SST Neurons: New Insights Into Neurocircuit Regulation

Somatostatin (SST) neurons play a key role in regulating neural circuits by modulating inhibitory signaling within the brain. These neurons influence sensory perception, cognition, and hormone secretion. Recent research has uncovered new insights into their molecular properties, distribution, and interactions with other neurotransmitter systems, shedding light on their broader significance in brain function.

Understanding SST neuron activity could have implications for neurological disorders where inhibitory balance is disrupted. Exploring their characteristics and roles in neurotransmission provides valuable information about how these cells contribute to neurocircuit regulation.

Distinguishing Molecular Characteristics

SST neurons are defined by their expression of the neuropeptide somatostatin, a 14- or 28-amino acid peptide that exerts inhibitory effects on target cells. These neurons primarily function through G-protein-coupled receptors (GPCRs), which mediate their influence on synaptic transmission and neuronal excitability. Their molecular identity is shaped by a distinct transcriptional profile, with genes such as Sst, Gad1, and Gad2 encoding somatostatin and glutamic acid decarboxylases, enzymes responsible for GABA synthesis. This co-expression of somatostatin and GABA underscores their role as inhibitory interneurons, particularly in cortical and subcortical circuits.

Beyond their neuropeptide and neurotransmitter expression, SST neurons exhibit unique ion channel compositions that regulate their excitability. High levels of Kv3-type potassium channels contribute to their characteristic firing patterns, allowing for sustained inhibitory control over local circuits. Additionally, T-type calcium channels influence burst firing and synaptic integration. These molecular features enable SST neurons to fine-tune inhibition in response to network activity, distinguishing them from other inhibitory interneuron subtypes such as parvalbumin-expressing (PV) or vasoactive intestinal peptide-expressing (VIP) neurons.

Epigenetic regulation also plays a role in defining SST neuron identity. DNA methylation and histone modifications influence Sst gene expression, affecting neuron differentiation and functional specialization. Single-cell RNA sequencing has revealed heterogeneity within SST neuron populations, with distinct subtypes exhibiting differential gene expression patterns based on their anatomical location and connectivity. For example, SST neurons in the somatosensory cortex show enriched expression of Tac1, a gene encoding substance P, whereas hippocampal SST neurons preferentially express Calb1, which encodes calbindin, a calcium-binding protein involved in buffering intracellular calcium levels.

Distribution in Neural Circuits

SST neurons are widely distributed across the central nervous system, with distinct localization patterns reflecting their diverse functional roles. In the cerebral cortex, they are particularly abundant in layers 2/3 and 5, where they regulate pyramidal neuron excitability through dendritic inhibition. This spatial arrangement enables SST neurons to shape cortical processing by selectively targeting apical dendrites of excitatory neurons, modulating synaptic integration and plasticity. Optogenetics and in vivo calcium imaging studies have demonstrated that SST neurons dynamically adjust their activity in response to sensory stimuli, contributing to feature-selective suppression and gain control mechanisms in sensory cortices.

In the hippocampus, SST neurons are primarily found in the stratum oriens and stratum radiatum. Often referred to as oriens-lacunosum moleculare (O-LM) interneurons, they exert a specialized inhibitory influence on the distal dendrites of CA1 pyramidal cells. This connectivity pattern plays a significant role in gating excitatory inputs from the entorhinal cortex, regulating information flow into the hippocampus. Electrophysiological studies show that hippocampal SST neurons exhibit theta-rhythmic firing, aligning their activity with oscillatory states that support memory encoding and retrieval. Their role in hippocampal inhibition has been highlighted in animal models of epilepsy, where deficits in SST neuron function are associated with hyperexcitability and seizure susceptibility.

In the basal ganglia, SST-expressing neurons form a subset of GABAergic interneurons in the striatum, modulating corticostriatal transmission. These neurons provide prolonged inhibition to medium spiny neurons, influencing motor control and reinforcement learning. Dysfunction of SST interneurons in the striatum has been implicated in movement disorders such as Huntington’s disease, where their selective degeneration contributes to dysregulated motor output. Similarly, in the amygdala, SST interneurons shape emotional processing by inhibiting excitatory circuits involved in fear and anxiety responses. Optogenetic studies reveal that activation of SST neurons in the basolateral amygdala suppresses fear expression, suggesting a role in adaptive threat responses.

