription factors. Many members of the nuclear receptor superfamily of transcription factors are expressed in the hippocampus immediately after learning, including the Nr4a family of orphan receptors. These activity-dependent transcription factors are critical for hippocampus-dependent contextual fear and object recognition memory, but their role in hippocampal synaptic function is unknown.