Receptor Subtypes in Somatostatin Signaling

Somatostatin exerts its inhibitory effects through five distinct GPCRs: sst1–sst5. These receptors are differentially expressed across brain regions and neuronal populations, contributing to the diverse physiological roles of SST neurons. Each receptor subtype exhibits unique signaling properties, binding affinities, and regulatory mechanisms that influence neurotransmission, synaptic plasticity, and neuronal excitability.

sst1

The sst1 receptor (SSTR1) is expressed in the cerebral cortex, hippocampus, and thalamus, where it modulates synaptic inhibition and neuronal excitability. Functionally, SSTR1 is primarily coupled to Gi/o proteins, leading to the inhibition of adenylyl cyclase and a reduction in cyclic AMP (cAMP) levels. This signaling cascade dampens excitatory neurotransmission by decreasing calcium influx and neurotransmitter release. In the hippocampus, SSTR1 activation enhances long-term depression (LTD), a synaptic plasticity mechanism involved in learning and memory. Pharmacological studies suggest that selective SSTR1 agonists can suppress excessive excitatory activity, indicating potential therapeutic applications for epilepsy.

sst2

The sst2 receptor (SSTR2) is one of the most abundantly expressed somatostatin receptors in the brain, particularly in the cortex, hippocampus, and amygdala. It plays a crucial role in mediating SST’s inhibitory effects by strongly suppressing neurotransmitter release and reducing neuronal excitability. SSTR2 activation inhibits voltage-gated calcium channels and activates inwardly rectifying potassium channels, leading to hyperpolarization. This receptor is particularly important in emotional and cognitive regulation, as SSTR2 knockout mice exhibit heightened anxiety-like behaviors and impaired fear extinction. Due to its strong modulatory effects, SSTR2 has been explored as a pharmacological target for neuropsychiatric disorders, including anxiety and depression.

sst3

The sst3 receptor (SSTR3) is notably present in the hypothalamus, hippocampus, and basal ganglia. Unlike other SST receptors, SSTR3 localizes to neuronal cilia, where it modulates ciliary signaling pathways. Functionally, SSTR3 activation inhibits adenylyl cyclase activity, reducing cAMP levels and suppressing excitatory neurotransmission. In the hypothalamus, SSTR3 regulates neuroendocrine functions, including growth hormone secretion and appetite control. Studies have linked SSTR3 to neuroprotection, as its activation reduces oxidative stress and promotes neuronal survival in neurodegenerative disease models.

sst4

The sst4 receptor (SSTR4) is expressed in the limbic system, including the hippocampus, amygdala, and cortex, where it modulates pain perception, inflammation, and neuroprotection. Unlike other SST receptors, SSTR4 does not undergo rapid desensitization, allowing for prolonged inhibitory effects. Functionally, SSTR4 activation suppresses cAMP production and pro-inflammatory signaling pathways. This receptor has been extensively studied for its role in pain modulation, as its activation reduces nociceptive signaling in chronic pain models.

sst5

The sst5 receptor (SSTR5) is predominantly expressed in the hypothalamus and pituitary gland, regulating hormone secretion. Functionally, SSTR5 activation suppresses cAMP production and inhibits calcium channel activity, reducing hormone release from endocrine cells. Beyond its role in the hypothalamic-pituitary axis, SSTR5 contributes to synaptic inhibition and neuroprotection in the hippocampus and cortex, with studies suggesting it reduces excitotoxicity and promotes neuronal survival in neurodegeneration models.

Functions in Neurotransmission

SST neurons regulate neurotransmission by shaping excitatory and inhibitory balance. By releasing both somatostatin and GABA, they impose dual inhibitory effects on target neurons, modulating dendritic excitability and limiting excessive synaptic input. Optogenetics studies show that SST neurons can impose long-lasting inhibition on pyramidal neurons, influencing sensory perception and decision-making.

Their contributions to synaptic plasticity are particularly evident in the hippocampus, where they regulate excitatory input timing and strength. SST neurons promote LTD by suppressing calcium influx in dendritic spines, reducing synaptic potentiation. Additionally, they synchronize with network oscillations, such as theta and gamma rhythms, essential for cognitive functions like attention and learning.

Relationship With Other Neuropeptides

SST neurons interact with various neuropeptides, shaping excitatory and inhibitory balance through complex co-transmission mechanisms. These interactions extend their influence beyond immediate inhibition, modulating neuromodulatory systems like opioidergic, cholinergic, and monoaminergic pathways.

A significant interaction occurs between SST and neuropeptide Y (NPY), another inhibitory neuromodulator widely expressed in the cortex and limbic system. SST neurons frequently co-express NPY, particularly in the hippocampus, where both peptides contribute to seizure suppression and stress regulation. Experimental models demonstrate that SST and NPY signaling work synergistically to dampen hyperexcitability, offering potential therapeutic targets for epilepsy and anxiety disorders.